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WO2023009500A1 - Pentaaza macrocyclic ring complex for enhanced surgical treatment - Google Patents

Pentaaza macrocyclic ring complex for enhanced surgical treatment Download PDF

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Publication number
WO2023009500A1
WO2023009500A1 PCT/US2022/038314 US2022038314W WO2023009500A1 WO 2023009500 A1 WO2023009500 A1 WO 2023009500A1 US 2022038314 W US2022038314 W US 2022038314W WO 2023009500 A1 WO2023009500 A1 WO 2023009500A1
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Prior art keywords
macrocycle
carbon atoms
mammalian subject
radiation
heterocycle
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PCT/US2022/038314
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French (fr)
Inventor
Robert A. Beardsley
Kranti Ashok MAPUSKAR
JR. Douglas R. SPITZ
Varun MONGA
Benjamin J. Miller
Bryan G. Allen
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Galera Labs, Llc
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Publication of WO2023009500A1 publication Critical patent/WO2023009500A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table

Definitions

  • the present disclosure generally relates to treatments to enhance the outcomes of surgery performed on a subject before or after exposure to radiation using pentaaza macrocyclic ring complexes, such as in the treatment of cancers, including methods and compositions for such treatments.
  • Transition metal-containing pentaaza macrocyclic ring complexes having the macrocyclic ring system corresponding to Formula A have been shown to be effective in a number of animal and cell models of human disease, as well as in treatment of conditions afflicting human patients.
  • GC4403 has been reported to very significantly reduce the injury to the colon of rats subjected to an experimental model of colitis (see Cuzzocrea et at., Europ. J. Pharmacol., 432, 79-89 (2001)).
  • GC4403 has also been reported to attenuate the radiation damage arising both in a clinically relevant hamster model of acute, radiation-induced oral mucositis (Murphy et al., Clin. Can. Res., 14(13), 4292 (2008)), and lethal total body irradiation of adult mice (Thompson et al., Free Radical Res., 44(5), 529-40 (2010)).
  • GC4419 has been shown to attenuate VEGFr inhibitor-induced pulmonary disease in a rat model (Tuder, et al., Am. J. Respir. Cell Mol. Biol., 29, 88–97 (2003)). Additionally, another such compound, GC4401 has been shown to provide protective effects in animal models of septic shock (S. Cuzzocrea, et al., Crit. Care Med., 32(1), 157 (2004) and pancreatitis (S. Cuzzocrea, et al., Shock, 22(3), 254-61 (2004)). [0004] Certain of these compounds have also been shown to possess potent anti-inflammatory activity and prevent oxidative damage in vivo.
  • GC4403 has been reported to inhibit inflammation in a rat model of inflammation (Salvemini, et.al., Science, 286, 304 (1999)), and prevent joint disease in a rat model of collagen- induced arthritis (Salvemini et al., Arthritis & Rheumatism, 44(12), 2009-2021 (2001)).
  • MdPAM and MnBAM have shown in vivo activity in the inhibition of colonic tissue injury and neutrophil accumulation into colonic tissue (Weiss et al., The Journal of Biological Chemistry, 271(42), 26149-26156 (1996)).
  • these compounds have been reported to possess analgesic activity and to reduce inflammation and edema in the rat-paw carrageenan hyperalgesia model, see, e.g.,
  • GC4419 has been shown to reduce oral mucositis in head-and-neck cancer patients undergoing chemoradiation therapy (Anderson, C., Phase 1 Trial of Superoxide Dismutase (SOD) Mimetic GC4419 to Reduce Chemoradiotherapy (CRT)-lnduced Mucositis (OM) in Patients (pts) with Mouth or Oropharyngeal Carcinoma (OCC), Oral Mucositis Research Workshop, MASCC/ISOO Annual Meeting on Supportive Care in Cancer, Copenhagen, Denmark (June 25, 2015)).
  • SOD Superoxide Dismutase
  • OM Chemoradiotherapy
  • OCC Oropharyngeal Carcinoma
  • transition metal-containing pentaaza macrocyclic ring complexes corresponding to this class have shown efficacy in the treatment of various cancers.
  • certain compounds corresponding to this class have been provided in combination with agents such as paclitaxel and gemcitabine to enhance cancer therapies, such as in the treatment of colorectal cancer and lung cancer (nonsmall cell lung cancer) (see, e.g., U.S. Patent No.
  • the GC4403 compound above has also been used for treatment in in vivo models of Meth A spindle cell squamous carcinoma and RENCA renal carcinoma (Samlowski et al., Nature Medicine, 9(6), 750-755 (2003), and has also been used for treatment in in vivo models of spindlecell squamous carcinoma metastasis (Samlowski et al., Madame Curie Bioscience Database (Internet), 230-249 (2006)).
  • aspects of the present disclosure are directed to a method of enhancing wound healing after a radiation exposure in a mammalian subject in need thereof, the method comprising:
  • M is Mn 2+ or Mn 3+ ;
  • R1, R2, R'2, R3, R4, R5, R'5, R6, Re, R7, Re, R9, R'9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11 R12, -N(ORii)(Ri2), -P(0)(ORii)(ORi2), -P(0)(ORII)(RI 2 ), and -OP(0)(ORII)(ORI 2 ), wherein Rn and R12 are independently hydrogen or alkyl;
  • W together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen- containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and Rio attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
  • X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
  • Z is a counterion
  • n is an integer from 0 to 3;
  • the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
  • FIG. 10 Further aspects of the disclosure are directed to a method of enhancing wound healing in a mammalian subject afflicted with a tumor that is treatable by tissue resection and radiation therapy, the method comprising:
  • FIG. 1 Further aspects of the disclosure are directed to a method of selectively increasing the migration of normal cells relative to the migration of malignant cells following surgery and radiation therapy for treatment of a tumor in a mammalian subject, the method comprising: [0044] exposing the mammalian subject to radiation as a part of the radiation therapy;
  • Further aspects of the disclosure are directed to a method of selectively increasing the migration of normal cells relative to the migration of malignant cells in a mammalian subject afflicted with a tumor that is treatable by surgery and radiation therapy, the method comprising:
  • administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy.
  • kits for therapeutic treatment of a mammalian subject comprising the pentaaza macrocyclic ring complex corresponding to Formula (I) as disclosed herein, optionally, a further anticancer agent; and instructions for administering the therapeutically effective amount of the pentaaza macrocyclic ring complex to perform any of the methods disclosed herein.
  • kit for therapeutic treatment of a mammalian subject comprising the pentaaza macrocyclic ring complex corresponding to Formula (I) as disclosed herein, optionally, a further anticancer agent; and instructions for administering the therapeutically effective amount of the pentaaza macrocyclic ring complex to perform any of the methods disclosed herein.
  • Figs. 1A and 1B are graphs illustrating increased levels of dihydroethidium (DHE) oxidation in sarcoma cell lines: Steady-state levels of ROS were assessed in M20 (normal human dermal fibroblasts), HT1080 (fibrosarcoma), SW872 (liposarcoma) and SKLMS1 (leiomyosarcoma) cells at 3 hours (see Fig. 1 A), and at 24 hours (see Fig. 1 B). Cells were treated with 5 mM of manganese pentaazamacrocycle (MnPAM) dismutase mimetic GC441924 hours prior to radiation with 4 Gy.
  • MnPAM manganese pentaazamacrocycle
  • Figs. 1 A-1 B demonstrate that sarcoma cells have increased levels of reactive oxygen species relative to non-malignant cells.
  • Fig. 2 is a plot illustrating that increasing concentrations of ascorbate (up to 10 pMol/cell) is toxic to sarcoma cell lines: HT 1080, SW872 and SKLMS-1.
  • 10 pMol/cell of ascorbate resulted in significant toxicity to FIT1080 compared to SW872 and SKLMS-1 cells. All cells were treated with an ascorbate titration using picomole/cell with concentrations adjusted to maintain 2 mM ascorbate.
  • Statistical analysis was analyzed using GraphPad Prism.
  • Figs. 3A and 3B are graphs illustrating that combined treatment with GC4419 and P-AscFL Enhance Sarcoma Response to Radiation.
  • Sarcoma cells lines, HT1080, SW872, and SKLMS-1 were treated with 4 Gy of ionizing radiation (IR) , 5 pM of a MnPAM dismutase mimetic (GC4419) (24 hours prior) or 10 pM/cell of ascorbate (see Fig. 3A).
  • Fig. 4 is a graph illustrating that GC4419 decreases migration of fibrosarcoma cells. Relative migration was assessed using transwell migration chambers from BD FalconTM (8 mM pore size, 353097; BD Biosciences) in M20 and FIT1080 cells treated with 5 uM of a MnPAM dismutase mimetic (GC4419) 24 hours prior to 4 Gy IR exposure, alone and in combination with 15 U/ml catalase. The experiment consisted of one biological replicate and 3 technical replicates. Treatment with GC4419 alone increased migration of M20 normal fibroblasts relative to FIT1080 sarcoma cells, while migration of both was decreased somewhat following exposure to IR.
  • GC4419 MnPAM dismutase mimetic
  • Treatment with GC4419 and IR substantially increased migration of M20 cells and decreased migration of FIT1080 cells (see Fig.4).
  • Data represent relative migration compared to controls. Accordingly, it was shown that dismutase mimetic increases migration of normal fibroblasts (M20) including after IR exposure, which should support more rapid and appropriate repopulation and repair of injured tissues. Importantly, dismutase mimetic also decreases relative migration of cancer (FIT1080) cells including following IR which should support maintaining or even increasing the anti-cancer efficacy of IR.
  • Figs. 5A-5B are an image (5A) and a plot (5B) illustrating that treatment with GC4419 accelerates radiation-induced wound closure in a murine wound healing model.
  • C57BI6/NFIsd mice were pre-treated with 10mg/kg MnPAM dismutase mimetic (GC4419) I.P. daily starting 3 days prior to a single dose of 15 Gy IR using SARRP (Small Animal Radiation Research Platform) and up to two weeks following IR. 60 days following IR exposure, wounds were created on the dorsal side of mice using 5 mm biopsy punches and wound closure was measured using calipers until complete closure in the control group (see Fig. 5A). There were 3 mice per group.
  • Fig. 5C is a schematic showing the timeline and experimental design used to obtain the results illustrated in Figs. 5A-5B. Accordingly, it was shown that treatment with dismutase mimetic enhances [enables and accelerates] wound healing following IR exposure.
  • Figs. 6-8 describe the parameters and timeline for a dismutase mimetic + SBRT pilot trial in pancreatic cancer.
  • Figs. 9-10 show results from the pancreatic cancer trial of Figs. 6-8.
  • M AcK68 refers to the acetylated form of manganese superoxide dismutase (MnSOD) having acetylation at the K68 residue of the MnSOD protein, and may also be referred to herein as MnSOD-K68-Ac.
  • MnSOD manganese superoxide dismutase
  • Acyl means a -COR moiety where R is alkyl, haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl as defined herein, e.g., acetyl, trifluoroacetyl, benzoyl, and the like.
  • Acyloxy means a -OCOR moiety where R is alkyl, haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl as defined herein, e.g., acetyl, trifluoroacetyl, benzoyl, and the like.
  • Alkoxy means a -OR moiety where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
  • Alkyl means a linear saturated monovalent hydrocarbon moiety such as of one to six carbon atoms, or a branched saturated monovalent hydrocarbon moiety, such as of three to six carbon atoms, e.g., C1-C6 alkyl groups such as methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
  • alkyl as used herein is intended to include both “unsubstituted alkyls” and “substituted alkyls,” the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone.
  • all groups recited herein are intended to include both substituted and unsubstituted options.
  • C x-y when used in conjunction with a chemical moiety, such as alkyl and aralkyl, is meant to include groups that contain from x to y carbons in the chain.
  • Cx- y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight chain alkyl and branched chain alkyl groups that contain from x to y carbon atoms in the chain.
  • Alkylene means a linear saturated divalent hydrocarbon moiety, such as of one to six carbon atoms, or a branched saturated divalent hydrocarbon moiety, such as of three to six carbon atoms, unless otherwise stated, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
  • Alkenyl a linear unsaturated monovalent hydrocarbon moiety, such as of two to six carbon atoms, or a branched saturated monovalent hydrocarbon moiety, such as of three to six carbon atoms, e.g., ethenyl (vinyl), propenyl, 2-propenyl, butenyl (including all isomeric forms), pentenyl (including all isomeric forms), and the like.
  • Alkaryl means a monovalent moiety derived from an aryl moiety by replacing one or more hydrogen atoms with an alkyl group.
  • Alkenylcycloalkenyl means a monovalent moiety derived from an alkenyl moiety by replacing one or more hydrogen atoms with a cycloalkenyl group.
  • Alkenylcycloalkyl means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with an alkenyl group.
  • Alkylcycloalkenyl means a monovalent moiety derived from a cycloalkenyl moiety by replacing one or more hydrogen atoms with an alkyl group.
  • Alkylcycloalkyl means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with an alkyl group.
  • Alkynyl means a linear unsaturated monovalent hydrocarbon moiety, such of two to six carbon atoms, or a branched saturated monovalent hydrocarbon moiety, such as of three to six carbon atoms, e.g., ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
  • Alkoxy means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a hydroxy group.
  • Amino means a -NR a R b group where R a and R b are independently hydrogen, alkyl or aryl.
  • Antibody as used herein includes an antibody of classes IgG, IgM,
  • the antibody may be a monoclonal antibody, polyclonal antibody, affinity purified antibody, or mixtures thereof, which exhibits sufficient binding specificity to a desired epitope or a sequence derived therefrom.
  • the antibody may also be a chimeric antibody.
  • the antibody may be derivatized by the attachment of one or more chemical, peptide, or polypeptide moieties known in the art.
  • the antibody may be conjugated with a chemical moiety.
  • the antibody may be a human or humanized antibody.
  • “Aralkyl” means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with an aryl group.
  • Aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon moiety of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • Cycle means a carbocyclic saturated monovalent hydrocarbon moiety of three to ten carbon atoms.
  • Cycloalkyl means a cyclic saturated monovalent hydrocarbon moiety of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
  • Cycloalkylalkyl means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a cycloalkyl group, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylethyl, and the like.
  • Cycloalkylcycloalkyl means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with a cycloalkyl group.
  • Cycloalkenyl means a cyclic monounsaturated monovalent hydrocarbon moiety of three to ten carbon atoms, e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and the like.
  • Cycloalkenylalkyl means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a cycloalkenyl group, e.g., cyclopropenylmethyl, cyclobutenylmethyl, cyclopentenylethyl, or cyclohexenylethyl, and the like.
  • “Ether” means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with an alkoxy group.
  • Halo means fluoro, chloro, bromo, or iodo, preferably fluoro orchloro.
  • Heterocycle or “heterocyclyl” means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C.
  • the heterocyclyl ring is optionally fused to a (one) aryl or heteroaryl ring as defined herein provided the aryl and heteroaryl rings are monocyclic.
  • the heterocyclyl ring fused to monocyclic aryl or heteroaryl ring is also referred to in this Application as “bicyclic heterocyclyl” ring.
  • heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like.
  • heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic.
  • the heterocyclyl group is a saturated ring and is not fused to aryl or heteroaryl ring as stated above, it is also referred to herein as saturated monocyclic heterocyclyl.
  • Heteroaryl means a monovalent monocyclic or bicyclic aromatic moiety of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon.
  • Representative examples include, but are not limited to, pyrrolyl, pyrazolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
  • Niro means -NO2.
  • Organicsulfur means a monovalent moiety a -SR group where R is hydrogen, alkyl or aryl.
  • “Substituted alkyl,” “substituted cycle,” “substituted phenyl,” “substituted aryl,” “substituted heterocycle,” and “substituted nitrogen heterocycles” means an alkyl, cycle, aryl, phenyl, heterocycle or nitrogen-containing heterocycle, respectively, optionally substituted with one, two, or three substituents, such as those independently selected from alkyl, alkoxy, alkoxyalkyl, halo, hydroxy, hydroxyalkyl, or organosulfur.
  • the term “substituted” includes groups that are substituted with any one or more of Ci-4alkyl, C2-4alkenyl, halogen, alcohol and/or amine.
  • Thioether means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with an -SR group wherein R is alkyl.
  • the compound referred to herein and in the Figures as compound 401 , 4401 or GC4401 is a reference to the same compound
  • the compound referred to herein and in the Figures as compound 403, 4403 or GC4403 is a reference to the same compound
  • the compound referred to herein and in the Figures as compound 419, 4419 or GC4419 is a reference to the same compound
  • the compound referred to herein and in the Figures as compound 444, 4444 or GC4444 is a reference to the same compound.
  • the use of the term “consisting essentially of,” in referring to a method of treatment, means that the method substantially does not involve providing another therapy and/or another active agent in amounts and/or under conditions that would be sufficient to significantly affect the treatment, and which are other than the therapies and/or active agents specifically recited in the claim.
  • the use of the term “consisting essentially of,” in referring to a kit for treatment means that the kit substantially does not include another therapy and/or another active agent provided in amounts and/or under conditions that would be sufficient to significantly affect the treatment, and which are other than the therapies and/or active agents specifically recited in the claim.
  • aspects of the present disclosure are directed to methods to enhance wound healing and/or reduce fibrotic tissue in mammalian subjects receiving radiation therapy prior to or following a surgical procedure, such as surgical resection to remove a tumor and/or cancerous tissue.
  • a surgical procedure such as surgical resection to remove a tumor and/or cancerous tissue.
  • aspects of the disclosure herein may allow for faster and more efficient healing from such surgical procedures.
  • aspects of the disclosure herein may also provide for more effective post-irradiation surgical procedures with fewer issues posed by fibrotic tissues that can form upon exposure of the mammalian subject’s tissue to irradiation.
  • aspects of the disclosure herein may also allow for surgical procedures to be performed shortly after exposure to irradiation, without requiring a long period of recovery of the irradiated tissue before surgical procedures can be performed.
  • aspects of the disclosure herein may also allow for radiation exppsure shortly after surgical procedures have been performed, without requiring a long period of recovery from surgery before subjecting tissue that has been surgically operated on to irradiation.
  • surgical procedures such as surgical resection to remove all or part of a tumor can be performed more efficiently pre- or post-irradiation, with improved patient outcomes.
  • the methods provided herein comprising administering to a mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below:
  • M is Mn 2+ or Mn 3+ ;
  • R1, R2, R'2, R3, R4, R5, R'5, R6, R6, R7, R6, R9, R'9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11 Ri2, -N(ORii)(Ri2), -P(0)(0Rii)(0Ri2), -P(0)(0RII)(RI 2 ), and -0P(0)(0Ri 1 )(ORI 2 ), wherein Rn and R12 are independently hydrogen or alkyl;
  • V together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
  • W together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen- containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
  • X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
  • Z is a counterion
  • n is an integer from 0 to 3;
  • the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
  • the pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein has been unexpectedly found to reduce the development of fibrotic tissues that can occur in irradiated tissue, and/or to improve wound healing, such as in the healing of wounds incurred during surgical procedures.
  • the pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein has unexpectedly been found to enhance wound healing in mammalian subjects receiving a surgical procedure, either pre-or postirradiation.
  • the wound healing may be accelerated in subjects receiving the pentaaza macrocyclic ring complex corresponding to Formula (I). Accordingly, the outcomes for patients undergoing surgical procedures following exposure to radiation as a part of a course of radiation therapy, or undergoing surgical procedures prior to such radiation exposure, can be improved.
  • a method of treatment comprises enhancing wound healing before or after a radiation exposure in a mammalian subject in need thereof.
  • the method comprises selecting the mammalian subject from among a population of mammalian subjects that has been or will be exposed to radiation.
  • the mammalian subject may be one that has already been exposed to radiation as a part of a course of radiation therapy.
  • the mammalian subject may be one for which an appropriate treatment includes radiation therapy, and so will be exposed to radiation therapy.
  • aspects of the method can include administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, prior to, concomitantly with, or after the radiation exposure.
  • the mammalian subject can be exposed to radiation as a part of a course of radiation therapy, and the pentaaza macrocyclic ring complex corresponding to the Formula (I) can be administered before, concomitantly with, or after exposure to radiation as a part of the radiation therapy.
  • the pentaaza macrocyclic ring complex corresponding to the Formula (I) can be administered before the mammalian subject is exposed to radiation.
  • the pentaaza macrocyclic ring complex corresponding to the Formula (I) can be administered after the mammalian subject is exposed to radiation.
  • the pentaaza macrocyclic ring complex corresponding to the Formula (I) can be administered on a same day the mammalian subject is exposed to radiation.
  • the exposure to radiation involves exposure of a tissue region containing cancerous cells and/or tumor cells to the radiation, to kill the cells.
  • the administration of the pentaaza macrocyclic ring complex corresponding to the Formula (I) to a patient who has been exposed to radiation, or administration in advance of (or concomitantly with) such radiation exposure can provide enhancements in pre- or post-irradiation surgical procesured with respect to wound healing in the mammalian subject.
  • a method of treatment comprises enhancing wound healing in a mammalian subject prior to or following radiation therapy for treatment of a tumor.
  • the method comprises selecting the mammalian subject from among a population of mammalian subjects afflicted with a tumor that is treatable by radiation therapy, and administering to the subject the radiation therapy in combination with a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy.
  • the mammalian subject that is selected may be one that is suffering from a cancer and/or tumor that is treatable by radiation therapy, such as by any method of radiation therapy that is currently known or that becomes known in the future.
  • the mammalian subject may be one suffering from a soft-tissue sarcoma.
  • the mammalian subject may be one suffering from pancreatic cancer.
  • the method comprising the administration of the pentaaza macrocyclic ring complex of Formula (I) can provide for improved outcomes in any surgical procedures performed post-irradiation.
  • a method of treatment comprises a method of enhancing wound healing in a mammalian subject afflicted with a tumor that is treatable by surgery and radiation therapy.
  • the method comprises selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and surgery, and administering to the subject radiation therapy in combination with a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy.
  • the mammalian subject that is selected may be one that is suffering from a cancer and/or tumor that is treatable by the combination of radiation therapy and surgical resection to remove the cancer and/or tumor, such as by any method of radiation therapy followed by resection that is currently known or that becomes known in the future.
  • the mammalian subject may be one suffering from a soft-tissue sarcoma.
  • the mammalian subject may be one suffering from pancreatic cancer.
  • the method comprising the administration of the pentaaza macrocyclic ring complex of Formula (I) can provide for improved outcomes in the surgical procedure performed pre- or post-irradiation.
  • a method of treatment comprises a method of enhancing an outcome of tumor treatment in the mammalian subject.
  • the method comprises selecting a predetermined period of time in which to perform surgery following an exposure to radiation administered as a part a radiation therapy to the mammalian subject, and performing surgery on the mammalian subject within the selected predetermined period of time.
  • the predetermined time is selected in relation to whether or not the mammalian subject has received or will receive administration of a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein.
  • the mammalian subject can be subjected to a surgical procedure during a period of time post-irradiation that is shorter than that for mammalian subjects that do not receive the administration of the therapeutically effective amount of the pentaaza macrocyclic ring complex according to Formula (I).
  • the administration of the pentaaza macrocyclic ring complex according to Formula (I) may, in certain embodiments, reduce fibrosis and preserve the condition of normal (non-cancerous) tissues, such that surgical procedures can be performed shortly after irradiation, without having to wait as long for recovery of the normal tissues post-irradiation.
  • the surgical resection is performed within a first predetermined period of time postirradiation, and in a case where the patient does not received the pentaaza macrocyclic ring complex of Formula (I), the surgical resection is performed within a second predetermined period of time post-irradiation that is longer than the first predetermined period of time.
  • the subject may be one that already has already received administration of the pentaaza macrocyclic ring complex, such as before, simultaneous with, or after exposure to radiation exposure, or that will receive administration of the pentaaza macrocyclic ring complex after exposure to radiation and before, simultaneous with, or after surgery.
  • the predetermined period of time is as measured from a last radiation exposure of the mammalian subject prior to performing the surgical procedure.
  • the predetermined period of time between the last exposure and performing of the surgical procedure can be selected according to factors such as a type of surgical procedure to be performed, an intensity of a radiation dose and/or dose fraction administered to the mammalian subject, an extend of fibrosis of the mammalian subject’s tissue, and/or the type of cancer and/or tumor from which the mammalian subject is suffering, among other factors.
  • the predetermined period of time in which surgery is performed following irradiation, in a case where the mammalian subject receives administration of the pentaaza macrocyclic ring complex according to Formula (I), is within 1 day, 2 days, 3 day, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, and/or 3 months of the last radiation exposure of the mammalian subject.
  • a method of enhancing an outcome of tumor treatment in a mammalian subject comprises selecting a predetermined period of time following surgery in which to expose the mammalian subject radiation administered as a part a radiation therapy to the mammalian subject, in relation to whether or not the mammalian subject has received or will receive administration of a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, and exposing the mammalian subject to radiation within the selected predetermined period of time following surgery.
  • the mammalian subject can be subjected to radiation exposure during a period of time post-surgery that is shorter than that for mammalian subjects that do not receive the administration of the therapeutically effective amount of the pentaaza macrocyclic ring complex according to Formula (I).
  • the subject may be one that already has received administration of the pentaaza macrocyclic ring complex before, simultaneous with, or after surgery, or that will receive administration of the pentaaza macrocyclic ring complex after surgery and before, simultaneous with, or after radiation exposure.
  • the administration of the pentaaza macrocyclic ring complex according to Formula (I) may, in certain embodiments, reduce fibrosis and preserve the condition of normal (non-cancerous) tissues, such that even when irradiation is performed shortly after surgical procedures, improved wound healing can be provided.
  • the expsosure to radiation is performed within a first predetermined period of time post-surgery
  • the exposure to radiation is performed within a second predetermined period of time post-surgery that is longer than the first predetermined period of time.
  • the predetermined period of time is as measured from the surgical procedure to a first (or only) radiation exposure of the mammalian subject provided as a course of radiation therapy.
  • the predetermined period of time between the surgical procedure and first exposure can be selected according to factors such as a type of surgical procedure to be performed, an intensity of a radiation dose and/or dose fraction administered to the mammalian subject, an extend of fibrosis of the mammalian subject’s tissue, and/or the type of cancer and/or tumor from which the mammalian subject is suffering, among other factors.
  • the predetermined period of time in which radiation expsoure is performed following surgery in a case where the mammalian subject receives administration of the pentaaza macrocyclic ring complex according to Formula (I), is within 1 day, 2 days, 3 day, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, and/or 3 months of the surgical procedure.
  • a method of preparing a mammalian subject for surgery before or after radiation therapy comprising administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to Formula (I) as disclosed herein, prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy.
  • a method of enhancing wound healing prior to or following tissue resection, in combination with radiation therapy, for treatment of a tumor in a mammalian subject is provided.
  • the method comprises exposing the mammalian subject to radiation as a part of radiation therapy, resecting a region of tissue at a location of the tumor in the mammalian subject, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after the radiation exposure.
  • a method of enhancing wound healing in a mammalian subject afflicted with a tumor that is treatable by tissue resection and radiation therapy is provided.
  • the method comprises selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and resection of the tumor, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy.
  • a method of treatment can be provided that selectively increases the migration of normal (non-malignant) cells at a wound site, relative to the migration of malignant cells.
  • a method of treatment can selectively increase the migration of normal cells relative to the migration of malignant cells following surgery and radiation therapy for treatment of a tumor in a mammalian subject.
  • aspects of the method comprise exposing the mammalian subject to radiation as a part of the radiation therapy, performing surgery on the mammalian subject, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) prior to, concomitantly with, or after the radiation exposure received as a part of the radiation therapy.
  • the selective increase in migration of normal cells relative to malignant cells can improve outcomes for surgical procedures in terms of wound healing time and recovery, and reductions in wound healing complications.
  • a method of treatment comprises selectively increasing the migration of normal cells relative to the migration of malignant cells in a mammalian subject afflicted with a tumor that is treatable by surgery and radiation therapy, the method comprising selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and surgery, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy.
  • a method of selectively increasing the migration of normal cells relative to the migration of malignant cells in a mammalian subject following radiation therapy comprising selecting the mammalian subject from among a population of mammalian subjects in need of enhanced wound healing following radiation therapy, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy.
  • the subject in need of enhanced wound healing may be one that would benefit from shortening the period of time between a last dose of radiation and the surgical procedure (or the time period between a surgical procedure and a following radiation exposure), or that is subject to increased levels of fibroses and/or decreased levels of wound healing, such as due to a type of radiation therapy or surgical procedure performed, a type of cancer being treated and/or other pre-existing health conditions.
  • kits for therapeutic treatment of a mammalian subject comprises the pentaaza macrocyclic ring complex corresponding to Formula (I) as disclosed herein, and optionally a further anticancer agent.
  • the kit further comprises instructions for administering the therapeutically effective amount of the pentaaza macrocyclic ring complex to perform any of the methods of treatment described herein, such as form example dosing, timing and/or administration instructions for any of the methods.
  • the kit can further comprise additional assays, therapeutic agents, and/or medical instruments for carrying out the methods.
  • embodiments of disclosure herein are capable of enhancing wound healing following surgery, such as by accelerating a rate of wound healing in a mammalian subject.
  • Such treatment methods may be beneficial, for example, in the case of a mammalian subject that is suffering from a tumor that is treatable by surgery, and/or suffering from complications associated with the tumor that are treatable by surgery, in which case the ability to enhance the healing of any wounds caused by the surgery can be of substantial medical benefit to the mammalian subject.
  • the surgery performed on the mammalian subject may be performed to remove all or a part of the tumor by tissue resection. For example, the boundaries of normal versus malignant tissue may be identified, and the malignant tissue may be surgically removed while preserving as much normal tissue as possible.
  • surgical procedures may be performed for purposes other than to remove tumor and/or malignant tissues.
  • surgery can be performed on the mammalian subject for diagnostic purposes and/or to perform a biopsy to determine assess properties of the tumor such as the stage and/or aggressiveness of the tumor, or to determine other tumor phenotypes that may be useful in treatment, such as resistance or conversely susceptibility to treatments with certain active agents or other modalities.
  • Surgical procedures may also be performed to assess the boundary of cancerous versus non-cancerous tissue.
  • the wounding may be concurrent with radiation exposure, such as in a surgical procedure performed concurrently with the radiation exposure.
  • the radiation exposure may be intentional, such as in a therapeutic treatment, or may be unintentional, such as via occupational hazard or environmental radiation exposure, or accidental radiation release into the environment.
  • the mammalian subject may incur a wound concurrently with radiation exposure, either intentionally or unintentionally, including as a part of surgery, and the surgery may be exploratory, definitive, curative, palliative, cosmetic, etc.
  • the surgery may be to treat a condition resulting from the radiation exposure performed to treat a tumor, or may be to treat a condition that is unrelated to radiation exposure to treat a tumor.
  • surgery may be performed on the mammalian subject for the treatment of complications associated with the tumor, such as to repair or restore physical structures impacted by the presence of the tumor.
  • surgical procedures are performed to make improvements in the cosmetic appearance of the mammalian subject, such as for example in a case where the mammalian subject has become somewhat disfigured or otherwise altered in appearance due to the presence of the tumor, or its removal from the mammalian subject.
  • aspects of the disclosure provide enhanced wound healing in the mammalian subject such that surgical options that were otherwise unfeasible become feasible. For example, it may be possible to operate very shortly after exposure to radiation, or to perform more precise and accurate surgical procedures, than would otherwise be possible. It may also be possible to operate on mammalian subjects that may otherwise have such poor wound healing outcomes that surgical procedures would not be a recommended option.
  • wound healing is sufficiently enhanced so as to make surgery to resect a tumor more efficient.
  • wound healing is sufficiently enhanced so as to make surgery to resect a tumor more accurate.
  • wound healing is sufficiently enhanced so as to improve the surgical outcome and/or recovery of the mammalian subject from the surgical procedure.
  • the development of fibrotic and/or abnormal tissue post-irradiation is reduced.
  • the condition of normal tissue subjected to radiation exposure is sufficiently preserved such that the normal tissue can be readily differentiated from malignant tissue, such as for purposes of tissue resection.
  • the ability to selectively remove malignant tissue from a mammalian subject while retaining normal tissue may be improved, by retaining normal tissue in a state where it can be differentiated, and readily removed from, malignant tissue, even postirradiation.
  • aspects of the disclosure may thus reduce the development of fibrotic and/or abnormal tissue that can otherwise interfere with the selective removal of malignant (cancerous) tissue during post-irradiation surgical procedures.
  • wound healing may be sufficiently enhanced that improved outcomes are provided even when radiation exposure occurs after a surgical procedure is performed.
  • the surgical outcome can be improved by making the surgery technically feasible versus embodiments in wich the pentaaza macrocyclic ring complex is not provided.
  • the surgical outcome can be improved by allowed for more complete resection of the tumor, providing R0 margins, providing reduced convalescence (recovery time) for the patient, reduced infectios or other complications, providing greater resulting functionality in the normal tissue, organ or limb post-surgery, along with other beneficial outcomes and effects.
  • aspects of the disclosure can provide for treatment in the case of a non-surgical wounding, such as an accidental or non-therapeutic wound.
  • aspects of the disclosure can provide for treatment even in the case where no tumor is being treated, such as in enhanced wound healing and/or enhanced surgical outcomes without providing any cancer treatment (e.g., even without radiation).
  • improvements are provided even in the case of non-therapeutic radiation.
  • increased migration of normal cells relative to malignant is provided at a wound site, even in the absence of radiation treatment and/or tumor treatment.
  • increased migration of normal cells relative to malignant at a tissue site is provided following radiation, even when no surgical procedure is performed and no wound incurred.
  • a mammalian subject is treated that has not yet been subject to radiation exposure, but which subject is selected for exposure to radiation, such as for example as a part of an overall treatment plan.
  • the mammalian subject is one that has been exposed to radiation within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day as administration of the pentaaza macrocyclic ring complex of Formula (I).
  • the mammalian subject is one that is selected to be exposed to radiation within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day as administration of the pentaaza macrocyclic ring complex of Formula (I).
  • the mammalian subject is one that has been exposed to radiation within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that surgery is performed on the mammalian subject.
  • the mammalian subject is one that is selected to be exposed to radiation within 6 months, 3 months, 2 months,
  • the mammalian subject is administered the pentaaza macrocyclic ring complex of Formula (I) within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that surgery is performed on the mammalian subject.
  • the mammalian subject is selected to have surgery within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that the pentaaza macrocyclic ring complex of Formula (I) is administered.
  • aspects of the disclosure herein comprise performing surgery on the mammalian subject before or after exposure to radiation.
  • the mammalian subject can receive radiation exposure to kill cancer cells, which is followed by a surgical procedure to, e.g. resect the cancerous tissue, for diagnostic or cosmetic purposes, etc.
  • the mammalian subject can receive radiation exposure to kill any remaining cancer cells, after a surgical procedure to, e.g., resect the cancerous tissue.
  • a mammalian subject is subjected to radiation exposure before a surgical procedure, and the mammalian subject is subjected to a further radiation exposure after the surgical procedure.
  • the mammalian subject may be subjected to a first radiation exposure to treat the tumor, before resection of the tumor (or other surgical procedure), and further radiation treatment may be provided following resection to eliminate remaining cancer cells.
  • a surgical procedure is performed before any radiation exposure, such as prior to a first radiation exposure administered as a part of radiation therapy (or prior to an only radiation exposure administered as a radiation therapy, in case where the therapy involves only a single exposure).
  • the mammalian subject may undergo a surgical procedure to resect the tumor and/or cancerous tissues before any radiation therapy is performed.
  • the enhanced wound healing provided according to methods herein by administering the pentaaza macrocyclic ring complex of Formula (I), can lessen the impact of the post-surgery irradiation on normal tissues, to provide an overall improvement in wound healing following irradiation.
  • wound healing for other surgical procedures described herein e.g. diagnostic procedures
  • aspects of the disclosure comprise administering the pentaaza macrocyclic ring complex according to Formula (I) as disclosed herein before subjecting the mammalian subject to radiation exposure.
  • the pentaaza macrocyclic ring complex according to Formula (I) is administered after subjecting the mammalian subject to radiation exposure.
  • the pentaaza macrocyclic ring complex according to Formula (I) is administered concomitantly with subjecting the mammalian subject to radiation exposure. According to another embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered on a same day as subjecting the mammalian subject to radiation exposure.
  • aspects of the disclosure herein comprise administering the pentaaza macrocyclic ring complex according to Formula (I) as disclosed herein, before performing surgery on the mammalian subject.
  • the pentaaza macrocyclic ring complex according to Formula (I) is administered after performing surgery on the mammalian subject According to yet another embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered concomitantly with performing surgery on the mammalian subject. According to another embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered on a same day as performing surgery on the mammalian subject.
  • aspects of the disclosure herein comprises a course of radiation therapy comprising administration of a plurality of radiation exposures to the mammalian subject, and wherein each of the plurality of radiation exposures comprises a dose fraction of an overall dosing regimen.
  • the pentaaza macrocyclic ring complex according to Formula (I) is administered prior to, concomitantly with, or after administration of a dose fraction of the overall dosing regimen.
  • the pentaaza macrocyclic ring complex according to Formula (I) is administered on a same day as a dose fraction of the overall dosing regimen.
  • surgery is performed prior to, concomitantly with, or after administration of a dose fraction of the overall dosing regimen.
  • surgery is performed on a same day as administration of a dose fraction of the overall dosing regimen.
  • a course of radiation therapy is provided that comprises administration of a plurality of doses of radiation, with each dose optionally comprising a plurality of dose fractions.
  • aspects of the disclpsure herein comprise radiation exposure that is administered as part of a course of radiation therapy comprising any selected from the group consisting of gamma irradiation, proton therapy, heavy ion therapy, brachytherapy, radionuclide therapy, conformal radiation therapy, intensity modulated radiation therapy, stereotactic body radiation therapy, stereoablative radiation therapy, and gamma knife therapy, whether delivered as standard fractionation, hypofractionation, accelerated fractionation or decelerated fractionation and variations thereof.
  • the radiation therapy comprises one or more radiation exposures comprising at least 4 Gy of radiation, at least 8 Gy of radiation, at least 10 Gy of radiation, at least 12 Gy of radiation, at least 16 Gy of radiation, at least 18 Gy of radiation, at least 20 Gy of radiation, at least 25 Gy of radiation, at least 30 Gy of radiation, at least 35 Gy of radiation, at least 40 Gy of radiation, at least 45 Gy of radiation, at least 50 Gy of radiation, at least 55 Gy of radiation, and/or at least 60 Gy of radiation.
  • methods of treatment can comprise administration of a further anti-cancer agent, such as a chemotherapeutic agent.
  • a further anti-cancer agent such as a chemotherapeutic agent.
  • Methods of treatment according to embodiments herein can be provide for the treatment of a mammalian subject afflicted with a tumor comprising a cancer selected from the group consisting of soft tissue sarcoma, breast cancer, prostate cancer, testicular cancer, glioma, glioblastoma, head and neck cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, desmoid tumors, pancreatic carcinoma, melanoma, and renal cell carcinoma, and other cancers.
  • the pentaaza macrocyclic ring complex corresponds to the complex of Formula (I): wherein
  • M is Mn 2+ or Mn 3+ ;
  • R1, R2, R'2, R3, R4, R5, R'5, R6, Re, R7, Re, R9, R'9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO 2NR11R12, -N(ORii)(Ri2), -P(0)(ORii)(ORi2), -P(0)(ORH )(RI2), and -0P(0)(0Rii)(0Ri2), wherein Rn and R12 are independently hydrogen or alkyl;
  • V together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
  • W together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
  • X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
  • Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
  • M is Mn 2+ or Mn 3+ .
  • M is Mn 2+ .
  • M is Mn 3+ .
  • suitable hydrocarbyl moieties include, but are not limited to alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and aralkyl.
  • Ri, R2, R'2, R3, R4, R5, R'5, R6, Re, R7, Re, R9, R'9, and Rio are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclyl. More preferably in this embodiment, R1, R2, R'2, R3, R4, Rs, R's, R6, R'6, R7, Re, R9, R'9, and R10 are independently hydrogen or lower alkyl ( e.g ., C1-C6 alkyl, more typically C1-C4 alkyl).
  • R1, R2, R'2, R3, R4, Rs, R's, R6, R'6, R7, Re, R9, R'9, and R10 may be independently hydrogen, methyl, ethyl, propyl, or butyl (straight, branched, or cyclic).
  • R1, R2, R'2, R3, R4, Rs, R's, R6, R'6, R7, Re, R9, R'9, and R10 are independently hydrogen or methyl.
  • R1, R2, R'2, R3, R4, Rs, R's, R7, Re, R9, R'9, and R10 are each hydrogen and one of R6 and R'6 is hydrogen and the other of R6 and R'6 is methyl.
  • R1, R2, R'2, R3, R4, Rs, R's, R6, R7, Re, R9, R'9, and R10 may each be hydrogen while R'6 is methyl.
  • R1, R2, R'2, R3, R4, Rs, R's, R'6, R7, Re, R9, R'9, and R10 may each be hydrogen while R6 is methyl.
  • R1, R3, R4, Rs, R's, R'6, R7, Re, and R10 are each hydrogen, one of R2 and R'2 is hydrogen and the other of R2 and R'2 is methyl, and one of R9 and R'9 is hydrogen and the other of R9 and R'9 is methyl.
  • R1, R'2, R3, R4, Rs, R's, R7, Re, R9, and R10 may each be hydrogen while R2 and R'9 are methyl.
  • R1, R2, R3, R4, Rs, R's, R7, Re, R'9, and R10 may each be hydrogen while R'2 and R9 are methyl.
  • the pentaaza macrocyclic ring complex corresponds to Formula (I)
  • R3, R4, Rs, R's, R6, R'6, R7, Re, R9, R'9, and R10 are each hydrogen.
  • the U and V moieties are independently substituted or unsubstituted fused cycloalkyl moieties having 3 to 20 ring carbon atoms, more preferably 4 to 10 ring carbon atoms. In a particular embodiment, the U and V moieties are each trans-cyclohexanyl fused rings.
  • the W moiety is a substituted or unsubstituted fused heteroaromatic moiety.
  • the W moiety is a substituted or unsubstituted fused pyridino moiety.
  • W is a substituted fused pyridino moiety
  • the W moiety is typically substituted with a hydrocarbyl or substituted hydrocarbyl moiety ( e.g ., alkyl, substituted alkyl) at the ring carbon atom positioned para to the nitrogen atom of the heterocycle.
  • the W moiety is an unsubstituted fused pyridino moiety.
  • X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof (for example benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion).
  • X and Y may be selected from the group consisting of halo, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl
  • X and Y if present are independently selected from the group consisting of halo, nitrate, and bicarbonate ligands.
  • Fo p , , and Y, if present, are halo ligands, such as chloro ligands.
  • X and Y are independently selected from the group consisting of charge-neutralizing anions which are derived from any monodentate or polydentate coordinating ligand and a ligand system and the corresponding anion thereof; or X and Y are independently attached to one or more of R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10.
  • Z is a counterion (e.g., a charge-neutralizing anion), wherein n is an integer from 0 to 3.
  • Z may correspond to counterions of the moieties recited above in connection for X and Y.
  • pentaaza macrocyclic ring complexes corresponding to Formula (I) wherein M is Mn 2+ or Mn 3+ ; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen or lower alkyl; U and V are each trans-cyclohexanyl fused rings; W is a substituted or unsubstituted fused pyridino moiety; X and Y are ligands; and Z, if present, is a charge-neutralizing anion.
  • M is Mn 2+ ;
  • R1 R, 2, R'2, R3, R4, R5, R'5, R6, Re, R7, Re, R9, R'9, and R10 are independently hydrogen or methyl;
  • U and V are each trans-cyclohexanyl fused rings;
  • W is an unsubstituted fused pyridino moiety;
  • X and Y are independently halo ligands (e.g., fluoro, chloro, bromo, iodo).
  • Z if present, may be a halide anion (e.g., fluoride, chloride, bromide, or iodide).
  • the pentaaza macrocyclic ring complex is represented by Formula (II) below: wherein
  • X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
  • RA, RB, RC, and RD are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -S O2NR11R12, -N(ORii)(Ri2), -P(0)(ORii)(ORi2), -P(0)(ORH)(RI2), and -OP(0)(ORii)(ORi2), wherein Rn and R12 are independently hydrogen or alkyl.
  • the pentaaza macrocyclic ring complex is represented by Formula (III) or Formula (IV): wherein
  • X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
  • RA, RB, RC, and RD are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -ORii, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO 2NR11R12, -N(ORii)(Ri2), -P(0)(ORii)(ORi2), -P(0)(ORH)(RI2), and -OP(0)(ORii)(ORi2), wherein Rn and R12 are independently hydrogen or alkyl.
  • the pentaaza macrocyclic ring complex is a compound represented by a formula selected from the group consisting of Formulae
  • X and Y in any of the formulae herein are independently selected from the group consisting of fluoro, chloro, bromo and iodo anions.
  • X and Y in any of the formulae herein are independently selected from the group consisting of alkyl carboxylates, aryl carboxylates and arylalkyl carboxylates.
  • X and Y in any of the formulae herein are independently amino acids.
  • the pentaaza macrocyclic ring complex has the following Formula (IA):
  • X5 is NH or O
  • the pentaaza macrocyclic ring complex corresponding to Formula (IA) is one of the complexes Formula (IE), such as (IERI), (IESI), (IER 2 ), (IES2), (IERS), or (IEs3):
  • IE complexes Formula
  • each Xi is -C(X2)(X3)(X4) and each -C(X2)(X3)(X4) corresponds to any of combinations 1 to 9 appearing in the table for Formula (IA) above.
  • the X and Y in pentaaza macrocyclic ring complex of Formula (I) correspond to the ligands in Formulas (IA) or (IE).
  • X and Y in the complex of Formula (I) may correspond to -0-C(0)-Xi, where Xi is as defined for the complex of Formula (IA) and (IE) above.
  • the pentaaza macrocyclic ring complexes corresponding to Formula (I) can comprise any of the following structures: ⁇
  • the pentaaza macrocyclic ring complexes for use in the methods and compositions described herein include those corresponding to Formulae (2), (3), (4), (5), (6), and (7):
  • the pentaaza macrocyclic ring complex for use in the methods and compositions described herein include those corresponding to Formulae (2), (3), (4), (5), (6), and (7) with X and Y in each of these formulae being halo, such as chloro.
  • X and Y may be ligands other than chloro, such as any of the ligands described above.
  • the pentaaza macrocyclic ring complex corresponds to Formula (6) or Formula (7):
  • the pentaaza macrocyclic ring complex may correspond to at least one of the complexes below:
  • the pentaaza macrocyclic ring complex may correspond to at least one of the complexes below, and/or an enantiomer thereof:
  • the enantiomeric purity of the pentaaza macrocyclic ring complex is greater than 95%, more preferably greater than 98%, more preferably greater than 99%, and most preferably greater than 99.5%.
  • the term “enantiomeric purity” refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its enantiomer.
  • the diastereomeric purity of the pentaaza macrocyclic ring complex is greater than 98%, more preferably greater than 99%, and most preferably greater than 99.5%.
  • diastereomeric purity refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its diastereomers.
  • Methods for determining diastereomeric and enantiomeric purity are well-known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers, such as high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • enantiomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its enantiomer. Examples of suitable analytical methods for determining enantiomeric purity include, without limitation, optical rotation of plane-polarized light using a polarimeter, and HPLC using a chiral column packing material.
  • a therapeutically effective amount of the pentaaza macrocyclic ring complex may be an amount sufficient to provide a peak plasma concentration of at least 0.1 mM when administered to a patient.
  • the pentaaza macrocyclic ring complex may be administered in an amount sufficient to provide a peak plasma concentration of at least 1 pM when administered to a patient.
  • the pentaaza macrocyclic ring complex may be administered in an amount sufficient to provide a peak plasma concentration of at least 10 pM when administered to a patient.
  • the pentaaza macrocyclic ring complex will not be administered in an amount that would provide a peak plasma concentration greater than 40 pM when administered to a patient.
  • the pentaaza macrocyclic ring complex may be administered in an amount sufficient to provide a peak plasma concentration in the range of from 0.1 pM to 40 pM in a patient.
  • the pentaaza macrocyclic ring complex may be administered in an amount sufficient to provide a peak plasma concentration in the range of from 0.5 pM to 20 pM in a patient.
  • the pentaaza macrocyclic ring complex may be administered in an amount sufficient to provide a peak plasma concentration in the range of from 1 pM to 10 pM in a patient.
  • a dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be at least 0.1 mg/kg, such as at least 0.2 mg/kg.
  • the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be at least 0.5 mg/kg.
  • the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be at least 1 mg/kg.
  • the pentaaza macrocyclic compound that is administered per kg body weight may be at least 2 mg/kg, such as at least 3 mg/kg, and even at least about 15 mg/kg, such as at least 24 mg/kg and even at least 40 mg/kg.
  • the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient will not exceed 1000 mg/kg.
  • the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be in the range of from 0.1 to 1000 mg/kg, such as from 0.2 mg/kg to 40 mg/kg, such as 0.2 mg/kg to 24 mg/kg, and even 0.2 mg/kg to 10 mg/kg.
  • the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight may be in a range of from 1 mg/kg to 1000 mg/kg, such as from 3 mg/kg to 1000 mg/kg, and even from 5 mg/kg to 1000 mg/kg, such as 10 mg/kg to 1000 mg/kg.
  • the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight may be in a range of from 2 mg/kg to 15 mg/kg.
  • the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight may be in a range of from 3 mg/kg to 10 mg/kg.
  • the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be in the range of from 0.5 to 5 mg/kg.
  • the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be in the range of from 1 to 5 mg/kg.
  • the dosages and/or plasma concentrations discussed above may be particularly suitable for the pentaaza macrocyclic ring complex corresponding to GC4419, although they may also be suitable for other pentaaza macrocyclic ring complexes.
  • one of ordinary skill in the art would recognize how to adjust the dosages and/or plasma concentrations based on factors such as the molecular weight and/or activity of the particular compound being used. For example, for a pentaaza macrocyclic ring complex having an activity twice that of GC4419, the dosage and/or plasma concentration may be halved, or for a pentaaza macrocyclic ring complex having a higher molecular weight that GC4419, a correspondingly higher dosage may be used.
  • the dosing schedule of the pentaaza macrocyclic ring complex can similarly be selected according to the intended treatment.
  • a suitable dosing schedule can comprise dosing a patient at least once per week, such as at least 2, 3, 4, 5, 6 or 7 days per week (e.g., daily), during a course of treatment.
  • the dosing may be at least once a day (qd), or even at least twice a day (bid).
  • the treatment provided herein can further comprise treatment with another therapy other than those specifically described above, such as for example one or more of immunotherapy and/or treatment with an anticancer agent such as a chemotherapeutic treatment.
  • an anticancer agent such as a chemotherapeutic treatment.
  • radiation therapies and anti-cancer therapeutic agents such as chemotherapeutic agents suitable for the treatment of cancer are provided below.
  • optional anti-cancer therapeutic agents can comprise an ascorbate compound such as ascorbic acid, and ascorbic acid ester, and/or salts thereof.
  • a radiation therapy can be administered concomitantly with administration of the pentaaza macrocyclic ring complex and optional anti-cancer therapeutic agent.
  • one or more of the optional anticancer therapeutic agent and pentaaza macrocyclic ring complexes may be administered during a course of radiation therapy, such as in between, before or after, or on the same day as exposure to radiation, such that the subject is receiving radiation therapy concurrently with one or more of the anti-cancer therapeutic agent and pentaaza macrocyclic ring complex.
  • the optional anti-cancer therapeutic agent is administered as a co-therapy or combination therapy with the pentaaza macrocyclic ring complex.
  • Co-therapy or combination therapy according to the methods described herein is intended to embrace administration of each compound in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent, or single or multiple parenteral administrations, or other routes of administration and dosage forms.
  • the therapeutic agents /. e.
  • the pentaaza macrocyclic ring complex and/or the anti-cancer therapeutic agent can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition.
  • Pharmaceutical compositions and formulations are discussed elsewhere herein.
  • the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent be administered simultaneously or essentially simultaneously; the agents and compounds may be administered in sequence.
  • the advantage of a simultaneous or essentially simultaneous administration, or sequential administration, is well within the determination of the skilled clinician.
  • a pharmaceutical composition or formulation comprising an anti-cancer therapeutic agent may be advantageous for administering first in the combination for one particular treatment, prior to administration of the pentaaza macrocyclic ring complex, prior administration of the pentaaza macrocyclic ring complex may be advantageous in another treatment.
  • the combination of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent may be used in conjunction with other methods of treating cancer (typically cancerous tumors).
  • another active agent such as a cytostatic or quiescent agent, or antiemetic agent, if any, may be administered sequentially or simultaneously with any or all of the other synergistic therapies.
  • embodiments of the therapeutic method include wherein a pentaaza macrocyclic ring complex and an optional anti-cancer therapeutic agent, and combinations thereof, are administered simultaneously or sequentially.
  • aspects of the present disclosure encompass a method for the treatment of cancer wherein a pentaaza macrocyclic ring complex and an anti-cancer therapeutic agent are administered simultaneously or sequentially.
  • Other active agents can also be administered simultaneously or sequentially with the pentaaza macrocyclic ring complex and the anti-cancer therapeutic agent.
  • the initial order of administration of the components may be varied.
  • the anti-cancer therapeutic agent may be administered first, followed by the administration of the pentaaza macrocyclic ring complex; or the pentaaza macrocyclic ring complex may be administered first, followed by the administration of the anti-cancer therapeutic agent.
  • This alternate administration may be repeated during a single treatment protocol.
  • Other sequences of administration to exploit the effects described herein are contemplated, and other sequences of administration of other active agents can also be provided.
  • the subject is pre-treated with an optional anticancer therapeutic agent, followed by administration of the pentaaza macrocyclic ring complex, or vice versa.
  • the pentaaza macrocyclic ring complex may be administered at least 1 hour, and even at least 3 days, after administration of the anti-cancer therapeutic agent, or vice versa.
  • the pentaaza macrocyclic ring complex is administered between 1 hour and 3 days after administration of the anti-cancer therapeutic agent, or vice versa.
  • the pentaaza macrocyclic ring complex is administered between 1 hour and 1 day after administration of the anticancer therapeutic agent, or vice versa.
  • the pentaaza macrocyclic ring complex may be administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks or 12 weeks after administration of the anti-cancer therapeutic agent, or vice versa.
  • the anticancer therapeutic agent may be administered in multiple doses leading up to administration of the pentaaza macrocyclic ring complex, or vice versa.
  • the subject may be pre-treated with the pentaaza macrocyclic ring complex, followed by administration of the anti-cancer therapeutic agent, or vice versa.
  • the pentaaza macrocyclic ring complex may be administered within at least 1 plasma half-life of the anti-cancer therapeutic agent, such as within 4 plasma half-lives of the anti-cancer therapeutic agent, or vice versa.
  • the pentaaza macrocyclic ring complex may be administered within 1 , 2, or 3 plasma half-lives of the other anti-cancer therapeutic agent, or vice versa.
  • the subject may be pre-treated with the anti-cancer therapeutic agent, followed by administration of the pentaaza macrocyclic ring complex, which is further followed by one or more additional administrations of the anti-cancer therapeutic agent, or vice versa.
  • the subject could be pre-treated with a dose of anti-cancer therapeutic agent, followed by administration of a dose of pentaaza macrocyclic ring complex, which is then followed by the administration of additional (or partial) dose of the same or different anti-cancer therapeutic agent, which may be further followed by another dose of pentaaza macrocyclic ring complex.
  • the subject could be pre-treated with a partial or full dose of pentaaza macrocyclic ring complex, followed by administration of an anti-cancer therapeutic agent, which is then followed by administration of an additional (or partial) dose of pentaaza macrocyclic complex.
  • combinations as described herein may also be co-administered with other well-known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Combinations may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
  • the pentaaza macrocyclic ring complex, and the optional anti-cancer therapeutic agent can generally be administered according to therapeutic protocols that may be known for these agents.
  • the administration of the pentaaza macrocyclic ring complex can be varied depending on the disease being treated and the effects of pentaaza macrocyclic ring complex on that disease.
  • the therapeutic protocols e.g., dosage amounts and times of administration
  • the administered therapeutic agents i.e., pentaaza macrocyclic ring complex, and optionally the anti-cancer therapeutic agent
  • the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes.
  • the pentaaza macrocyclic ring complex may be administered orally to generate and maintain good blood levels thereof, while the anti-cancer therapeutic agent may be administered intravenously or via transfusion, or vice versa.
  • the mode of administration may include, where possible, in the same pharmaceutical composition, or in separate pharmaceutical compositions ( e.g ., two or three separate compositions).
  • the dosage, modes of administration and times of administration can be modified.
  • pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent, and other related therapies (such as radiation, immunotherapy, or other chemotherapies), will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
  • other related therapies such as radiation, immunotherapy, or other chemotherapies
  • the practicing physician may modify each protocol for the administration of a component (the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent) of the treatment according to the individual patient's needs, as the treatment proceeds.
  • a component the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent
  • the attending clinician in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
  • any combination may be administered simultaneously, separately or spaced out over a period of time so as to obtain the maximum efficacy of the combination; it being possible for each administration to vary in its duration from a rapid administration to a relatively continuous perfusion of either component (in separate formulations or in a single formulation).
  • the combinations are not exclusively limited to those which are obtained by physical association of the constituents, but also to those which permit a separate administration, which can be simultaneous or spaced out over a period of time.
  • administration of the components described herein can occur as a single event or over a time course of treatment.
  • the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent can be administered (simultaneously or in sequence) hourly (e.g ., every hour, every two hours, every three hours, every four hours, every five hours, every six hours, and so on), daily, weekly, bi-weekly, or monthly.
  • the time course of treatment may be at least several hours or days. Certain conditions could extend treatment from several days to several weeks. For example, treatment could extend over one week, two weeks, or three weeks.
  • treatment could extend from several weeks to several months, a year or more, or the lifetime of the patient in need of such treatment.
  • the compounds and agents can be administered hourly, daily, weekly, bi-weekly, or monthly, for a period of several weeks, months, years, or over the lifetime of the patient as a prophylactic measure.
  • the dose or amount of pharmaceutical compositions including the pentaaza macrocyclic ring complex, and the optional anti-cancer therapeutic agent administered to the patient should be an effective amount for the intended purpose, i.e., treatment or prophylaxis of one or more of the diseases, pathological disorders, and medical conditions discussed herein, including wound healing and cancer treatment.
  • the effective amount of the composition administered can vary according to a variety of factors such as, for example, the age, weight, sex, diet, route of administration, and the medical condition of the patient in need of the treatment. Specifically preferred doses are discussed more fully herein. It will be understood, however, that the total daily usage of the compositions described herein will be decided by the attending physician or veterinarian within the scope of sound medical judgment.
  • combinations of components can be co-administered (via a co-formulated dosage form or in separate dosage forms administered at about the same time).
  • the combinations of components can also be administered separately, at different times, with each agent in a separate unit dosage form.
  • Numerous approaches for administering the optional anti-cancer therapeutic agent and pentaaza macrocyclic ring complex can be readily adapted for use in the present disclosure.
  • the pharmaceutical compositions may be delivered orally, e.g., in a tablet or capsule unit dosage form, or parenterally, e.g., in an injectable unit dosage form, or by some other route.
  • the pharmaceutical composition can be administered by, for example, intravenous infusion (continuous or bolus).
  • the compositions can be used for any therapeutic or prophylactic treatment where the patient benefits from treatment with the pentaaza macrocyclic ring complex.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound(s) employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound(s) employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound(s) employed and like factors well known in the medical and/or veterinary arts.
  • the effective daily doses may be divided into multiple doses for purposes of administration. Consequently, single dose compositions may contain such amounts or submultiples to make up the daily dose.
  • suitable or preferred doses for each of the components are employed in the methods or included in the compositions described herein.
  • Preferred dosages for the pentaaza macrocyclic ring complex may be within the range of 10 to 500 mg per patient per day. However, the dosage may vary depending on the dosing schedule, which can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit the disclosure and represent exemplary dose ranges.
  • the most preferred dosage will be tailored to the individual subject, taking into account, among other things, the particular combinations employed, and the patient's age, sex, weight, physical condition, diet, etc., as is understood and determinable by one of ordinary skill in the art without undue experimentation.
  • Treatment of cancer, or cancer therapies, described herein includes achieving a therapeutic benefit, however the therapy may also be administered to achieve a prophylactic benefit.
  • Therapeutic benefits generally refer to at least a partial eradication or amelioration of the underlying disorder being treated.
  • therapeutic benefit includes (partial or complete) eradication or amelioration of the underlying cancer.
  • a therapeutic benefit is achieved with at least partial, or complete, eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding the fact that the patient may still be afflicted with the underlying disorder.
  • a method of the disclosure may be performed on, or a composition of the invention administered to, a patient at risk of developing cancer, or to a patient reporting one or more of the physiological symptoms of such conditions, even though a diagnosis of the condition may not have been made.
  • any subject having, or suspected of having, a cancer or other proliferative disorder may be treated using the compositions and methods of the present disclosure.
  • Subjects receiving treatment according to the methods described herein are mammalian subjects, and typically human patients.
  • Other mammals that may be treated according to the present disclosure include companion animals such as dogs and cats, farm animals such as cows, horses, and swine, as well as birds and more exotic animals (e.g., those found in zoos or nature preserves).
  • a method is provided for the treatment of cancerous tumors, particularly solid tumors.
  • the methods described herein may reduce the development of tumors, reduce tumor burden, or produce tumor regression in a mammalian host. Cancer patients and individuals desiring cancer prophylaxis can be treated with the compositions and methods described herein.
  • Cancer and tumors generally refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • various tumors can be treated such as tumors of the breast, heart, lung, small intestine, colon, spleen, kidney, bladder, head and neck, ovary, prostate, brain, pancreas, skin, bone, bone marrow, blood, thymus, uterus, testicles, cervix, and liver.
  • the tumor or cancer is chosen from adenoma, angio-sarcoma, astrocytoma, epithelial carcinoma, germinoma, glioblastoma, glioma, hamartoma, hemangioendothelioma, hemangiosarcoma, hematoma, hepatoblastoma, leukemia, lymphoma, medulloblastoma, melanoma, neuroblastoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, sarcoma, and teratoma.
  • the tumor can be chosen from acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangio-carcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gas
  • the present disclosure provides methods for the treatment of a variety of cancers, including, but not limited to, the following: carcinoma including that of the bladder (including accelerated and metastatic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and nonsmall cell lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, histiocytic
  • leukemias that can be treated with the compositions and methods described herein include, but are not limited to, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia
  • Lymphomas can also be treated with the compositions and methods described herein. Lymphomas are generally neoplastic transformations of cells that reside primarily in lymphoid tissue. Lymphomas are tumors of the immune system and generally are present as both T cell- and as B cell-associated disease. Among lymphomas, there are two major distinct groups: non-Hodgkin's lymphoma (NHL) and Hodgkin's disease. Bone marrow, lymph nodes, spleen and circulating cells, among others, may be involved. Treatment protocols include removal of bone marrow from the patient and purging it of tumor cells, often using antibodies directed against antigens present on the tumor cell type, followed by storage. The patient is then given a toxic dose of radiation or chemotherapy and the purged bone marrow is then re-infused in order to repopulate the patient's hematopoietic system.
  • NDL non-Hodgkin's lymphoma
  • Treatment protocols include removal of bone marrow from the patient and
  • MDS myelodysplastic syndromes
  • MPS myeloproliferative syndromes
  • myelomas such as solitary myeloma and multiple myeloma.
  • Multiple myeloma also called plasma cell myeloma
  • Solitary myeloma involves solitary lesions that tend to occur in the same locations as multiple myeloma.
  • the methods and pharmaceutical compositions described herein are used to treat a cancer that is any of breast cancer, melanoma, oral squamous cell carcinoma, lung cancer including non-small cell lung cancer, renal cell carcinoma, colorectal cancer, prostate cancer, brain cancer, spindle cell carcinoma, urothelial cancer, bladder cancer, colorectal cancer, head and neck cancers such as squamous cell carcinoma, and pancreatic cancer.
  • a cancer that is any of breast cancer, melanoma, oral squamous cell carcinoma, lung cancer including non-small cell lung cancer, renal cell carcinoma, colorectal cancer, prostate cancer, brain cancer, spindle cell carcinoma, urothelial cancer, bladder cancer, colorectal cancer, head and neck cancers such as squamous cell carcinoma, and pancreatic cancer.
  • the cancer that is treated any one selected from the group consisting of breast cancer, prostate cancer, testicular cancer, glioma, glioblastoma, head and neck cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, desmoid tumors, pancreatic carcinoma, melanoma, and renal cell carcinoma.
  • cancers treatable according to compositions and methods herein can comprise those selected from the group consisting of soft tissue sarcoma, breast cancer, prostate cancer, testicular cancer, glioma, glioblastoma, head and neck cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, desmoid tumors, pancreatic carcinoma, melanoma, and renal cell carcinoma.
  • the cancer treatment involves administering the pentaaza macrocyclic ring complex, and optionally the further anticancer therapeutic agent, in a therapeutically effective amount that results in an increase in wound healing and/or reduced fibrosis of tissue exposed to radiation.
  • compositions comprising the pentaaza macrocyclic ring complex, together with a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions include the pentaaza macrocyclic ring complex (e.g ., those corresponding to Formula (I)), and can optionally include at least one anti-cancer therapeutic agent, and combinations thereof, as discussed above, typically formulated as a pharmaceutical dosage form, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient.
  • the pharmaceutical composition comprises a pentaaza macrocyclic ring complex, optional anti-cancer therapeutic agent and a pharmaceutically acceptable excipient.
  • Pharmaceutical compositions according to the present disclosure may be used in the treatment of cancer.
  • the pharmaceutical compositions described herein are products that result from the mixing or combining of more than one active ingredient and include both fixed and non-fixed combinations of the active ingredients.
  • Fixed combinations are those in which the active ingredients, e.g., a pentaaza macrocyclic ring complex and an optional anti-cancer therapeutic agent, are administered to a patient simultaneously in the form of a single entity or dosage.
  • Other active agents may also be administered as a part of the single entity or dosage, or may be separately administered.
  • Non-fixed combinations are those in which the active ingredients, e.g., a pentaaza macrocyclic ring complex and an optional anti-cancer therapeutic agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the compounds in the body of the patient.
  • the latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.
  • the pentaaza macrocyclic ring complex can also be administered as a pharmaceutical composition in the absence of any other anti-cancer therapeutic agent.
  • the above-described pentaaza macrocyclic ring complex may be dispersed in a pharmaceutically acceptable carrier prior to administration to the mammal; i.e., the components described herein are preferably co-form ulated.
  • the carrier also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is typically a substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the efficacy of the compound.
  • the carrier is generally considered to be "pharmaceutically or pharmacologically acceptable” if it does not produce an unacceptably adverse, allergic or other untoward reaction when administered to a mammal, especially a human.
  • compositions of the described herein can be formulated for any route of administration so long as the blood circulation system is available via that route, and in accordance with the conventional route of administration.
  • suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration.
  • parenteral e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal
  • topical nasal, transdermal, intraocular
  • intravesical, intrathecal enteral
  • compositions of the present disclosure are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular compound(s) and agent(s) used, and its/their concentration, stability and intended bioavailability; the subject, its age, size and general condition; and the route of administration.
  • Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., a-glycerol formal, 6-glycerol formal, 1 ,3-butyleneglycol, aliphatic or aromatic alcohols having 2 to 30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA),
  • saccharide fatty acid esters i.e., the condensation product of a monosaccharide ⁇ e.g., pentoses such as ribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses such as glucose, fructose, galactose, mannose and sorbose, trioses, tetroses, heptoses, and octoses), disaccharide ⁇ e.g., sucrose, maltose, lactose and trehalose) or oligosaccharide or mixture thereof with a C4 to C22 fatty acid(s) ⁇ e.g., saturated fatty acids such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmi
  • saccharide fatty acid esters i.e., the condensation product of a monosacc
  • oils or non-aqueous solvents may be employed in the formulations, e.g., to bring one or more of the compounds into solution, due to, for example, the presence of large lipophilic moieties.
  • emulsions, suspensions, or other preparations for example, liposomal preparations, may be used.
  • liposomal preparations for example, any known methods for preparing liposomes may be used. See, for example, Bangham et at., J. Mol. Biol, 23: 238-252 (1965) and Szoka etal., Proc. Natl Acad. Sci 75: 4194-4198 (1978), incorporated herein by reference.
  • compounds can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines.
  • Ligands may also be attached to the liposomes, for instance, to direct these compositions to particular sites of action.
  • Formulations containing the pentaaza macrocyclic ring complex may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms such as, for instance, aerosols, capsules, creams, emulsions, foams, gels/jellies, lotions, ointments, pastes, powders, soaps, solutions, sprays, suppositories, suspensions, sustained-release formulations, tablets, tinctures, transdermal patches, and the like, preferably in unit dosage forms suitable for simple administration of precise dosages. If formulated as a fixed dose, such pharmaceutical compositions or formulation products employ the pentaaza macrocyclic ring complex (and optionally the anti-cancer therapeutic agent) within accepted dosage ranges.
  • a formulation is provided that contains the pentaaza macrocyclic ring complex provided as a part of a sterile liquid dosage form suitable for injection, either in the same liquid dosage form with the anti-cancer therapeutic agent or as a separate dosage form.
  • the liquid form can further comprise one or more further ingredients, such as edetate disodium (EDTA).
  • EDTA edetate disodium
  • the liquid form can comprise EDTA in an amount suitable to act as a preservative and/or metal-chelating agent, such as an amount of about 0.025%.
  • the liquid form can further comprise water, and may also comprise a pH adjuster, such as sodium bicarbonate, for pH adjustment in the range of pH 5.5 to 7.0.
  • formulations of the pentaaza macrocyclic ring complex may employ conventional formulation techniques for these components individually, or alternative formulation routes, subject to compatibility and efficacy of the various components, in combination.
  • compositions including the pentaaza macrocyclic compound may additionally include one or more additional pharmaceutically active components.
  • suitable pharmaceutically active agents that may be included in the compositions according to aspects of the present invention include, for instance, antiemetics, anesthetics, antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatory agents, antipsychotic agents, cognitive enhancers, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's Disease agents, antibiotics, antidepressants, and antiviral agents.
  • the individual components of such compositions may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • a kit may be provided that includes a pentaaza macrocyclic ring complex and optionally the anti-cancer therapeutic agent, for treatment of a condition such as cancer, and/or to reduce the likelihood of recurrence of cancer.
  • the kit may comprise a first vessel or container having therein a formulation comprising the pentaaza macrocyclic ring complex, such as an oral or injectable formulation of the pentaaza macrocyclic ring complex, and a second vessel or container having therein a formulation comprising the anti-cancer therapeutic agent, such as an injectable formulation of anti-cancer therapeutic agent.
  • the kit may further comprise a label or other instructions for administration of the active agents, recommended dosage amounts, durations and administration regimens, warnings, listing of possible drug-drug interactions, and other relevant instructions, such as a label instructing therapeutic regimens (e.g., dosing, frequency of dosing, etc.) corresponding to any of those described herein.
  • a label instructing therapeutic regimens e.g., dosing, frequency of dosing, etc.
  • the pentaaza macrocyclic ring complex (and optionally the anti-cancer therapeutic agent), is administered in combination with a radiation therapy treatment regime.
  • the temporal aspects of the administration of the pentaaza macrocyclic ring complex may depend for example, on the particular radiation therapy that is selected, or the type, nature, and/or duration of the radiation exposure. Other considerations may include the disease or disorder being treated and the severity of the disease or disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the , administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors.
  • the pentaaza macrocyclic ring complex may be administered in various embodiments before, during, and/or after the administration of the radiation therapy (e.g., before, during or after exposure to and/or before, during or after a course of radiation therapy comprising multiple exposures and/or doses).
  • the pentaaza macrocyclic ring complex may be administered in various embodiments before, during, and/or after an exposure to radiation.
  • the radiation therapy can comprise any selected from the group consisting of gamma irradiation, proton therapy, heavy ion therapy, brachytherapy, radionuclide therapy, conformal radiation therapy, intensity modulated radiation therapy, stereotactic body radiation therapy, stereoablative radiation therapy, and gamma knife therapy, whether delivered as standard fractionation, hypofractionation, accelerated fractionation or decelerated fractionation and variations thereof.
  • the effective dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the dose.
  • the pentaaza macrocyclic ring complex is administered to the patient prior to or simultaneous with the radiation exposure.
  • the pentaaza macrocyclic ring complex is administered to the patient prior to, but not after, the radiation exposure.
  • the pentaaza macrocyclic ring complex is administered to the patient at least 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 5 days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or longer, prior to the radiation exposure, such as an initial radiation exposure in a course of radiation treatment, or prior to another dose or dose fraction of radiation that is one of the doses or dose fractions of radiation in the course of treatment.
  • the pentaaza macrocyclic ring complex is administered to the patient after the radiation exposure; thus, for example, the compound may be administered up to 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 180 minutes, 0.5 days, 1 day, 3 days, 5 days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or longer, after the radiation exposure, which may be a dose or dose fraction of radiation in a multi-dose course of radiation therapy, or may be the single or final dose or dose fraction of radiation in the radiation therapy.
  • a patient receives a dose or dose fraction of ionizing radiation to kill or control the growth of cancerous cells.
  • the dose or dose fraction of radiation may be directed at a specific part of the body, and the beam of radiation may also be shaped according to a predetermined treatment regimen, to reduce deleterious effects on parts of the body not afflicted with cancer.
  • a typical course of radiation therapy may include one or a plurality of doses or dose fractions of radiation, which can be administered over the course of days, weeks and even months.
  • a total “dose” of radiation given during a course of radiation therapy typically refers to the amount of radiation a patient receives during the entire course of radiation therapy, which doses may be administered as dose “fractions” corresponding to multiple radiation exposures in the case where the total dose is administered over several sessions, with the sum of the fractions administered corresponding to the overall dose.
  • the pentaaza macrocyclic ring complex is administered within a predetermined time period before or after a radiation exposure, such as before or after a radiation dose or dose fraction.
  • a radiation exposure such as before or after a radiation dose or dose fraction.
  • the pentaaza macrocyclic ring complex may be administered within 1 week, 48 hours, 24 hours, 12 hours, 6, hours, 2 hours, 1 hour or even within 30 minutes of the patient receiving the radiation exposure, such as the dose or dose fraction (either before or after the radiation exposure corresponding to the radiation dose or dose fraction).
  • Other durations between the radiation exposure and administration of the compound that result in the enhanced the killing of cancer cells may also be suitable.
  • one or more of the pentaaza macrocyclic ring complex and/or the optional anti-cancer therapeutic agent may be administered before the radiation exposure, and the remaining one or more of the pentaaza macrocyclic ring complex and/or the anti-cancer therapeutic agent can be administered after the radiation exposure.
  • One or more of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent may also be administered both before and after administration of a radiation exposure.
  • a course of radiation therapy includes a plurality of radiation doses or dose fractions given over a predetermined period of time, such as over the course of hours, weeks, days and even months, with the plural doses or dose fractions being either of the same magnitude or varying.
  • a course of radiation therapy can comprise the administration of a series of multiple doses or dose fractions of radiation.
  • the pentaaza macrocyclic ring complex can be administered before one or more radiation doses or dose fractions in the series, such as before each radiation dose or dose fraction, or before some number of the radiation doses or dose fractions.
  • the administration of the pentaaza macrocyclic ring complex and optional anti-cancer therapeutic agent during the course of radiation therapy can be selected to enhance the cancer treating effects of the radiation therapy, such as by sensitizing cancer cells to the radiation therapy.
  • the pentaaza macrocyclic ring complex is administered within a predetermined duration before or after of each dose or dose fraction, such as the predetermined duration discussed above.
  • the pentaaza macrocyclic ring complex is administered within a predetermined duration of time before or after only select doses or dose fractions. In yet another embodiment, at least one of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent is administered within a predetermined duration of time before the doses, while another of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent is administered within a predetermined duration of time after the doses or dose fraction.
  • At least one of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent is administered only within the predetermined duration before or after select doses or dose fractions, while another of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent is administered only within the predetermined duration before or after doses or dose fractions other than the select doses or dose fractions.
  • a suitable overall dose to provide during a course of therapy can be determined according to the type of treatment to be provided, the physical characteristics of the patient and other factors, and the dose fractions that are to be provided can be similarly determined.
  • a dose fraction of radiation that is administered to a patient may be at least 1.8 Gy, such as at least 2 Gy, and even at least 3 Gy, such as at least 5 Gy, and even at least 6 Gy.
  • a dose fraction of radiation that is administered to a patient may be at least 10 Gy, such as at least 12 Gy, and even at least 15 Gy, such as at least 18 Gy, and even at least 20 Gy, such as at least 24 Gy.
  • a dose fraction of radiation administered to a patient will not exceed 54 Gy.
  • a dose fraction delivered to a subject may refer to an amount delivered to a specific target region of a subject, such as a target region of a tumor, whereas other regions of the tumor or surrounding tissue may be exposed to more or less radiation than that specified by the nominal dose fraction amount.
  • the optional anti-cancer therapeutic agent comprises a chemotherapeutic agent.
  • chemotherapeutic agents are administered to a patient to kill or control the growth of cancerous cells.
  • a typical course of chemotherapy may include one or a plurality of doses of one or more chemotherapeutic agents, which can be administered over the course of days, weeks and even months.
  • Chemotherapeutic agents can include at least one of: alkylating antineoplastic agents such as nitrogen mustards (e.g. cyclophosphamide, chlorambucil), nitrosoureas (e.g. n-nitroso-n-methylurea, carmustine, semustine), tetrazines (e.g.
  • antimetabolites such as anti-folates (e.g. methotrexate and pemetrexed), fluoropyrimidines (e.g., fluorouracil, capecitabine), anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin), deoxynucleoside analogs (e.g. cytarabine, gemcitabine, decitabine) and thiopurines (e.g., thioguanine, mercaptopurine); anti microtubule agents such as taxanes (e.g.
  • paclitaxel paclitaxel, docetaxel
  • topoisomerase inhibitors e.g. etoposide, doxorubicin, mitoxantrone, teniposide
  • antitumor antibiotics e.g. bleomycin, mitomycin
  • the chemotherapeutic agent may be selected from the group consisting of all-trans retinoic acid, arsenic trioxide, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, tiguanine, valrubicin, vinblastine, vincristine, vindesine, and vinorelbine.
  • the optional anti-cancer therapeutic agent comprises a chemotherapeutic agent that is any of a platinum-containing chemotherapeutic agent and an anthracycline chemotherapeutic agent.
  • the chemotherapeutic agent can comprise any of a platinum-containing chemotherapeutic agent selected from the group consisting of cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplation, lipoplatin, LA-12, phosphaplatin, phenanthriplatin, prolindac, triplatin tetranitrate, picoplatin, satraplatin and/or pharmaceutically acceptable salts thereof, and/or an anthracycline chemotherapeutic agent selected from the group consisting of doxorubicin, daunorubicin, epirubicin and idarubicin, and/or pharmaceutically acceptable salts thereof.
  • a platinum-containing chemotherapeutic agent selected from the group consisting of cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplation, lipop
  • the anti-cancer therapeutic agent comprises a cell cycle inhibitor such as a CDK4/6 inhibitor, such as any selected from the group consisting of group of palbociclib, abemaciclib, ribociclib, and derivatives, salts and/or prodrugs thereof.
  • a cell cycle inhibitor such as a CDK4/6 inhibitor, such as any selected from the group consisting of group of palbociclib, abemaciclib, ribociclib, and derivatives, salts and/or prodrugs thereof.
  • the optional anti-cancer therapeutic agent comprise a chemotherapeutic agent selected from the group consisting of cisplatin, doxorubicin, bleomycin, and paclitaxel.
  • the chemotherapeutic agent may be selected from the group consisting of a taxane, an anticancer antibiotic, and an anthracycline.
  • Other chemotherapeutic agents can include arsenic trioxide and 5-FU, which agents can also be used in the methods and compositions described herein. (Alexandre et al., Cancer Res. 67: (8), 3512-3517 (2007); Yen etal., J. Clin. Invest. 98 (5), 1253-1260 (1996); Masuda etal., Cancer Chemother. Pharmacol. 47(2), 155-160 (2001)).
  • the chemotherapeutic agent can include at least one of an antimetabolite anti-cancer agents and antimitotic anti-cancer agents, and combinations thereof, which may include some of the agents described above and well as other agents described further herein.
  • an antimetabolite anti-cancer agents and antimitotic anti-cancer agents and combinations thereof, which may include some of the agents described above and well as other agents described further herein.
  • Various antimetabolite and antimitotic agents may be employed in the methods and compositions described herein.
  • Antimetabolic agents typically structurally resemble natural metabolites, which are involved in normal metabolic processes of cancer cells such as the synthesis of nucleic acids and proteins.
  • the antimetabolites differ enough from the natural metabolites such that they interfere with the metabolic processes of cancer cells.
  • antimetabolites are mistaken for the metabolites they resemble, and are processed by the cell in a manner analogous to the normal compounds.
  • the presence of the “decoy” metabolites prevents the cells from carrying out vital functions and the cells are unable to grow and survive.
  • antimetabolites may exert cytotoxic activity by substituting these fraudulent nucleotides into cellular DNA, thereby disrupting cellular division, or by inhibition of critical cellular enzymes, which prevents replication of DNA.
  • the antimetabolite agent is a nucleotide or a nucleotide analog.
  • the antimetabolite agent may comprise purine (e.g., guanine or adenosine) or analogs thereof, or pyrimidine (cytidine or thymidine) or analogs thereof, with or without an attached sugar moiety.
  • Suitable antimetabolite agents for use in the present disclosure may be generally classified according to the metabolic process they affect, and can include, but are not limited to, analogues and derivatives of folic acid, pyrimidines, purines, and cytidine.
  • the antimetabolite agent(s) is selected from the group consisting of cytidine analogs, folic acid analogs, purine analogs, pyrimidine analogs, and combinations thereof.
  • the antimetabolite agent is a cytidine analog.
  • the cytidine analog may be selected from the group consisting of cytarabine (cytosine arabinodside), azacitidine (5-azacytidine), and salts, analogs, and derivatives thereof.
  • the antimetabolite agent is a folic acid analog.
  • Folic acid analogs or antifolates generally function by inhibiting dihydrofolate reductase (DFIFR), an enzyme involved in the formation of nucleotides; when this enzyme is blocked, nucleotides are not formed, disrupting DNA replication and cell division.
  • DFIFR dihydrofolate reductase
  • the folic acid analog may be selected from the group consisting of denopterin, methotrexate (amethopterin), pemetrexed, pteropterin, raltitrexed, trimetrexate, and salts, analogs, and derivatives thereof.
  • the antimetabolite agent is a purine analog.
  • Purine-based antimetabolite agents function by inhibiting DNA synthesis, for example, by interfering with the production of purine containing nucleotides, adenine and guanine which halts DNA synthesis and thereby cell division.
  • Purine analogs can also be incorporated into the DNA molecule itself during DNA synthesis, which can interfere with cell division.
  • the purine analog may be selected from the group consisting of acyclovir, allopurinol, 2-aminoadenosine, arabinosyl adenine (ara-A), azacitidine, azathiprine, 8- aza-adenosine, 8-fluoro-adenosine, 8-methoxy-adenosine, 8-oxo-adenosine, cladribine, deoxycoformycin, fludarabine, gancylovir, 8-aza-guanosine, 8-fluoro-guanosine, 8- methoxy-guanosine, 8-oxo-guanosine, guanosine diphosphate, guanosine diphosphate- beta-L-2-aminofucose, guanosine diphosphate-D-arabinose, guanosine diphosphate-2 - fluorofucose, guanosine diphosphate, guanosine
  • the antimetabolite agent is a pyrimidine analog. Similar to the purine analogs discussed above, pyrimidine-based antimetabolite agents block the synthesis of pyrimidine-containing nucleotides (cytosine and thymine in DNA; cytosine and uracil in RNA). By acting as “decoys,” the pyrimidine-based compounds can prevent the production of nucleotides, and/or can be incorporated into a growing DNA chain and lead to its termination.
  • the pyrimidine analog may be selected from the group consisting of ancitabine, azacitidine, 6-azauridine, bromouracil (e.g., 5- bromouracil), capecitabine, carmofur, chlorouracil (e.g.
  • 5-chlorouracil 5-chlorouracil
  • cytarabine cytosine arabinoside
  • cytosine dideoxyuridine, 3'-azido-3'-deoxythymidine, 3'-dideoxycytidin-2'-ene, 3'-deoxy-3'-deoxythymidin-2'-ene, dihydrouracil, doxifluridine, enocitabine, floxuridine, 5-fluorocytosine, 2-fluorodeoxycytidine, 3-fluoro-3'- deoxythymidine, fluorouracil (e.g., 5-fluorouracil (also known as 5-FU), gemcitabine, 5- methylcytosine, 5-propynylcytosine, 5-propynylthymine, 5-propynyluracil, thymine, uracil, uridine, and salts, analogs, and derivatives thereof.
  • the pyrimidine analog is other than 5-
  • the antimetabolite agent is selected from the group consisting of 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof.
  • the antimetabolite agent is selected from the group consisting of capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof.
  • the antimetabolite agent is other than 5- fluorouracil.
  • the antimetabolite agent is gemcitabine or a salt or thereof (e.g ., gemcitabine HCI (Gemzar®)).
  • antimetabolite agents may be selected from, but are not limited to, the group consisting of acanthifolic acid, aminothiadiazole, brequinar sodium, Ciba- Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, Wellcome EHNA, Merck & Co.
  • EX-015 benzrabine, fludarabine phosphate, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO- 152, 5-FU-fibrinogen, isopropyl pyrrolizine, Lilly LY-188011; Lilly LY-264618, methobenzaprim, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC- 264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, tiazofurin, Erbamont TIF, tyrosine kinase inhibitors, Taiho LIFT and uricytin, among others.
  • the chemotherapeutic agent comprises an antimitotic agent that is a microtubule inhibitor or a mictrotubule stabilizer.
  • microtubule stabilizers such as taxanes (some of which are also described above) and epothilones, bind to the interior surface of the beta-microtubule chain and enhance microtubule assembly by promoting the nucleation and elongation phases of the polymerization reaction and by reducing the critical tubulin subunit concentration required for microtubules to assemble.
  • the microtubule stabilizers decrease the lag time and dramatically shift the dynamic equilibrium between tubulin dimers and microtubule polymers towards polymerization.
  • the microtubule stabilizer is a taxane or an epothilone.
  • the microtubule inhibitor is a vinca alkaloid.
  • the taxane may be a naturally derived compound or a related form, or may be a chemically synthesized compound or a derivative thereof, with antineoplastic properties.
  • the taxanes are a family of terpenes, including, but not limited to paclitaxel (Taxol®) and docetaxel (Taxotere®), which are derived primarily from the Pacific yew tree, Taxus brevifolia, and which have activity against certain tumors, particularly breast and ovarian tumors.
  • the taxane is docetaxel or paclitaxel.
  • Paclitaxel is a preferred taxane and is considered an antimitotic agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.
  • Taxane derivatives include, but are not limited to, galactose and mannose derivatives described in International Patent Application No. WO 99/18113; piperazino and other derivatives described in WO 99/14209; taxane derivatives described in WO 99/09021, WO 98/22451, and U.S.
  • it further includes prodrugs of paclitaxel including, but not limited to, those described in WO 98/58927; WO 98/13059; and U.S. Patent No. 5,824,701.
  • the taxane may also be a taxane conjugate such as, for example, paclitaxel-PEG, paclitaxel-dextran, paclitaxel-xylose, docetaxel-PEG, docetaxel-dextran, docetaxel-xylose, and the like.
  • Other derivatives are mentioned in "Synthesis and Anticancer Activity of Taxol Derivatives," D. G. I. Scientific et al., Studies in Organic Chemistry, vol. 26, entitled “New Trends in Natural Products Chemistry” (1986), Atta-ur-Rabman, P. W. le Quesne, Eds. (Elsevier, Amsterdam 1986), among other references. Each of these references is hereby incorporated by reference herein in its entirety.
  • the antimitotic agent can be a microtubule inhibitor; in one preferred embodiment, the microtubule inhibitor is a vinca alkaloid.
  • the vinca alkaloids are mitotic spindle poisons.
  • the vinca alkaloid agents act during mitosis when chromosomes are split and begin to migrate along the tubules of the mitosis spindle towards one of its poles, prior to cell separation. Under the action of these spindle poisons, the spindle becomes disorganized by the dispersion of chromosomes during mitosis, affecting cellular reproduction.
  • the vinca alkaloid is selected from the group consisting of vinblastine, vincristine, vindesine, vinorelbine, and salts, analogs, and derivatives thereof.
  • the antimitotic agent can also be an epothilone.
  • members of the epothilone class of compounds stabilize microtubule function according to mechanisms similar to those of the taxanes.
  • Epothilones can also cause cell cycle arrest at the G2-M transition phase, leading to cytotoxicity and eventually apoptosis.
  • Suitable epithiolones include epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, and epothilone F, and salts, analogs, and derivatives thereof.
  • One particular epothilone analog is an epothilone B analog, ixabepilone (IxempraTM).
  • the antimitotic anti-cancer agent is selected from the group consisting of taxanes, epothilones, vinca alkaloids, and salts and combinations thereof.
  • the antimitotic agent is a taxane. More preferably in this embodiment the antimitotic agent is paclitaxel or docetaxel, still more preferably paclitaxel.
  • the antimitotic agent is an epothilone (e.g., an epothilone B analog).
  • the antimitotic agent is a vinca alkaloid.
  • the pentaaza macrocyclic ring complex may be administered within 1 week, 48 hours, 24 hours, 12 hours, 6, hours, 2 hours, 1 hour or even within 30 minutes of the patient receiving the dose of the chemotherapeutic agent (either before or after the dose of chemotherapeutic agent).
  • Other durations between the additional chemotherapeutic agent dose and administration of the pentaaza macrocyclic ring complex that result in the enhanced the killing of cancer cells may also be suitable.
  • a course of chemotherapy includes a singular dose of the additional chemotherapeutic agent.
  • a course of chemotherapy includes a plurality of doses of the additional chemotherapeutic agent given over a predetermined period of time, such as over the course of hours, weeks, days and even months.
  • the plural doses may be either of the same magnitude or varying, and can include doses of the same or different chemotherapeutic agents and/or a combination of chemotherapeutic agents.
  • M20 Dermat firboblasts (20 yr old male
  • HT1080 fibrosarcoma
  • SW872 liposarcoma
  • SKLMS1 leiomyosarcoma
  • DHE dihydroethidium
  • sarcoma sarcoma cell lines.
  • Steady-state levels of ROS were assessed in M20 (normal human dermal fibroblasts), HT1080 (fibrosarcoma), SW872 (liposarcoma) and SKLMS1 (leiomyosarcoma) cells at 3 hours (see Fig. 1 A), and at 24 hours (see Fig. 1 B).
  • Cells were treated with 5 mM of manganese pentaazamacrocycle (MnPAM) dismutase mimetic GC441924 hours prior to radiation with 4 Gy. Following DFIE staining, the cells were analyzed using a LSR-UV in flow cytometry.
  • MnPAM manganese pentaazamacrocycle
  • GC4419 decreases migration of fibrosarcoma cells. Relative migration was assessed using transwell migration chambers from BD FalconTM (8 pM pore size, 353097; BD Biosciences) in M20 and FIT1080 cells treated with 5 uM of a MnPAM dismutase mimetic (GC4419) 24 hours prior to 4 Gy IR exposure, alone and in combination with 15 U/ml catalase. The experiment consisted of one biological replicate and 3 technical replicates. Treatment with GC4419 alone increased migration of M20 normal fibroblasts relative to FIT1080 sarcoma cells, while migration of both was decreased somewhat following exposure to IR.
  • Treatment with GC4419 and IR substantially increased migration of M20 cells and decreased migration of FIT1080 cells, (see Fig.4).
  • Data represent relative migration compared to controls. Accordingly, it was shown that dismutase mimetic increases migration of normal fibroblasts (M20) including after IR exposure, which should support more rapid and appropriate repopulation and repair of injured tissues. Importantly, dismutase mimetic also decreases relative migration of cancer (HT1080) cells including following IR which should support maintaining or even increasing the anti-cancer efficacy of IR.
  • M20 normal fibroblasts
  • HT1080 cancer
  • GC4419 Treatment with GC4419 accelerates radiation-induced wound closure in a murine wound healing model.
  • C57BI6/NHsd mice were pre-treated with 10mg/kg MnPAM dismutase mimetic (GC4419) I.P. daily starting 3 days prior to a single dose of 15 Gy IR using SARRP (Small Animal Radiation Research Platform) and up to two weeks following IR. 60 days following IR exposure, wounds were created on the dorsal side of mice using 5 mm biopsy punches and wound closure was measured using calipers until complete closure in the control group (see Fig. 5A). There were 3 mice per group.
  • Fig. 5C is a schematic showing the timeline and experimental design used to obtain the results illustrated in Figs 5A-5B.
  • Figs. 6-8 described the parameters and timeline for a randomized, placebo controlled trial of a MnPAM dismutase mimetic (GC4419) + stereotactic body radiation therapy (SBRT) in patients with locally advanced pancreatic cancer.
  • GC4419 MnPAM dismutase mimetic
  • SBRT stereotactic body radiation therapy
  • either 90 mg dismutase mimetic or placecbo were administered as a 60-minute intravenous infusion before each of five daily doses of 10 Gy IR delivered as SBRT.
  • Patients treated in this study were judged to either be “unresectable” or “borderline” as to the resectability of the tumor before treatment, as detailed in the figures.
  • Figs. 9-10 show some of the surgical results from the trial of Figs. 6-8. The results show that more patients treated with dismutase mimetic + SBRT were resected (5 of 24) than with placebo + SBRT (2 of 18), and that surgical outcomes in terms of absence of observable cancer in the edges of the resected tumor-containing tissue (negative margins, or Ro) were better with dismutase mimetic + SBRT (5 of 5) than with placebo + SBRT (1 of 2).

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Abstract

A method of enhancing wound healing after a radiation exposure in a mammalian subject is provided. The mammalian subject is selected from among a population of mammalian subjects that has been or will be exposed to radiation, and the mammalian subject is administered a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after the radiation exposure.

Description

PENTAAZA MACROCYCLIC RING COMPLEX FOR ENHANCED SURGICAL
TREATMENT
Cross Reference to Related Applications
[0001] The present application claims benefit of U.S. Provisional Patent Application Serial No. 63/203,631 , filed on July 27, 2021 which application is incorporated by reference herein in its entirety.
Field of the Invention
[0002] The present disclosure generally relates to treatments to enhance the outcomes of surgery performed on a subject before or after exposure to radiation using pentaaza macrocyclic ring complexes, such as in the treatment of cancers, including methods and compositions for such treatments.
Summary of the Invention
[0003] Transition metal-containing pentaaza macrocyclic ring complexes having the macrocyclic ring system corresponding to Formula A have been shown to be effective in a number of animal and cell models of human disease, as well as in treatment of conditions afflicting human patients.
Figure imgf000003_0001
FORMULA A
For example, in a rodent model of colitis, one such compound, GC4403, has been reported to very significantly reduce the injury to the colon of rats subjected to an experimental model of colitis (see Cuzzocrea et at., Europ. J. Pharmacol., 432, 79-89 (2001)).
Figure imgf000004_0002
GC4403 has also been reported to attenuate the radiation damage arising both in a clinically relevant hamster model of acute, radiation-induced oral mucositis (Murphy et al., Clin. Can. Res., 14(13), 4292 (2008)), and lethal total body irradiation of adult mice (Thompson et al., Free Radical Res., 44(5), 529-40 (2010)). Similarly, another such compound, GC4419, has been shown to attenuate VEGFr inhibitor-induced pulmonary disease in a rat model (Tuder, et al., Am. J. Respir. Cell Mol. Biol., 29, 88–97 (2003)). Additionally, another such compound, GC4401 has been shown to provide protective effects in animal models of septic shock (S. Cuzzocrea, et al., Crit. Care Med., 32(1), 157 (2004) and pancreatitis (S. Cuzzocrea, et al., Shock, 22(3), 254-61 (2004)).
Figure imgf000004_0001
[0004] Certain of these compounds have also been shown to possess potent anti-inflammatory activity and prevent oxidative damage in vivo. For example, GC4403 has been reported to inhibit inflammation in a rat model of inflammation (Salvemini, et.al., Science, 286, 304 (1999)), and prevent joint disease in a rat model of collagen- induced arthritis (Salvemini et al., Arthritis & Rheumatism, 44(12), 2009-2021 (2001)). Yet others of these compounds, MdPAM and MnBAM, have shown in vivo activity in the inhibition of colonic tissue injury and neutrophil accumulation into colonic tissue (Weiss et al., The Journal of Biological Chemistry, 271(42), 26149-26156 (1996)). In addition, these compounds have been reported to possess analgesic activity and to reduce inflammation and edema in the rat-paw carrageenan hyperalgesia model, see, e.g.,
U.S. Pat. No. 6,180,620.
[0005] Compounds of this class have also been shown to be safe and effective in the prevention and treatment of disease in human subjects. For example, GC4419 has been shown to reduce oral mucositis in head-and-neck cancer patients undergoing chemoradiation therapy (Anderson, C., Phase 1 Trial of Superoxide Dismutase (SOD) Mimetic GC4419 to Reduce Chemoradiotherapy (CRT)-lnduced Mucositis (OM) in Patients (pts) with Mouth or Oropharyngeal Carcinoma (OCC), Oral Mucositis Research Workshop, MASCC/ISOO Annual Meeting on Supportive Care in Cancer, Copenhagen, Denmark (June 25, 2015)).
[0006] In addition, transition metal-containing pentaaza macrocyclic ring complexes corresponding to this class have shown efficacy in the treatment of various cancers. For example, certain compounds corresponding to this class have been provided in combination with agents such as paclitaxel and gemcitabine to enhance cancer therapies, such as in the treatment of colorectal cancer and lung cancer (nonsmall cell lung cancer) (see, e.g., U.S. Patent No. 9,198,893) The GC4403 compound above has also been used for treatment in in vivo models of Meth A spindle cell squamous carcinoma and RENCA renal carcinoma (Samlowski et al., Nature Medicine, 9(6), 750-755 (2003), and has also been used for treatment in in vivo models of spindlecell squamous carcinoma metastasis (Samlowski et al., Madame Curie Bioscience Database (Internet), 230-249 (2006)).
[0007 ] For certain types of cancer, such as for example soft tissue sarcomas, one standard of care treatment approach is to provide radiation therapy, in combination with surgical resection of the tumor. Flowever, currently about 35% of soft tissue sarcoma patients receiving pre-surgery radiation will develop fibrosis and have poor wound healing, and similar issues occur with radiation therapy administered for other types of cancers.
[0008] Accordingly, there is a need for reducing the occurrence of fibrosis and enhancing wound healing for surgical patients receiving radiation. There is also a need for improved methods of surgical resection and other post-radiation surgical treatments. [0009] Briefly, therefore, aspects of the present disclosure are directed to a method of enhancing wound healing after a radiation exposure in a mammalian subject in need thereof, the method comprising:
[0010] selecting the mammalian subject from among a population of mammalian subjects that has been or will be exposed to radiation, and
[0011] administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after the radiation exposure:
[0012]
[0013]
Figure imgf000006_0001
[0014] wherein
[0015] M is Mn2+ or Mn3+;
[0016] R1, R2, R'2, R3, R4, R5, R'5, R6, Re, R7, Re, R9, R'9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11 R12, -N(ORii)(Ri2), -P(0)(ORii)(ORi2), -P(0)(ORII)(RI2), and -OP(0)(ORII)(ORI2), wherein Rn and R12 are independently hydrogen or alkyl;
[0017] U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; [0018] V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
[0019] W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen- containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and Rio attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
[0020] X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
[0021] Z is a counterion;
[0022] n is an integer from 0 to 3; and
[0023] the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
[0024] Other aspects of the present disclosure are directed to a method of enhancing wound healing in a mammalian subject following radiation therapy for treatment of a tumor, the method comprising:
[0025] selecting the mammalian subject from among a population of mammalian subjects afflicted with a tumor that is treatable by radiation therapy, and administering to the subject the radiation therapy in combination with a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy.
[0026] Further aspects of the present disclosure are directed to a method of enhancing wound healing in a mammalian subject afflicted with a tumor that is treatable by surgery and radiation therapy, the method comprising:
[0027] selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and surgery, and administering to the subject radiation therapy in combination with a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy: [0028] Further aspects of the present disclosure are directed to a method of enhancing an outcome of tumor treatment in a mammalian subject, the method comprising:
[0029] selecting a predetermined period of time in which to perform surgery following an exposure to radiation administered as a part a radiation therapy to the mammalian subject, in relation to whether or not the mammalian subject has received or will receive administration of a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, and
[0030] performing surgery on the mammalian subject within the selected predetermined period of time.
[0031] Further aspectsof the disclosure are directed to a method of enhancing an outcome of tumor treatment in a mammalian subject, the method comprising:
[0032] selecting a predetermined period of time following surgery in which to expose the mammalian subject radiation administered as a part a radiation therapy to the mammalian subject, in relation to whether or not the mammalian subject has received or will receive administration of a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, and
[0033] exposing the mammalian subject to radiation within the selected predetermined period of time following surgery. [0034] Further aspects of the disclosure are directed to a method of preparing a mammalian subject for surgery following radiation therapy, the method comprising:
[0035] administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to Formula (I) as disclosed herein, prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy: [0036] Further aspects of the disclosure are directed to a method of enhancing wound healing following tissue resection and radiation therapy for treatment of a tumor in a mammalian subject, the method comprising:
[0037] exposing the mammalian subject to radiation as a part of radiation therapy;
[0038] resecting a region of tissue at a location of the tumor in the mammalian subject; and
[0039] administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after the radiation exposure.
[0040] Further aspects of the disclosure are directed to a method of enhancing wound healing in a mammalian subject afflicted with a tumor that is treatable by tissue resection and radiation therapy, the method comprising:
[0041] selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and resection of the tumor, and
[0042] administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy:
[0043] Further aspects of the disclosure are directed to a method of selectively increasing the migration of normal cells relative to the migration of malignant cells following surgery and radiation therapy for treatment of a tumor in a mammalian subject, the method comprising: [0044] exposing the mammalian subject to radiation as a part of the radiation therapy;
[0045] performing surgery on the mammalian subject; and
[0046] administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after the radiation exposure received as a part of the radiation therapy.
[0047] Further aspects of the disclosure are directed to a method of selectively increasing the migration of normal cells relative to the migration of malignant cells in a mammalian subject afflicted with a tumor that is treatable by surgery and radiation therapy, the method comprising:
[0048] selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and surgery, and
[0049] administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy.
[0050] Further aspects of the disclosure are directed to a method of selectively increasing the migration of normal cells relative to the migration of malignant cells in a mammalian subject following radiation therapy, the method comprising:
[0051] selecting the mammalian subject from among a population of mammalian subjects in need of enhanced wound healing following radiation therapy, and
[0052] administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy.
[0053] Further aspects of the disclosure are directed to a kit for therapeutic treatment of a mammalian subject, the kit comprising the pentaaza macrocyclic ring complex corresponding to Formula (I) as disclosed herein, optionally, a further anticancer agent; and instructions for administering the therapeutically effective amount of the pentaaza macrocyclic ring complex to perform any of the methods disclosed herein. [0054 ] Other aspects, features and embodiments of the present disclosure will be, in part, discussed and, in part, apparent in the following description and drawings.
Brief Description of the Drawings
[0055] Figs. 1A and 1B are graphs illustrating increased levels of dihydroethidium (DHE) oxidation in sarcoma cell lines: Steady-state levels of ROS were assessed in M20 (normal human dermal fibroblasts), HT1080 (fibrosarcoma), SW872 (liposarcoma) and SKLMS1 (leiomyosarcoma) cells at 3 hours (see Fig. 1 A), and at 24 hours (see Fig. 1 B). Cells were treated with 5 mM of manganese pentaazamacrocycle (MnPAM) dismutase mimetic GC441924 hours prior to radiation with 4 Gy. Following DFIE staining, the cells were analyzed using a LSR-UV in flow cytometry. All experiments are n=2, **=p<0.05 versus M20 control group as determined by two-way ANOVA, post-hoc Tukey test using GraphPad prism software. The results as shown in Figs. 1 A-1 B demonstrate that sarcoma cells have increased levels of reactive oxygen species relative to non-malignant cells.
[0056] Fig. 2 is a plot illustrating that increasing concentrations of ascorbate (up to 10 pMol/cell) is toxic to sarcoma cell lines: HT 1080, SW872 and SKLMS-1. 10 pMol/cell of ascorbate resulted in significant toxicity to FIT1080 compared to SW872 and SKLMS-1 cells. All cells were treated with an ascorbate titration using picomole/cell with concentrations adjusted to maintain 2 mM ascorbate. 10 pMol per cell resulted in almost 100-fold clonogenic cell killing in SKLMS-1 cells. Error bars indicate the standard error of the mean of n=3 per group. * indicates p<0.05. Statistical analysis was analyzed using GraphPad Prism.
[0057] Figs. 3A and 3B are graphs illustrating that combined treatment with GC4419 and P-AscFL Enhance Sarcoma Response to Radiation. Sarcoma cells lines, HT1080, SW872, and SKLMS-1, were treated with 4 Gy of ionizing radiation (IR) , 5 pM of a MnPAM dismutase mimetic (GC4419) (24 hours prior) or 10 pM/cell of ascorbate (see Fig. 3A). To determine if the combined treatment of ascorbate (PAscFL) and GC4419 enhanced sarcoma cell killing, cells were exposed to 4 Gy IR, 5 pM of GC4419 (24 hours prior to IR) and 10 pM/cell ascorbate (1 hr prior to IR) and plated for clonogenic cell survival. The combination of P-AscFL and GC4419 enhanced IR-induced cell killing compared to the IR alone group in both HT1080 and SW872 cells (see Fig. 3B). All experiments are at least n=2, *=p<0.01 versus the respective IR alone group as determined by one-way ANOVA, post-hoc Tukey test using GraphPad prism software. Accordingly, it was shown that treatment with dismutase mimetic kills at least some sarcoma cell lines, that combination with P-AscFh kills all sarcoma cell lines tested, and further exacerbates IR-included killing of sarcoma cells.
[0058] Fig. 4 is a graph illustrating that GC4419 decreases migration of fibrosarcoma cells. Relative migration was assessed using transwell migration chambers from BD Falcon™ (8 mM pore size, 353097; BD Biosciences) in M20 and FIT1080 cells treated with 5 uM of a MnPAM dismutase mimetic (GC4419) 24 hours prior to 4 Gy IR exposure, alone and in combination with 15 U/ml catalase. The experiment consisted of one biological replicate and 3 technical replicates. Treatment with GC4419 alone increased migration of M20 normal fibroblasts relative to FIT1080 sarcoma cells, while migration of both was decreased somewhat following exposure to IR. Treatment with GC4419 and IR substantially increased migration of M20 cells and decreased migration of FIT1080 cells (see Fig.4). Data represent relative migration compared to controls. Accordingly, it was shown that dismutase mimetic increases migration of normal fibroblasts (M20) including after IR exposure, which should support more rapid and appropriate repopulation and repair of injured tissues. Importantly, dismutase mimetic also decreases relative migration of cancer (FIT1080) cells including following IR which should support maintaining or even increasing the anti-cancer efficacy of IR.
[0059] Figs. 5A-5B are an image (5A) and a plot (5B) illustrating that treatment with GC4419 accelerates radiation-induced wound closure in a murine wound healing model. C57BI6/NFIsd mice were pre-treated with 10mg/kg MnPAM dismutase mimetic (GC4419) I.P. daily starting 3 days prior to a single dose of 15 Gy IR using SARRP (Small Animal Radiation Research Platform) and up to two weeks following IR. 60 days following IR exposure, wounds were created on the dorsal side of mice using 5 mm biopsy punches and wound closure was measured using calipers until complete closure in the control group (see Fig. 5A). There were 3 mice per group. Wound measurements taken at day 0, 7, and 11 showed that radiation alone delayed wound healing and resulted in a larger percentage of the wound staying open. Treatment with 10 mg/kg GC4419 in combination with IR resulted in faster and more complete wound closure compared to IR treated mice and at least as fast as control sham-irradiated mice (see Fig. 5B). Fig 5C is a schematic showing the timeline and experimental design used to obtain the results illustrated in Figs. 5A-5B. Accordingly, it was shown that treatment with dismutase mimetic enhances [enables and accelerates] wound healing following IR exposure.
[0060] Figs. 6-8 describe the parameters and timeline for a dismutase mimetic + SBRT pilot trial in pancreatic cancer.
[0061] Figs. 9-10 show results from the pancreatic cancer trial of Figs. 6-8.
[0062] Abbreviations and Definitions
[0063] The following definitions and methods are provided to better define the present invention and to guide those of ordinary skill in the art in the practice of the present invention. Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.
[0064 ] The term MAcK68" as used herein refers to the acetylated form of manganese superoxide dismutase (MnSOD) having acetylation at the K68 residue of the MnSOD protein, and may also be referred to herein as MnSOD-K68-Ac.
[0065] “Acyl” means a -COR moiety where R is alkyl, haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl as defined herein, e.g., acetyl, trifluoroacetyl, benzoyl, and the like.
[0066] “Acyloxy” means a -OCOR moiety where R is alkyl, haloalkyl, optionally substituted aryl, or optionally substituted heteroaryl as defined herein, e.g., acetyl, trifluoroacetyl, benzoyl, and the like.
[0067] “Alkoxy” means a -OR moiety where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.
[0068] “Alkyl” means a linear saturated monovalent hydrocarbon moiety such as of one to six carbon atoms, or a branched saturated monovalent hydrocarbon moiety, such as of three to six carbon atoms, e.g., C1-C6 alkyl groups such as methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric forms), pentyl (including all isomeric forms), and the like.
[0069] Moreover, unless otherwise indicated, the term “alkyl” as used herein is intended to include both “unsubstituted alkyls” and “substituted alkyls,” the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Indeed, unless otherwise indicated, all groups recited herein are intended to include both substituted and unsubstituted options.
[0070] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl and aralkyl, is meant to include groups that contain from x to y carbons in the chain. For example, the term Cx-y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight chain alkyl and branched chain alkyl groups that contain from x to y carbon atoms in the chain.
[0071] “Alkylene” means a linear saturated divalent hydrocarbon moiety, such as of one to six carbon atoms, or a branched saturated divalent hydrocarbon moiety, such as of three to six carbon atoms, unless otherwise stated, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.
[0072] “Alkenyl” a linear unsaturated monovalent hydrocarbon moiety, such as of two to six carbon atoms, or a branched saturated monovalent hydrocarbon moiety, such as of three to six carbon atoms, e.g., ethenyl (vinyl), propenyl, 2-propenyl, butenyl (including all isomeric forms), pentenyl (including all isomeric forms), and the like.
[0073] “Alkaryl” means a monovalent moiety derived from an aryl moiety by replacing one or more hydrogen atoms with an alkyl group.
[0074 ] “Alkenylcycloalkenyl” means a monovalent moiety derived from an alkenyl moiety by replacing one or more hydrogen atoms with a cycloalkenyl group.
[0075] “Alkenylcycloalkyl” means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with an alkenyl group.
[0076] “Alkylcycloalkenyl” means a monovalent moiety derived from a cycloalkenyl moiety by replacing one or more hydrogen atoms with an alkyl group.
[0077] “Alkylcycloalkyl” means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with an alkyl group.
[0078] “Alkynyl” means a linear unsaturated monovalent hydrocarbon moiety, such of two to six carbon atoms, or a branched saturated monovalent hydrocarbon moiety, such as of three to six carbon atoms, e.g., ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. [0079] “Alkoxy” means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a hydroxy group.
[0080] “Amino” means a -NRaRb group where Ra and Rb are independently hydrogen, alkyl or aryl.
[0081] “Antibody” as used herein includes an antibody of classes IgG, IgM,
IgA, IgD, or IgE, or fragments or derivatives thereof, including Fab, F(ab')2, Fd, and single chain antibodies, diabodies, bispecific antibodies, and bifunctional antibodies. The antibody may be a monoclonal antibody, polyclonal antibody, affinity purified antibody, or mixtures thereof, which exhibits sufficient binding specificity to a desired epitope or a sequence derived therefrom. The antibody may also be a chimeric antibody. The antibody may be derivatized by the attachment of one or more chemical, peptide, or polypeptide moieties known in the art. The antibody may be conjugated with a chemical moiety. The antibody may be a human or humanized antibody. [0082] “Aralkyl” means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with an aryl group.
[0083] “Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbon moiety of 6 to 10 ring atoms e.g., phenyl or naphthyl.
[0084 ] “Cycle” means a carbocyclic saturated monovalent hydrocarbon moiety of three to ten carbon atoms.
[0085] “Cycloalkyl” means a cyclic saturated monovalent hydrocarbon moiety of three to ten carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like.
[0086] “Cycloalkylalkyl” means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a cycloalkyl group, e.g., cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, or cyclohexylethyl, and the like.
[0087] “Cycloalkylcycloalkyl” means a monovalent moiety derived from a cycloalkyl moiety by replacing one or more hydrogen atoms with a cycloalkyl group.
[0088] “Cycloalkenyl” means a cyclic monounsaturated monovalent hydrocarbon moiety of three to ten carbon atoms, e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, or cyclohexenyl, and the like. [0089] “Cycloalkenylalkyl” means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with a cycloalkenyl group, e.g., cyclopropenylmethyl, cyclobutenylmethyl, cyclopentenylethyl, or cyclohexenylethyl, and the like.
[0090] “Ether” means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with an alkoxy group.
[0091] “Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro orchloro.
[0092 ] “Heterocycle” or “heterocyclyl” means a saturated or unsaturated monovalent monocyclic group of 4 to 8 ring atoms in which one or two ring atoms are heteroatom selected from N, O, or S(0)n, where n is an integer from 0 to 2, the remaining ring atoms being C. The heterocyclyl ring is optionally fused to a (one) aryl or heteroaryl ring as defined herein provided the aryl and heteroaryl rings are monocyclic. The heterocyclyl ring fused to monocyclic aryl or heteroaryl ring is also referred to in this Application as “bicyclic heterocyclyl” ring. Additionally, one or two ring carbon atoms in the heterocyclyl ring can optionally be replaced by a -CO- group. More specifically the term heterocyclyl includes, but is not limited to, pyrrolidino, piperidino, homopiperidino, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino, tetrahydropyranyl, thiomorpholino, and the like. When the heterocyclyl ring is unsaturated it can contain one or two ring double bonds provided that the ring is not aromatic. When the heterocyclyl group is a saturated ring and is not fused to aryl or heteroaryl ring as stated above, it is also referred to herein as saturated monocyclic heterocyclyl.
[0093] “Heteroaryl” means a monovalent monocyclic or bicyclic aromatic moiety of 5 to 10 ring atoms where one or more, preferably one, two, or three, ring atoms are heteroatom selected from N, O, or S, the remaining ring atoms being carbon. Representative examples include, but are not limited to, pyrrolyl, pyrazolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like.
[0094] “Nitro” means -NO2.
[0095] “Organosulfur” means a monovalent moiety a -SR group where R is hydrogen, alkyl or aryl. [0096] “Substituted alkyl,” “substituted cycle,” “substituted phenyl,” “substituted aryl,” “substituted heterocycle,” and “substituted nitrogen heterocycles” means an alkyl, cycle, aryl, phenyl, heterocycle or nitrogen-containing heterocycle, respectively, optionally substituted with one, two, or three substituents, such as those independently selected from alkyl, alkoxy, alkoxyalkyl, halo, hydroxy, hydroxyalkyl, or organosulfur. Generally, the term “substituted” includes groups that are substituted with any one or more of Ci-4alkyl, C2-4alkenyl, halogen, alcohol and/or amine.
[0097] “Thioether” means a monovalent moiety derived from an alkyl moiety by replacing one or more hydrogen atoms with an -SR group wherein R is alkyl.
[0098] As used herein, (i) the compound referred to herein and in the Figures as compound 401 , 4401 or GC4401 is a reference to the same compound, (ii) the compound referred to herein and in the Figures as compound 403, 4403 or GC4403 is a reference to the same compound, (iii) the compound referred to herein and in the Figures as compound 419, 4419 or GC4419 is a reference to the same compound, and (iv) the compound referred to herein and in the Figures as compound 444, 4444 or GC4444 is a reference to the same compound.
[0099] Furthermore, the use of the term “consisting essentially of,” in referring to a method of treatment, means that the method substantially does not involve providing another therapy and/or another active agent in amounts and/or under conditions that would be sufficient to significantly affect the treatment, and which are other than the therapies and/or active agents specifically recited in the claim. Similarly, the use of the term “consisting essentially of,” in referring to a kit for treatment, means that the kit substantially does not include another therapy and/or another active agent provided in amounts and/or under conditions that would be sufficient to significantly affect the treatment, and which are other than the therapies and/or active agents specifically recited in the claim.
Detailed Description
[00100] In one embodiment, aspects of the present disclosure are directed to methods to enhance wound healing and/or reduce fibrotic tissue in mammalian subjects receiving radiation therapy prior to or following a surgical procedure, such as surgical resection to remove a tumor and/or cancerous tissue. Aspects of the disclosure herein may allow for faster and more efficient healing from such surgical procedures. Aspects of the disclosure herein may also provide for more effective post-irradiation surgical procedures with fewer issues posed by fibrotic tissues that can form upon exposure of the mammalian subject’s tissue to irradiation. Aspects of the disclosure herein may also allow for surgical procedures to be performed shortly after exposure to irradiation, without requiring a long period of recovery of the irradiated tissue before surgical procedures can be performed. Aspects of the disclosure herein may also allow for radiation exppsure shortly after surgical procedures have been performed, without requiring a long period of recovery from surgery before subjecting tissue that has been surgically operated on to irradiation. According to certain embodiments, surgical procedures such as surgical resection to remove all or part of a tumor can be performed more efficiently pre- or post-irradiation, with improved patient outcomes.
[00101] According to certain embodiments, the methods provided herein comprising administering to a mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below:
[00102]
[00103]
Figure imgf000018_0001
[00104] wherein
[00105] M is Mn2+ or Mn3+;
[00106] R1, R2, R'2, R3, R4, R5, R'5, R6, R6, R7, R6, R9, R'9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11 Ri2, -N(ORii)(Ri2), -P(0)(0Rii)(0Ri2), -P(0)(0RII)(RI2), and -0P(0)(0Ri 1 )(ORI2), wherein Rn and R12 are independently hydrogen or alkyl;
[00107] U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
[00108] V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
[00109] W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen- containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
[00110] X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
[00111] Z is a counterion;
[00112] n is an integer from 0 to 3; and
[00113] the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
[00114 ] The pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein has been unexpectedly found to reduce the development of fibrotic tissues that can occur in irradiated tissue, and/or to improve wound healing, such as in the healing of wounds incurred during surgical procedures. According to certain aspects, the pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein has unexpectedly been found to enhance wound healing in mammalian subjects receiving a surgical procedure, either pre-or postirradiation. For example, the wound healing may be accelerated in subjects receiving the pentaaza macrocyclic ring complex corresponding to Formula (I). Accordingly, the outcomes for patients undergoing surgical procedures following exposure to radiation as a part of a course of radiation therapy, or undergoing surgical procedures prior to such radiation exposure, can be improved.
[00115] In one embodiment, a method of treatment comprises enhancing wound healing before or after a radiation exposure in a mammalian subject in need thereof. According to certain aspects, the method comprises selecting the mammalian subject from among a population of mammalian subjects that has been or will be exposed to radiation. For example, the mammalian subject may be one that has already been exposed to radiation as a part of a course of radiation therapy. As another example, the mammalian subject may be one for which an appropriate treatment includes radiation therapy, and so will be exposed to radiation therapy. Aspects of the method can include administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, prior to, concomitantly with, or after the radiation exposure. For example, the mammalian subject can be exposed to radiation as a part of a course of radiation therapy, and the pentaaza macrocyclic ring complex corresponding to the Formula (I) can be administered before, concomitantly with, or after exposure to radiation as a part of the radiation therapy. As an example, the pentaaza macrocyclic ring complex corresponding to the Formula (I) can be administered before the mammalian subject is exposed to radiation. As another example, the pentaaza macrocyclic ring complex corresponding to the Formula (I) can be administered after the mammalian subject is exposed to radiation. As yet another example, the pentaaza macrocyclic ring complex corresponding to the Formula (I) can be administered on a same day the mammalian subject is exposed to radiation. According to certain embodiments, the exposure to radiation involves exposure of a tissue region containing cancerous cells and/or tumor cells to the radiation, to kill the cells. According to aspects herein, the administration of the pentaaza macrocyclic ring complex corresponding to the Formula (I) to a patient who has been exposed to radiation, or administration in advance of (or concomitantly with) such radiation exposure can provide enhancements in pre- or post-irradiation surgical procesured with respect to wound healing in the mammalian subject.
[00116] According to one embodiment, a method of treatment comprises enhancing wound healing in a mammalian subject prior to or following radiation therapy for treatment of a tumor. According to certain aspects, the method comprises selecting the mammalian subject from among a population of mammalian subjects afflicted with a tumor that is treatable by radiation therapy, and administering to the subject the radiation therapy in combination with a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy. For example, the mammalian subject that is selected may be one that is suffering from a cancer and/or tumor that is treatable by radiation therapy, such as by any method of radiation therapy that is currently known or that becomes known in the future. For example, the mammalian subject may be one suffering from a soft-tissue sarcoma. As another example, the mammalian subject may be one suffering from pancreatic cancer. The method comprising the administration of the pentaaza macrocyclic ring complex of Formula (I) can provide for improved outcomes in any surgical procedures performed post-irradiation.
[ 00117 ] According to yet another embodiment, a method of treatment comprises a method of enhancing wound healing in a mammalian subject afflicted with a tumor that is treatable by surgery and radiation therapy. According to certain embodiments, the method comprises selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and surgery, and administering to the subject radiation therapy in combination with a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy. For example, the mammalian subject that is selected may be one that is suffering from a cancer and/or tumor that is treatable by the combination of radiation therapy and surgical resection to remove the cancer and/or tumor, such as by any method of radiation therapy followed by resection that is currently known or that becomes known in the future. For example, the mammalian subject may be one suffering from a soft-tissue sarcoma. As another example, the mammalian subject may be one suffering from pancreatic cancer. The method comprising the administration of the pentaaza macrocyclic ring complex of Formula (I) can provide for improved outcomes in the surgical procedure performed pre- or post-irradiation. [00118] According to yet another embodiment, a method of treatment comprises a method of enhancing an outcome of tumor treatment in the mammalian subject. The method comprises selecting a predetermined period of time in which to perform surgery following an exposure to radiation administered as a part a radiation therapy to the mammalian subject, and performing surgery on the mammalian subject within the selected predetermined period of time. The predetermined time is selected in relation to whether or not the mammalian subject has received or will receive administration of a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein. For example, in certain embodiments, for mammalian subjects that have received administration of a therapeutically effective amount of the pentaaza macrocyclic ring complex according to Formula (I), or that will receive administration of the pentaaza macrocyclic ring complex, the mammalian subject can be subjected to a surgical procedure during a period of time post-irradiation that is shorter than that for mammalian subjects that do not receive the administration of the therapeutically effective amount of the pentaaza macrocyclic ring complex according to Formula (I). The administration of the pentaaza macrocyclic ring complex according to Formula (I) may, in certain embodiments, reduce fibrosis and preserve the condition of normal (non-cancerous) tissues, such that surgical procedures can be performed shortly after irradiation, without having to wait as long for recovery of the normal tissues post-irradiation. In one embodiment, in a case where the patient has or will receive a pentaaza macrocyclic ring complex of Formula (I), the surgical resection is performed within a first predetermined period of time postirradiation, and in a case where the patient does not received the pentaaza macrocyclic ring complex of Formula (I), the surgical resection is performed within a second predetermined period of time post-irradiation that is longer than the first predetermined period of time. The subject may be one that already has already received administration of the pentaaza macrocyclic ring complex, such as before, simultaneous with, or after exposure to radiation exposure, or that will receive administration of the pentaaza macrocyclic ring complex after exposure to radiation and before, simultaneous with, or after surgery. The predetermined period of time is as measured from a last radiation exposure of the mammalian subject prior to performing the surgical procedure. The predetermined period of time between the last exposure and performing of the surgical procedure can be selected according to factors such as a type of surgical procedure to be performed, an intensity of a radiation dose and/or dose fraction administered to the mammalian subject, an extend of fibrosis of the mammalian subject’s tissue, and/or the type of cancer and/or tumor from which the mammalian subject is suffering, among other factors. In one embodiment, the predetermined period of time in which surgery is performed following irradiation, in a case where the mammalian subject receives administration of the pentaaza macrocyclic ring complex according to Formula (I), is within 1 day, 2 days, 3 day, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, and/or 3 months of the last radiation exposure of the mammalian subject.
[ 00119 ] According to another embodiment, a method of enhancing an outcome of tumor treatment in a mammalian subject comprises selecting a predetermined period of time following surgery in which to expose the mammalian subject radiation administered as a part a radiation therapy to the mammalian subject, in relation to whether or not the mammalian subject has received or will receive administration of a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, and exposing the mammalian subject to radiation within the selected predetermined period of time following surgery. For example, in certain embodiments, for mammalian subjects that have received or will receive administration of a therapeutically effective amount of the pentaaza macrocyclic ring complex according to Formula (I), the mammalian subject can be subjected to radiation exposure during a period of time post-surgery that is shorter than that for mammalian subjects that do not receive the administration of the therapeutically effective amount of the pentaaza macrocyclic ring complex according to Formula (I). The subject may be one that already has received administration of the pentaaza macrocyclic ring complex before, simultaneous with, or after surgery, or that will receive administration of the pentaaza macrocyclic ring complex after surgery and before, simultaneous with, or after radiation exposure. The administration of the pentaaza macrocyclic ring complex according to Formula (I) may, in certain embodiments, reduce fibrosis and preserve the condition of normal (non-cancerous) tissues, such that even when irradiation is performed shortly after surgical procedures, improved wound healing can be provided. In one embodiment, in a case where the patient receives a pentaaza macrocyclic ring complex of formula (I), the expsosure to radiation is performed within a first predetermined period of time post-surgery, and in a case where the patient does not receive the pentaaza macrocyclic ring complex of formula (I), the exposure to radiation is performed within a second predetermined period of time post-surgery that is longer than the first predetermined period of time. The predetermined period of time is as measured from the surgical procedure to a first (or only) radiation exposure of the mammalian subject provided as a course of radiation therapy. The predetermined period of time between the surgical procedure and first exposure can be selected according to factors such as a type of surgical procedure to be performed, an intensity of a radiation dose and/or dose fraction administered to the mammalian subject, an extend of fibrosis of the mammalian subject’s tissue, and/or the type of cancer and/or tumor from which the mammalian subject is suffering, among other factors. In one embodiment, the predetermined period of time in which radiation expsoure is performed following surgery, in a case where the mammalian subject receives administration of the pentaaza macrocyclic ring complex according to Formula (I), is within 1 day, 2 days, 3 day, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, and/or 3 months of the surgical procedure.
[00120] According to yet another embodiment, a method of preparing a mammalian subject for surgery before or after radiation therapy is provided, the method comprising administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to Formula (I) as disclosed herein, prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy. According to yet another embodiment, a method of enhancing wound healing prior to or following tissue resection, in combination with radiation therapy, for treatment of a tumor in a mammalian subject is provided. The method comprises exposing the mammalian subject to radiation as a part of radiation therapy, resecting a region of tissue at a location of the tumor in the mammalian subject, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after the radiation exposure. According to yet another embodiment, a method of enhancing wound healing in a mammalian subject afflicted with a tumor that is treatable by tissue resection and radiation therapy is provided. The method comprises selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and resection of the tumor, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy.
[00121] According to yet another embodiment, a method of treatment can be provided that selectively increases the migration of normal (non-malignant) cells at a wound site, relative to the migration of malignant cells. According to certain aspects, a method of treatment can selectively increase the migration of normal cells relative to the migration of malignant cells following surgery and radiation therapy for treatment of a tumor in a mammalian subject. Aspects of the method comprise exposing the mammalian subject to radiation as a part of the radiation therapy, performing surgery on the mammalian subject, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) prior to, concomitantly with, or after the radiation exposure received as a part of the radiation therapy. The selective increase in migration of normal cells relative to malignant cells can improve outcomes for surgical procedures in terms of wound healing time and recovery, and reductions in wound healing complications.
[00122] According to yet another embodiment, a method of treatment comprises selectively increasing the migration of normal cells relative to the migration of malignant cells in a mammalian subject afflicted with a tumor that is treatable by surgery and radiation therapy, the method comprising selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and surgery, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy. In another embodiment, a method of selectively increasing the migration of normal cells relative to the migration of malignant cells in a mammalian subject following radiation therapy is provided, the method comprising selecting the mammalian subject from among a population of mammalian subjects in need of enhanced wound healing following radiation therapy, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) as disclosed herein, prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy. For example the subject in need of enhanced wound healing may be one that would benefit from shortening the period of time between a last dose of radiation and the surgical procedure (or the time period between a surgical procedure and a following radiation exposure), or that is subject to increased levels of fibroses and/or decreased levels of wound healing, such as due to a type of radiation therapy or surgical procedure performed, a type of cancer being treated and/or other pre-existing health conditions.
[ 00123 ] According to one embodiment, a kit for therapeutic treatment of a mammalian subject is provided. The kit comprises the pentaaza macrocyclic ring complex corresponding to Formula (I) as disclosed herein, and optionally a further anticancer agent. The kit further comprises instructions for administering the therapeutically effective amount of the pentaaza macrocyclic ring complex to perform any of the methods of treatment described herein, such as form example dosing, timing and/or administration instructions for any of the methods. The kit can further comprise additional assays, therapeutic agents, and/or medical instruments for carrying out the methods.
As described above, embodiments of disclosure herein are capable of enhancing wound healing following surgery, such as by accelerating a rate of wound healing in a mammalian subject. Such treatment methods may be beneficial, for example, in the case of a mammalian subject that is suffering from a tumor that is treatable by surgery, and/or suffering from complications associated with the tumor that are treatable by surgery, in which case the ability to enhance the healing of any wounds caused by the surgery can be of substantial medical benefit to the mammalian subject. In one embodiment, the surgery performed on the mammalian subject may be performed to remove all or a part of the tumor by tissue resection. For example, the boundaries of normal versus malignant tissue may be identified, and the malignant tissue may be surgically removed while preserving as much normal tissue as possible. Often, some normal tissue is also removed as a part of the tumor resection, to increase the likelihood that all malignant cells are removed from the tissue site. In other embodiments, surgical procedures may be performed for purposes other than to remove tumor and/or malignant tissues. For example, in some embodiments, surgery can be performed on the mammalian subject for diagnostic purposes and/or to perform a biopsy to determine assess properties of the tumor such as the stage and/or aggressiveness of the tumor, or to determine other tumor phenotypes that may be useful in treatment, such as resistance or conversely susceptibility to treatments with certain active agents or other modalities. Surgical procedures may also be performed to assess the boundary of cancerous versus non-cancerous tissue. According to certain embodiments, the wounding may be concurrent with radiation exposure, such as in a surgical procedure performed concurrently with the radiation exposure. According to another embodiment, the radiation exposure may be intentional, such as in a therapeutic treatment, or may be unintentional, such as via occupational hazard or environmental radiation exposure, or accidental radiation release into the environment. According to yet another embodiment, the mammalian subject may incur a wound concurrently with radiation exposure, either intentionally or unintentionally, including as a part of surgery, and the surgery may be exploratory, definitive, curative, palliative, cosmetic, etc. According to another embodiment, the surgery may be to treat a condition resulting from the radiation exposure performed to treat a tumor, or may be to treat a condition that is unrelated to radiation exposure to treat a tumor.
[00124] In further embodiments, surgery may be performed on the mammalian subject for the treatment of complications associated with the tumor, such as to repair or restore physical structures impacted by the presence of the tumor. In other embodiments, surgical procedures are performed to make improvements in the cosmetic appearance of the mammalian subject, such as for example in a case where the mammalian subject has become somewhat disfigured or otherwise altered in appearance due to the presence of the tumor, or its removal from the mammalian subject.
[00125] In certain embodiments, aspects of the disclosure provide enhanced wound healing in the mammalian subject such that surgical options that were otherwise unfeasible become feasible. For example, it may be possible to operate very shortly after exposure to radiation, or to perform more precise and accurate surgical procedures, than would otherwise be possible. It may also be possible to operate on mammalian subjects that may otherwise have such poor wound healing outcomes that surgical procedures would not be a recommended option. In one embodiment, wound healing is sufficiently enhanced so as to make surgery to resect a tumor more efficient. In another embodiment, wound healing is sufficiently enhanced so as to make surgery to resect a tumor more accurate. In further embodiments, wound healing is sufficiently enhanced so as to improve the surgical outcome and/or recovery of the mammalian subject from the surgical procedure. In one embodiment, the development of fibrotic and/or abnormal tissue post-irradiation is reduced. In yet another embodiment, the condition of normal tissue subjected to radiation exposure is sufficiently preserved such that the normal tissue can be readily differentiated from malignant tissue, such as for purposes of tissue resection. For example, the ability to selectively remove malignant tissue from a mammalian subject while retaining normal tissue may be improved, by retaining normal tissue in a state where it can be differentiated, and readily removed from, malignant tissue, even postirradiation. Aspects of the disclosure may thus reduce the development of fibrotic and/or abnormal tissue that can otherwise interfere with the selective removal of malignant (cancerous) tissue during post-irradiation surgical procedures. According to another embodiment, wound healing may be sufficiently enhanced that improved outcomes are provided even when radiation exposure occurs after a surgical procedure is performed. According to yet another embodiment, the surgical outcome can be improved by making the surgery technically feasible versus embodiments in wich the pentaaza macrocyclic ring complex is not provided. According to yet another embodiment, the surgical outcome can be improved by allowed for more complete resection of the tumor, providing R0 margins, providing reduced convalescence (recovery time) for the patient, reduced infectios or other complications, providing greater resulting functionality in the normal tissue, organ or limb post-surgery, along with other beneficial outcomes and effects. According to another embodiment, aspects of the disclosure can provide for treatment in the case of a non-surgical wounding, such as an accidental or non-therapeutic wound. According to another embodiment, aspects of the disclosure can provide for treatment even in the case where no tumor is being treated, such as in enhanced wound healing and/or enhanced surgical outcomes without providing any cancer treatment (e.g., even without radiation). According to another embodiment, improvements are provided even in the case of non-therapeutic radiation. According to another embodiment, increased migration of normal cells relative to malignant is provided at a wound site, even in the absence of radiation treatment and/or tumor treatment. According to another embodiment, increased migration of normal cells relative to malignant at a tissue site is provided following radiation, even when no surgical procedure is performed and no wound incurred. [ 00126 ] As described above, according to certain embodiments, aspects of the disclosure herein comprise treating a mammalian subject that has been exposed to radiation, such as during a course of radiation therapy. According to yet another embodiment, a mammalian subject is treated that has not yet been subject to radiation exposure, but which subject is selected for exposure to radiation, such as for example as a part of an overall treatment plan. In one embodiment, the mammalian subject is one that has been exposed to radiation within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day as administration of the pentaaza macrocyclic ring complex of Formula (I). In another embodiment, the mammalian subject is one that is selected to be exposed to radiation within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day as administration of the pentaaza macrocyclic ring complex of Formula (I). In yet another embodiment, the mammalian subject is one that has been exposed to radiation within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that surgery is performed on the mammalian subject. In another embodiment, the mammalian subject is one that is selected to be exposed to radiation within 6 months, 3 months, 2 months,
1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that surgery is performed on the mammalian subject. In a further embodiment, the mammalian subject is administered the pentaaza macrocyclic ring complex of Formula (I) within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that surgery is performed on the mammalian subject. In another embodiment, the mammalian subject is selected to have surgery within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that the pentaaza macrocyclic ring complex of Formula (I) is administered.
[ 00127 ] According to certain embodiments, aspects of the disclosure herein comprise performing surgery on the mammalian subject before or after exposure to radiation. For example, the mammalian subject can receive radiation exposure to kill cancer cells, which is followed by a surgical procedure to, e.g. resect the cancerous tissue, for diagnostic or cosmetic purposes, etc. As another example, the mammalian subject can receive radiation exposure to kill any remaining cancer cells, after a surgical procedure to, e.g., resect the cancerous tissue. In certain embodiments, a mammalian subject is subjected to radiation exposure before a surgical procedure, and the mammalian subject is subjected to a further radiation exposure after the surgical procedure. For example, the mammalian subject may be subjected to a first radiation exposure to treat the tumor, before resection of the tumor (or other surgical procedure), and further radiation treatment may be provided following resection to eliminate remaining cancer cells. As another embodiment, a surgical procedure is performed before any radiation exposure, such as prior to a first radiation exposure administered as a part of radiation therapy (or prior to an only radiation exposure administered as a radiation therapy, in case where the therapy involves only a single exposure). For example, the mammalian subject may undergo a surgical procedure to resect the tumor and/or cancerous tissues before any radiation therapy is performed. According to certain aspects, the enhanced wound healing provided according to methods herein, by administering the pentaaza macrocyclic ring complex of Formula (I), can lessen the impact of the post-surgery irradiation on normal tissues, to provide an overall improvement in wound healing following irradiation. In certain aspects, wound healing for other surgical procedures described herein (e.g. diagnostic procedures) may also be improved by administration of the pentaaza macrocyclic ring complex, in cases where such surgical procedures are followed by post-surgical irradiation.
[00128] In one embodiment, aspects of the disclosure comprise administering the pentaaza macrocyclic ring complex according to Formula (I) as disclosed herein before subjecting the mammalian subject to radiation exposure. In yet another embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered after subjecting the mammalian subject to radiation exposure.
According to another embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered concomitantly with subjecting the mammalian subject to radiation exposure. According to another embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered on a same day as subjecting the mammalian subject to radiation exposure.
[00129] According to another embodiment, aspects of the disclosure herein comprise administering the pentaaza macrocyclic ring complex according to Formula (I) as disclosed herein, before performing surgery on the mammalian subject.
According to another embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered after performing surgery on the mammalian subject According to yet another embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered concomitantly with performing surgery on the mammalian subject. According to another embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered on a same day as performing surgery on the mammalian subject.
[ 00130 ] According to another embodiment, aspects of the disclosure herein comprises a course of radiation therapy comprising administration of a plurality of radiation exposures to the mammalian subject, and wherein each of the plurality of radiation exposures comprises a dose fraction of an overall dosing regimen. According to a further embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered prior to, concomitantly with, or after administration of a dose fraction of the overall dosing regimen. According to yet another embodiment, the pentaaza macrocyclic ring complex according to Formula (I) is administered on a same day as a dose fraction of the overall dosing regimen. According to certain embodiments, surgery is performed prior to, concomitantly with, or after administration of a dose fraction of the overall dosing regimen. In another embodiment, surgery is performed on a same day as administration of a dose fraction of the overall dosing regimen. In yet another embodiment, a course of radiation therapy is provided that comprises administration of a plurality of doses of radiation, with each dose optionally comprising a plurality of dose fractions.
[ 00131 ] In certain embodiments, aspects of the disclpsure herein comprise radiation exposure that is administered as part of a course of radiation therapy comprising any selected from the group consisting of gamma irradiation, proton therapy, heavy ion therapy, brachytherapy, radionuclide therapy, conformal radiation therapy, intensity modulated radiation therapy, stereotactic body radiation therapy, stereoablative radiation therapy, and gamma knife therapy, whether delivered as standard fractionation, hypofractionation, accelerated fractionation or decelerated fractionation and variations thereof. In further embodiments, the radiation therapy comprises one or more radiation exposures comprising at least 4 Gy of radiation, at least 8 Gy of radiation, at least 10 Gy of radiation, at least 12 Gy of radiation, at least 16 Gy of radiation, at least 18 Gy of radiation, at least 20 Gy of radiation, at least 25 Gy of radiation, at least 30 Gy of radiation, at least 35 Gy of radiation, at least 40 Gy of radiation, at least 45 Gy of radiation, at least 50 Gy of radiation, at least 55 Gy of radiation, and/or at least 60 Gy of radiation.
[00132] According to yet another embodiment, methods of treatment can comprise administration of a further anti-cancer agent, such as a chemotherapeutic agent. Methods of treatment according to embodiments herein can be provide for the treatment of a mammalian subject afflicted with a tumor comprising a cancer selected from the group consisting of soft tissue sarcoma, breast cancer, prostate cancer, testicular cancer, glioma, glioblastoma, head and neck cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, desmoid tumors, pancreatic carcinoma, melanoma, and renal cell carcinoma, and other cancers.
Transition Metal Pentaaza Macrocyclic Ring Complex
[00133] In one embodiment, the pentaaza macrocyclic ring complex corresponds to the complex of Formula (I):
Figure imgf000032_0001
wherein
M is Mn2+ or Mn3+;
R1, R2, R'2, R3, R4, R5, R'5, R6, Re, R7, Re, R9, R'9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO 2NR11R12, -N(ORii)(Ri2), -P(0)(ORii)(ORi2), -P(0)(ORH )(RI2), and -0P(0)(0Rii)(0Ri2), wherein Rn and R12 are independently hydrogen or alkyl;
U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
[00134 ] As noted above in connection with the pentaaza macrocyclic ring complex of Formula (I), M is Mn2+ or Mn3+. In one particular embodiment in which the pentaaza macrocyclic ring complex corresponds to Formula (I), M is Mn2+. In another particular embodiment in which the pentaaza macrocyclic ring complex corresponds to Formula (I), M is Mn3+.
[00135] In the embodiments in which one or more of R1, R2, R'2, R3, R4, Rs, R's, R6, Re, R7, Re, R9, R'9, and R10 are hydrocarbyl, for example, suitable hydrocarbyl moieties include, but are not limited to alkenyl, alkenylcycloalkenyl, alkenylcycloalkyl, alkyl, alkylcycloalkenyl, alkylcycloalkyl, alkynyl, aralkyl, aryl, cycloalkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylcycloalkyl, cycloalkenylalkyl, and aralkyl. In one embodiment, Ri, R2, R'2, R3, R4, R5, R'5, R6, Re, R7, Re, R9, R'9, and Rio are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclyl. More preferably in this embodiment, R1, R2, R'2, R3, R4, Rs, R's, R6, R'6, R7, Re, R9, R'9, and R10 are independently hydrogen or lower alkyl ( e.g ., C1-C6 alkyl, more typically C1-C4 alkyl). Thus, for example, R1, R2, R'2, R3, R4, Rs, R's, R6, R'6, R7, Re, R9, R'9, and R10 may be independently hydrogen, methyl, ethyl, propyl, or butyl (straight, branched, or cyclic). In one preferred embodiment, R1, R2, R'2, R3, R4, Rs, R's, R6, R'6, R7, Re, R9, R'9, and R10 are independently hydrogen or methyl.
[00136] In one preferred embodiment in which the pentaaza macrocyclic ring complex corresponds to Formula (I), R1, R2, R'2, R3, R4, Rs, R's, R7, Re, R9, R'9, and R10 are each hydrogen and one of R6 and R'6 is hydrogen and the other of R6 and R'6 is methyl. In this embodiment, for example, R1, R2, R'2, R3, R4, Rs, R's, R6, R7, Re, R9, R'9, and R10 may each be hydrogen while R'6 is methyl. Alternatively, for example, R1, R2, R'2, R3, R4, Rs, R's, R'6, R7, Re, R9, R'9, and R10 may each be hydrogen while R6 is methyl. In another preferred embodiment in which the pentaaza macrocyclic ring complex corresponds to Formula (I), R1, R3, R4, Rs, R's, R'6, R7, Re, and R10 are each hydrogen, one of R2 and R'2 is hydrogen and the other of R2 and R'2 is methyl, and one of R9 and R'9 is hydrogen and the other of R9 and R'9 is methyl. In this embodiment, for example, R1, R'2, R3, R4, Rs, R's, R7, Re, R9, and R10 may each be hydrogen while R2 and R'9 are methyl. Alternatively, for example, R1, R2, R3, R4, Rs, R's, R7, Re, R'9, and R10 may each be hydrogen while R'2 and R9 are methyl. In another embodiment in which the pentaaza macrocyclic ring complex corresponds to Formula (I), R1, R2, R'2,
R3, R4, Rs, R's, R6, R'6, R7, Re, R9, R'9, and R10 are each hydrogen.
[00137] In certain embodiments the U and V moieties are independently substituted or unsubstituted fused cycloalkyl moieties having 3 to 20 ring carbon atoms, more preferably 4 to 10 ring carbon atoms. In a particular embodiment, the U and V moieties are each trans-cyclohexanyl fused rings.
[00138] In certain embodiments the W moiety is a substituted or unsubstituted fused heteroaromatic moiety. In a particular embodiment, the W moiety is a substituted or unsubstituted fused pyridino moiety. Where W is a substituted fused pyridino moiety, for example, the W moiety is typically substituted with a hydrocarbyl or substituted hydrocarbyl moiety ( e.g ., alkyl, substituted alkyl) at the ring carbon atom positioned para to the nitrogen atom of the heterocycle. In a one preferred embodiment, the W moiety is an unsubstituted fused pyridino moiety.
[00139] As noted above, X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof (for example benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion). For example, X and Y may be selected from the group consisting of halo, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinous acid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite, tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate, citrate, ascorbate, saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions of ion exchange resins, or the corresponding anions thereof, among other possibilities.
In one embodiment, X and Y if present, are independently selected from the group consisting of halo, nitrate, and bicarbonate ligands. Fo p , , and Y, if present, are halo ligands, such as chloro ligands. [00140] Furthermore, in one embodiment X and Y correspond to -O-C(O)-X1, where each X1 is -C(X2)(X3)(X4), and each X1 is independently substituted or unsubstituted phenyl or -C(-X2)(-X3)(-X4); each X2 is independently substituted or unsubstituted phenyl, methyl, ethyl or propyl; each X3 is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, - X5C(=O)R13 where X5 is NH or O, and R13 is C1-C18 alkyl, substituted or unsubstituted aryl or C1-C18 aralkyl, or -OR14, where R14 is C1-C18 alkyl, substituted or unsubstituted aryl or C1-C18 aralkyl, or together with X4 is (=O); and each X4 is independently hydrogen or together with X3 is (=O). [00141] In yet another embodiment, X and Y are independently selected from the group consisting of charge-neutralizing anions which are derived from any monodentate or polydentate coordinating ligand and a ligand system and the corresponding anion thereof; or X and Y are independently attached to one or more of R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10. [00142] In the pentaaza macrocyclic ring complex corresponding to Formula (I), Z is a counterion (e.g., a charge-neutralizing anion), wherein n is an integer from 0 to 3. In general, Z may correspond to counterions of the moieties recited above in connection for X and Y. [00143] In combination, among certain preferred embodiments are pentaaza macrocyclic ring complexes corresponding to Formula (I) wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen or lower alkyl; U and V are each trans-cyclohexanyl fused rings; W is a substituted or unsubstituted fused pyridino moiety; X and Y are ligands; and Z, if present, is a charge-neutralizing anion.
[00144] More preferably in these embodiments, M is Mn2+; R1 R, 2, R'2, R3, R4, R5, R'5, R6, Re, R7, Re, R9, R'9, and R10 are independently hydrogen or methyl; U and V are each trans-cyclohexanyl fused rings; W is an unsubstituted fused pyridino moiety; and X and Y are independently halo ligands (e.g., fluoro, chloro, bromo, iodo). Z, if present, may be a halide anion (e.g., fluoride, chloride, bromide, or iodide).
[00145] In yet another embodiment, the pentaaza macrocyclic ring complex is represented by Formula (II) below:
Figure imgf000037_0001
wherein
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; and
RA, RB, RC, and RD are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -S O2NR11R12, -N(ORii)(Ri2), -P(0)(ORii)(ORi2), -P(0)(ORH)(RI2), and -OP(0)(ORii)(ORi2), wherein Rn and R12 are independently hydrogen or alkyl. [00146] Furthermore, in one embodiment, the pentaaza macrocyclic ring complex is represented by Formula (III) or Formula (IV):
Figure imgf000038_0001
wherein
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; and
RA, RB, RC, and RD are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -ORii, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO 2NR11R12, -N(ORii)(Ri2), -P(0)(ORii)(ORi2), -P(0)(ORH)(RI2), and -OP(0)(ORii)(ORi2), wherein Rn and R12 are independently hydrogen or alkyl.
[00147] In yet another embodiment, the pentaaza macrocyclic ring complex is a compound represented by a formula selected from the group consisting of Formulae
(V)-(XVI):
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
[00148] In one embodiment, X and Y in any of the formulae herein are independently selected from the group consisting of fluoro, chloro, bromo and iodo anions. In yet another embodiment, X and Y in any of the formulae herein are independently selected from the group consisting of alkyl carboxylates, aryl carboxylates and arylalkyl carboxylates. In yet another embodiment, X and Y in any of the formulae herein are independently amino acids. [00149] In one embodiment, the pentaaza macrocyclic ring complex has the following Formula (IA):
Figure imgf000042_0001
wherein M is Mn2+ or Mn3+; R1A, R1B, R2, R3, R4A, R4B, R5, R6, R7A, R7B, R8, R9, R10A, and R10B are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety independently selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -C(=O) NR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R12, -N(OR11)(R12), -P(=O)(OR11)(OR 12), -P(=O)(OR11)(R12), and -OP(=O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and R5 and R6 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent; wherein each Xi is independently substituted or unsubstituted phenyl or -C(-X2)(-X3)(-X4); each X2 is independently substituted or unsubstituted phenyl or alkyl; each X3 is independently hydrogen, hydroxyl, alkyl, amino, -X5C(=0)Ri3 where
X5 is NH or O, and R13 is C1-C18 alkyl, substituted or unsubstituted aryl or C1-C18 aralkyl, or -OR14, where R14 is C1-C1 ealkyl, substituted or unsubstituted aryl or Ci- C18 aralkyl, or together with X4 is (=0); each X4 is independently hydrogen or together with X3 is (=0); and the bonds between the transition metal M and the macrocyclic nitrogen atoms and the bonds between the transition metal M and the oxygen atoms of the axial ligands -0C(=0)Xi are coordinate covalent bonds.
[00150] In one embodiment, within Formula (IA), and groups contained therein, in one group of compounds Xi is -C(-X2)(-X3)(-X4) and each X2, X3, and X4, in combination, corresponds to any of the combinations identified in the following table:
Figure imgf000043_0001
[00151] Furthermore, in another embodiment, within Formula (IA), and groups contained therein, in one group of compounds Xi is -C(-X2)(-X3)(-X4), and X3 is - XsC(=0)Ri3, such that the combinations of X2, X3 and X4 include any of the combinations identified in the following table:
Figure imgf000044_0002
where R13 is C1-C18 alkyl, substituted or unsubstituted aryl or C1-C18 aralkyl, or - ORi4, where R14 is C1-C18 alkyl, substituted or unsubstituted aryl or C1-C18 aralkyl.
[00152] In one embodiment, the pentaaza macrocyclic ring complex corresponding to Formula (IA) is one of the complexes Formula (IE), such as (IERI), (IESI), (IER2), (IES2), (IERS), or (IEs3):
Figure imgf000044_0001
Figure imgf000045_0001
wherein
M is Mn+2 or Mn+3; each Xi is independently substituted or unsubstituted phenyl or -C(X2)(X3)(X4); each X2 is independently substituted or unsubstituted phenyl, methyl, ethyl, or propyl; each X3 is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, or together with X4 is =0; each X4 is independently hydrogen or together with X3 is =0; and the bonds between the manganese and the macrocyclic nitrogen atoms and the bonds between the manganese and the oxygen atoms of the axial ligands -OC(0)Xi are coordinate covalent bonds.
[00153] In one embodiment, each Xi is -C(X2)(X3)(X4) and each -C(X2)(X3)(X4) corresponds to any of combinations 1 to 9 appearing in the table for Formula (IA) above.
[00154 ] In yet another embodiment, the X and Y in pentaaza macrocyclic ring complex of Formula (I) correspond to the ligands in Formulas (IA) or (IE). For example, X and Y in the complex of Formula (I) may correspond to -0-C(0)-Xi, where Xi is as defined for the complex of Formula (IA) and (IE) above.
[00155] In one embodiment, the pentaaza macrocyclic ring complexes corresponding to Formula (I) (e.g., of Formula (I) or any of the subsets of Formula (I) corresponding to Formula (ll)-(XIV), (IA) and (IE)), can comprise any of the following structures:
Figure imgf000046_0001
Figure imgf000047_0001
.
Figure imgf000048_0001
[00156] In one embodiment, the pentaaza macrocyclic ring complexes for use in the methods and compositions described herein include those corresponding to Formulae (2), (3), (4), (5), (6), and (7):
Figure imgf000049_0001
wherein X and Y in each of Formulae (2), (3), (4), (5), (6), and (7) are independently ligands. For example, according to one embodiment, the pentaaza macrocyclic ring complex for use in the methods and compositions described herein include those corresponding to Formulae (2), (3), (4), (5), (6), and (7) with X and Y in each of these formulae being halo, such as chloro. Alternatively, X and Y may be ligands other than chloro, such as any of the ligands described above. [00157] In another embodiment, the pentaaza macrocyclic ring complex corresponds to Formula (6) or Formula (7):
Figure imgf000050_0001
[00158] The chemical structures of 6 (such as the dichloro complex form described, for example, in Riley, D.P., Schall, O.F., 2007, Advances in Inorganic
Chemistry, 59: 233-263) and of 7 herein (such as the dichloro complex form of 7), are identical except that they possess mirror image chirality; that is, the enantiomeric structures are non-superimposable.
[00159] For example, the pentaaza macrocyclic ring complex may correspond to at least one of the complexes below:
Figure imgf000050_0002
[00160] In yet another embodiment, the pentaaza macrocyclic ring complex may correspond to at least one of the complexes below, and/or an enantiomer thereof:
Figure imgf000051_0001
[00161] In one embodiment, the enantiomeric purity of the pentaaza macrocyclic ring complex is greater than 95%, more preferably greater than 98%, more preferably greater than 99%, and most preferably greater than 99.5%. As used herein, the term “enantiomeric purity” refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its enantiomer. In one embodiment, the diastereomeric purity of the pentaaza macrocyclic ring complex is greater than 98%, more preferably greater than 99%, and most preferably greater than 99.5%. As used herein, the term “diastereomeric purity” refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its diastereomers. Methods for determining diastereomeric and enantiomeric purity are well-known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers, such as high performance liquid chromatography (HPLC). Similarly, enantiomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its enantiomer. Examples of suitable analytical methods for determining enantiomeric purity include, without limitation, optical rotation of plane-polarized light using a polarimeter, and HPLC using a chiral column packing material.
[ 00162 ] In one embodiment, a therapeutically effective amount of the pentaaza macrocyclic ring complex may be an amount sufficient to provide a peak plasma concentration of at least 0.1 mM when administered to a patient. For example, in one embodiment, the pentaaza macrocyclic ring complex may be administered in an amount sufficient to provide a peak plasma concentration of at least 1 pM when administered to a patient. In yet another embodiment, the pentaaza macrocyclic ring complex may be administered in an amount sufficient to provide a peak plasma concentration of at least 10 pM when administered to a patient. Generally, the pentaaza macrocyclic ring complex will not be administered in an amount that would provide a peak plasma concentration greater than 40 pM when administered to a patient. For example, the pentaaza macrocyclic ring complex may be administered in an amount sufficient to provide a peak plasma concentration in the range of from 0.1 pM to 40 pM in a patient. As another example, the pentaaza macrocyclic ring complex may be administered in an amount sufficient to provide a peak plasma concentration in the range of from 0.5 pM to 20 pM in a patient. As another example, the pentaaza macrocyclic ring complex may be administered in an amount sufficient to provide a peak plasma concentration in the range of from 1 pM to 10 pM in a patient.
[ 00163 ] In yet another embodiment, a dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be at least 0.1 mg/kg, such as at least 0.2 mg/kg. For example, the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be at least 0.5 mg/kg. As another example, the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be at least 1 mg/kg. In another example, the pentaaza macrocyclic compound that is administered per kg body weight may be at least 2 mg/kg, such as at least 3 mg/kg, and even at least about 15 mg/kg, such as at least 24 mg/kg and even at least 40 mg/kg. Generally, the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient will not exceed 1000 mg/kg. For example the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be in the range of from 0.1 to 1000 mg/kg, such as from 0.2 mg/kg to 40 mg/kg, such as 0.2 mg/kg to 24 mg/kg, and even 0.2 mg/kg to 10 mg/kg. As another example, the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight may be in a range of from 1 mg/kg to 1000 mg/kg, such as from 3 mg/kg to 1000 mg/kg, and even from 5 mg/kg to 1000 mg/kg, such as 10 mg/kg to 1000 mg/kg. As another example, the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight may be in a range of from 2 mg/kg to 15 mg/kg. As yet another example, the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight may be in a range of from 3 mg/kg to 10 mg/kg. As another example, the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be in the range of from 0.5 to 5 mg/kg. As yet a further example, the dose of the pentaaza macrocyclic ring complex that is administered per kg body weight of the patient may be in the range of from 1 to 5 mg/kg.
[00164 ] In one embodiment, the dosages and/or plasma concentrations discussed above may be particularly suitable for the pentaaza macrocyclic ring complex corresponding to GC4419, although they may also be suitable for other pentaaza macrocyclic ring complexes. In addition, one of ordinary skill in the art would recognize how to adjust the dosages and/or plasma concentrations based on factors such as the molecular weight and/or activity of the particular compound being used. For example, for a pentaaza macrocyclic ring complex having an activity twice that of GC4419, the dosage and/or plasma concentration may be halved, or for a pentaaza macrocyclic ring complex having a higher molecular weight that GC4419, a correspondingly higher dosage may be used.
[00165] The dosing schedule of the pentaaza macrocyclic ring complex can similarly be selected according to the intended treatment. For example, in one embodiment, a suitable dosing schedule can comprise dosing a patient at least once per week, such as at least 2, 3, 4, 5, 6 or 7 days per week (e.g., daily), during a course of treatment. As another example, in one embodiment, the dosing may be at least once a day (qd), or even at least twice a day (bid).
Other Cancer Therapies
[00166] In one embodiment, the treatment provided herein can further comprise treatment with another therapy other than those specifically described above, such as for example one or more of immunotherapy and/or treatment with an anticancer agent such as a chemotherapeutic treatment. Further detailed description of radiation therapies and anti-cancer therapeutic agents such as chemotherapeutic agents suitable for the treatment of cancer are provided below. According to certain embodiments, optional anti-cancer therapeutic agents can comprise an ascorbate compound such as ascorbic acid, and ascorbic acid ester, and/or salts thereof.
[00167] In one embodiment, a radiation therapy can be administered concomitantly with administration of the pentaaza macrocyclic ring complex and optional anti-cancer therapeutic agent. For example, one or more of the optional anticancer therapeutic agent and pentaaza macrocyclic ring complexes may be administered during a course of radiation therapy, such as in between, before or after, or on the same day as exposure to radiation, such that the subject is receiving radiation therapy concurrently with one or more of the anti-cancer therapeutic agent and pentaaza macrocyclic ring complex.
METHODS OF ADMINISTRATION
[00168] According to one embodiment, the optional anti-cancer therapeutic agent, is administered as a co-therapy or combination therapy with the pentaaza macrocyclic ring complex. Co-therapy or combination therapy according to the methods described herein is intended to embrace administration of each compound in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of these active agents or in multiple, separate capsules for each agent, or single or multiple parenteral administrations, or other routes of administration and dosage forms. When administered in combination, therefore, the therapeutic agents (/. e. , the pentaaza macrocyclic ring complex and/or the anti-cancer therapeutic agent) can be formulated as separate compositions that are administered at the same time or sequentially at different times, or the therapeutic agents can be given as a single composition. Pharmaceutical compositions and formulations are discussed elsewhere herein.
[00169] According to certain embodiments, it is not necessary that the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent be administered simultaneously or essentially simultaneously; the agents and compounds may be administered in sequence. The advantage of a simultaneous or essentially simultaneous administration, or sequential administration, is well within the determination of the skilled clinician. For instance, while a pharmaceutical composition or formulation comprising an anti-cancer therapeutic agent may be advantageous for administering first in the combination for one particular treatment, prior to administration of the pentaaza macrocyclic ring complex, prior administration of the pentaaza macrocyclic ring complex may be advantageous in another treatment. It is also understood that the combination of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent may be used in conjunction with other methods of treating cancer (typically cancerous tumors). It is further understood that another active agent, such as a cytostatic or quiescent agent, or antiemetic agent, if any, may be administered sequentially or simultaneously with any or all of the other synergistic therapies.
[00170] Thus, embodiments of the therapeutic method include wherein a pentaaza macrocyclic ring complex and an optional anti-cancer therapeutic agent, and combinations thereof, are administered simultaneously or sequentially. For instance, aspects of the present disclosure encompass a method for the treatment of cancer wherein a pentaaza macrocyclic ring complex and an anti-cancer therapeutic agent are administered simultaneously or sequentially. Other active agents can also be administered simultaneously or sequentially with the pentaaza macrocyclic ring complex and the anti-cancer therapeutic agent.
[00171] As noted above, if the pentaaza macrocyclic ring complex and the anticancer therapeutic agent are not administered simultaneously or essentially simultaneously, then the initial order of administration of the components may be varied. Thus, for example, the anti-cancer therapeutic agent may be administered first, followed by the administration of the pentaaza macrocyclic ring complex; or the pentaaza macrocyclic ring complex may be administered first, followed by the administration of the anti-cancer therapeutic agent. This alternate administration may be repeated during a single treatment protocol. Other sequences of administration to exploit the effects described herein are contemplated, and other sequences of administration of other active agents can also be provided.
[00172] In one embodiment, the subject is pre-treated with an optional anticancer therapeutic agent, followed by administration of the pentaaza macrocyclic ring complex, or vice versa. In accordance with such embodiments, the pentaaza macrocyclic ring complex may be administered at least 1 hour, and even at least 3 days, after administration of the anti-cancer therapeutic agent, or vice versa. For example, in one embodiment, the pentaaza macrocyclic ring complex is administered between 1 hour and 3 days after administration of the anti-cancer therapeutic agent, or vice versa. In another embodiment, for example, the pentaaza macrocyclic ring complex is administered between 1 hour and 1 day after administration of the anticancer therapeutic agent, or vice versa. For example, the pentaaza macrocyclic ring complex may be administered within 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, one week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 9 weeks, 10 weeks or 12 weeks after administration of the anti-cancer therapeutic agent, or vice versa. In these and other embodiments, the anticancer therapeutic agent may be administered in multiple doses leading up to administration of the pentaaza macrocyclic ring complex, or vice versa.
[00173] Alternatively, the subject may be pre-treated with the pentaaza macrocyclic ring complex, followed by administration of the anti-cancer therapeutic agent, or vice versa. In accordance with such embodiments, the pentaaza macrocyclic ring complex may be administered within at least 1 plasma half-life of the anti-cancer therapeutic agent, such as within 4 plasma half-lives of the anti-cancer therapeutic agent, or vice versa. For example, the pentaaza macrocyclic ring complex may be administered within 1 , 2, or 3 plasma half-lives of the other anti-cancer therapeutic agent, or vice versa.
[00174 ] In other alternative embodiments, the subject may be pre-treated with the anti-cancer therapeutic agent, followed by administration of the pentaaza macrocyclic ring complex, which is further followed by one or more additional administrations of the anti-cancer therapeutic agent, or vice versa. For example, the subject could be pre-treated with a dose of anti-cancer therapeutic agent, followed by administration of a dose of pentaaza macrocyclic ring complex, which is then followed by the administration of additional (or partial) dose of the same or different anti-cancer therapeutic agent, which may be further followed by another dose of pentaaza macrocyclic ring complex. Further, the subject could be pre-treated with a partial or full dose of pentaaza macrocyclic ring complex, followed by administration of an anti-cancer therapeutic agent, which is then followed by administration of an additional (or partial) dose of pentaaza macrocyclic complex.
[00175] As described in further detail below, combinations as described herein may also be co-administered with other well-known therapeutic agents that are selected for their particular usefulness against the condition that is being treated. Combinations may alternatively be used sequentially with known pharmaceutically acceptable agent(s) when a multiple combination formulation is inappropriate.
[00176] In one embodiment, the pentaaza macrocyclic ring complex, and the optional anti-cancer therapeutic agent, can generally be administered according to therapeutic protocols that may be known for these agents. For example, the administration of the pentaaza macrocyclic ring complex can be varied depending on the disease being treated and the effects of pentaaza macrocyclic ring complex on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents (i.e., pentaaza macrocyclic ring complex, and optionally the anti-cancer therapeutic agent) on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.
[00177] Also, in general, the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent do not have to be administered in the same pharmaceutical composition, and may, because of different physical and chemical characteristics, have to be administered by different routes. For example, the pentaaza macrocyclic ring complex may be administered orally to generate and maintain good blood levels thereof, while the anti-cancer therapeutic agent may be administered intravenously or via transfusion, or vice versa. The mode of administration may include, where possible, in the same pharmaceutical composition, or in separate pharmaceutical compositions ( e.g ., two or three separate compositions). Furthermore, once the initial administration has been made, then based upon the observed effects, the dosage, modes of administration and times of administration can be modified.
[00178] The particular choice of pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent, and other related therapies (such as radiation, immunotherapy, or other chemotherapies), will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.
[00179] Thus, in accordance with experience and knowledge, the practicing physician may modify each protocol for the administration of a component (the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent) of the treatment according to the individual patient's needs, as the treatment proceeds.
[00180] The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of disease-related symptoms, inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help judge effectiveness of treatment.
[00181] The products of which any combination is composed may be administered simultaneously, separately or spaced out over a period of time so as to obtain the maximum efficacy of the combination; it being possible for each administration to vary in its duration from a rapid administration to a relatively continuous perfusion of either component (in separate formulations or in a single formulation). As a result, for the purposes of the present disclosure, the combinations are not exclusively limited to those which are obtained by physical association of the constituents, but also to those which permit a separate administration, which can be simultaneous or spaced out over a period of time.
[00182] Accordingly, administration of the components described herein can occur as a single event or over a time course of treatment. For example, the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent can be administered (simultaneously or in sequence) hourly ( e.g ., every hour, every two hours, every three hours, every four hours, every five hours, every six hours, and so on), daily, weekly, bi-weekly, or monthly. For treatment of acute conditions, the time course of treatment may be at least several hours or days. Certain conditions could extend treatment from several days to several weeks. For example, treatment could extend over one week, two weeks, or three weeks. For more chronic conditions, treatment could extend from several weeks to several months, a year or more, or the lifetime of the patient in need of such treatment. Alternatively, the compounds and agents can be administered hourly, daily, weekly, bi-weekly, or monthly, for a period of several weeks, months, years, or over the lifetime of the patient as a prophylactic measure.
[00183] The dose or amount of pharmaceutical compositions including the pentaaza macrocyclic ring complex, and the optional anti-cancer therapeutic agent administered to the patient should be an effective amount for the intended purpose, i.e., treatment or prophylaxis of one or more of the diseases, pathological disorders, and medical conditions discussed herein, including wound healing and cancer treatment. Generally speaking, the effective amount of the composition administered can vary according to a variety of factors such as, for example, the age, weight, sex, diet, route of administration, and the medical condition of the patient in need of the treatment. Specifically preferred doses are discussed more fully herein. It will be understood, however, that the total daily usage of the compositions described herein will be decided by the attending physician or veterinarian within the scope of sound medical judgment.
[00184] As noted above, according to certain embodiments, combinations of components can be co-administered (via a co-formulated dosage form or in separate dosage forms administered at about the same time). The combinations of components can also be administered separately, at different times, with each agent in a separate unit dosage form. Numerous approaches for administering the optional anti-cancer therapeutic agent and pentaaza macrocyclic ring complex can be readily adapted for use in the present disclosure. The pharmaceutical compositions may be delivered orally, e.g., in a tablet or capsule unit dosage form, or parenterally, e.g., in an injectable unit dosage form, or by some other route. For systemic administration, for example, the pharmaceutical composition can be administered by, for example, intravenous infusion (continuous or bolus). The compositions can be used for any therapeutic or prophylactic treatment where the patient benefits from treatment with the pentaaza macrocyclic ring complex.
[00185] The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound(s) employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound(s) employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound(s) employed and like factors well known in the medical and/or veterinary arts. If desired, the effective daily doses may be divided into multiple doses for purposes of administration. Consequently, single dose compositions may contain such amounts or submultiples to make up the daily dose.
[00186] In one embodiment, suitable or preferred doses for each of the components are employed in the methods or included in the compositions described herein. Preferred dosages for the pentaaza macrocyclic ring complex, for instance, may be within the range of 10 to 500 mg per patient per day. However, the dosage may vary depending on the dosing schedule, which can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit the disclosure and represent exemplary dose ranges. The most preferred dosage will be tailored to the individual subject, taking into account, among other things, the particular combinations employed, and the patient's age, sex, weight, physical condition, diet, etc., as is understood and determinable by one of ordinary skill in the art without undue experimentation.
[00187] Treatment of cancer, or cancer therapies, described herein includes achieving a therapeutic benefit, however the therapy may also be administered to achieve a prophylactic benefit. Therapeutic benefits generally refer to at least a partial eradication or amelioration of the underlying disorder being treated. For example, in a cancer patient, therapeutic benefit includes (partial or complete) eradication or amelioration of the underlying cancer. Also, a therapeutic benefit is achieved with at least partial, or complete, eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding the fact that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, a method of the disclosure may be performed on, or a composition of the invention administered to, a patient at risk of developing cancer, or to a patient reporting one or more of the physiological symptoms of such conditions, even though a diagnosis of the condition may not have been made.
Cancer Treatment Methods
[00188] In general, any subject having, or suspected of having, a cancer or other proliferative disorder may be treated using the compositions and methods of the present disclosure. Subjects receiving treatment according to the methods described herein are mammalian subjects, and typically human patients. Other mammals that may be treated according to the present disclosure include companion animals such as dogs and cats, farm animals such as cows, horses, and swine, as well as birds and more exotic animals (e.g., those found in zoos or nature preserves). In one embodiment of the disclosure, a method is provided for the treatment of cancerous tumors, particularly solid tumors. Advantageously, the methods described herein may reduce the development of tumors, reduce tumor burden, or produce tumor regression in a mammalian host. Cancer patients and individuals desiring cancer prophylaxis can be treated with the compositions and methods described herein.
[00189] Cancer and tumors generally refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. By means of the pharmaceutical compositions and methods of the present disclosure, various tumors can be treated such as tumors of the breast, heart, lung, small intestine, colon, spleen, kidney, bladder, head and neck, ovary, prostate, brain, pancreas, skin, bone, bone marrow, blood, thymus, uterus, testicles, cervix, and liver.
[00190] In one embodiment, the tumor or cancer is chosen from adenoma, angio-sarcoma, astrocytoma, epithelial carcinoma, germinoma, glioblastoma, glioma, hamartoma, hemangioendothelioma, hemangiosarcoma, hematoma, hepatoblastoma, leukemia, lymphoma, medulloblastoma, melanoma, neuroblastoma, osteosarcoma, retinoblastoma, rhabdomyosarcoma, sarcoma, and teratoma. The tumor can be chosen from acral lentiginous melanoma, actinic keratoses, adenocarcinoma, adenoid cycstic carcinoma, adenomas, adenosarcoma, adenosquamous carcinoma, astrocytic tumors, bartholin gland carcinoma, basal cell carcinoma, bronchial gland carcinomas, capillary, carcinoids, carcinoma, carcinosarcoma, cavernous, cholangio-carcinoma, chondosarcoma, choriod plexus papilloma/carcinoma, clear cell carcinoma, cystadenoma, endodermal sinus tumor, endometrial hyperplasia, endometrial stromal sarcoma, endometrioid adenocarcinoma, ependymal, epitheloid, Ewing's sarcoma, fibrolamellar, focal nodular hyperplasia, gastrinoma, germ cell tumors, glioblastoma, glucagonoma, hemangiblastomas, hemangioendothelioma, hemangiomas, hepatic adenoma, hepatic adenomatosis, hepatocellular carcinoma, insulinoma, intaepithelial neoplasia, interepithelial squamous cell neoplasia, invasive squamous cell carcinoma, large cell carcinoma, leiomyosarcoma, lentigo maligna melanomas, malignant melanoma, malignant mesothelial tumors, medulloblastoma, medulloepithelioma, melanoma, meningeal, mesothelial, metastatic carcinoma, mucoepidermoid carcinoma, neuroblastoma, neuroepithelial adenocarcinoma nodular melanoma, oat cell carcinoma, oligodendroglial, osteosarcoma, pancreatic, papillary serous adeno-carcinoma, pineal cell, pituitary tumors, plasmacytoma, pseudo-sarcoma, pulmonary blastoma, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, serous carcinoma, small cell carcinoma, soft tissue carcinomas, somatostatin-secreting tumor, squamous carcinoma, squamous cell carcinoma, submesothelial, superficial spreading melanoma, undifferentiated carcinoma, uveal melanoma, verrucous carcinoma, vipoma, well differentiated carcinoma, and Wilm's tumor.
[00191] Thus, for example, the present disclosure provides methods for the treatment of a variety of cancers, including, but not limited to, the following: carcinoma including that of the bladder (including accelerated and metastatic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and nonsmall cell lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burketts lymphoma; hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias, myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia; tumors of the central and peripheral nervous system including astrocytoma, neuroblastoma, glioma, and schwannomas; tumors of mesenchymal origin including fibrosarcoma, rhabdomyoscarcoma, and osteosarcoma; and other tumors including melanoma, xenoderma pigmentosum, keratoactanthoma, seminoma, thyroid follicular cancer, and teratocarcinoma.
[00192] For example, particular leukemias that can be treated with the compositions and methods described herein include, but are not limited to, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, and undifferentiated cell leukemia.
[00193] Lymphomas can also be treated with the compositions and methods described herein. Lymphomas are generally neoplastic transformations of cells that reside primarily in lymphoid tissue. Lymphomas are tumors of the immune system and generally are present as both T cell- and as B cell-associated disease. Among lymphomas, there are two major distinct groups: non-Hodgkin's lymphoma (NHL) and Hodgkin's disease. Bone marrow, lymph nodes, spleen and circulating cells, among others, may be involved. Treatment protocols include removal of bone marrow from the patient and purging it of tumor cells, often using antibodies directed against antigens present on the tumor cell type, followed by storage. The patient is then given a toxic dose of radiation or chemotherapy and the purged bone marrow is then re-infused in order to repopulate the patient's hematopoietic system.
[00194 ] Other hematological malignancies that can be treated with the compositions and methods described herein include myelodysplastic syndromes (MDS), myeloproliferative syndromes (MPS) and myelomas, such as solitary myeloma and multiple myeloma. Multiple myeloma (also called plasma cell myeloma) involves the skeletal system and is characterized by multiple tumorous masses of neoplastic plasma cells scattered throughout that system. It may also spread to lymph nodes and other sites such as the skin. Solitary myeloma involves solitary lesions that tend to occur in the same locations as multiple myeloma.
[00195] In one embodiment, the methods and pharmaceutical compositions described herein are used to treat a cancer that is any of breast cancer, melanoma, oral squamous cell carcinoma, lung cancer including non-small cell lung cancer, renal cell carcinoma, colorectal cancer, prostate cancer, brain cancer, spindle cell carcinoma, urothelial cancer, bladder cancer, colorectal cancer, head and neck cancers such as squamous cell carcinoma, and pancreatic cancer. According to yet another embodiment, the cancer that is treated any one selected from the group consisting of breast cancer, prostate cancer, testicular cancer, glioma, glioblastoma, head and neck cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, desmoid tumors, pancreatic carcinoma, melanoma, and renal cell carcinoma.
[00196] In one embodiment, cancers treatable according to compositions and methods herein can comprise those selected from the group consisting of soft tissue sarcoma, breast cancer, prostate cancer, testicular cancer, glioma, glioblastoma, head and neck cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, desmoid tumors, pancreatic carcinoma, melanoma, and renal cell carcinoma.
[00197] According to one embodiment, the cancer treatment involves administering the pentaaza macrocyclic ring complex, and optionally the further anticancer therapeutic agent, in a therapeutically effective amount that results in an increase in wound healing and/or reduced fibrosis of tissue exposed to radiation.
Pharmaceutical Formulations
[00198] Another aspect of the present disclosure relates to the pharmaceutical compositions comprising the pentaaza macrocyclic ring complex, together with a pharmaceutically acceptable excipient. The pharmaceutical compositions include the pentaaza macrocyclic ring complex ( e.g ., those corresponding to Formula (I)), and can optionally include at least one anti-cancer therapeutic agent, and combinations thereof, as discussed above, typically formulated as a pharmaceutical dosage form, optionally in combination with a pharmaceutically acceptable carrier, additive or excipient. In one embodiment, for example, the pharmaceutical composition comprises a pentaaza macrocyclic ring complex, optional anti-cancer therapeutic agent and a pharmaceutically acceptable excipient. Pharmaceutical compositions according to the present disclosure may be used in the treatment of cancer.
[ 00199 ] The pharmaceutical compositions described herein are products that result from the mixing or combining of more than one active ingredient and include both fixed and non-fixed combinations of the active ingredients. Fixed combinations are those in which the active ingredients, e.g., a pentaaza macrocyclic ring complex and an optional anti-cancer therapeutic agent, are administered to a patient simultaneously in the form of a single entity or dosage. Other active agents may also be administered as a part of the single entity or dosage, or may be separately administered. Non-fixed combinations are those in which the active ingredients, e.g., a pentaaza macrocyclic ring complex and an optional anti-cancer therapeutic agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients. The pentaaza macrocyclic ring complex can also be administered as a pharmaceutical composition in the absence of any other anti-cancer therapeutic agent.
[00200] The above-described pentaaza macrocyclic ring complex (and optionally the anti-cancer therapeutic agent) may be dispersed in a pharmaceutically acceptable carrier prior to administration to the mammal; i.e., the components described herein are preferably co-form ulated. The carrier, also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is typically a substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the efficacy of the compound. The carrier is generally considered to be "pharmaceutically or pharmacologically acceptable" if it does not produce an unacceptably adverse, allergic or other untoward reaction when administered to a mammal, especially a human.
[00201] The selection of a pharmaceutically acceptable carrier will also, in part, be a function of the route of administration. In general, the compositions of the described herein can be formulated for any route of administration so long as the blood circulation system is available via that route, and in accordance with the conventional route of administration. For example, suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration.
[00202] Pharmaceutically acceptable carriers for use in combination with the compositions of the present disclosure are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular compound(s) and agent(s) used, and its/their concentration, stability and intended bioavailability; the subject, its age, size and general condition; and the route of administration. Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., a-glycerol formal, 6-glycerol formal, 1 ,3-butyleneglycol, aliphatic or aromatic alcohols having 2 to 30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N- (6-hydroxyethyl)-lactamide, N,N-dimethylacetamide amides, 2-pyrrolidinone, 1-methyl- 2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidinone, 2- pyrrolidinone, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di-, or triglyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di-, or tri-glycerides, fatty acid esters such as isopropyl myristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methyl pyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyester, polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalm itate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas, Wilmington, DE, polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (. e.g ., Cremophor® EL solution or Cremophor® RH 40 solution), saccharide fatty acid esters (i.e., the condensation product of a monosaccharide {e.g., pentoses such as ribose, ribulose, arabinose, xylose, lyxose and xylulose, hexoses such as glucose, fructose, galactose, mannose and sorbose, trioses, tetroses, heptoses, and octoses), disaccharide {e.g., sucrose, maltose, lactose and trehalose) or oligosaccharide or mixture thereof with a C4 to C22 fatty acid(s) {e.g., saturated fatty acids such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or steroidal esters); alkyl, aryl, or cyclic ethers having 2 to 30 carbon atoms {e.g., diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having 3 to 30 carbon atoms {e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4 to 30 carbon atoms {e.g., benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n- dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene, di methylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral, vegetable, animal, essential or synthetic origin {e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil, vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, persic and peanut oil and glycerides such as mono-, di- or triglycerides, animal oils such as fish, marine, sperm, cod-liver, haliver, squalene, squalane, and shark liver oil, oleic oils, and polyoxyethylated castor oil); alkyl or aryl halides having 1 to 30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate.
[00203] In some embodiments, oils or non-aqueous solvents may be employed in the formulations, e.g., to bring one or more of the compounds into solution, due to, for example, the presence of large lipophilic moieties. Alternatively, emulsions, suspensions, or other preparations, for example, liposomal preparations, may be used. With respect to liposomal preparations, for example, any known methods for preparing liposomes may be used. See, for example, Bangham et at., J. Mol. Biol, 23: 238-252 (1965) and Szoka etal., Proc. Natl Acad. Sci 75: 4194-4198 (1978), incorporated herein by reference. Thus, in one embodiment, compounds can be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phophatidylcholines. Ligands may also be attached to the liposomes, for instance, to direct these compositions to particular sites of action.
[00204 ] Other pharmaceutically acceptable solvents for use in the pharmaceutical compositions described herein are well known to those of ordinary skill in the art, and are identified in The Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et at., eds., 3d ed.)
(Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman etal., eds.) (Marcel Dekker, Inc., New York, New York, 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.) (Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, PA, 2000), and A.J. Spiegel etai, Use of Nonaqueous Solvents in Parenteral Products, Journal of Pharmaceutical Sciences, Vol. 52, No. 10, pp. 917-927 (1963). [00205] Formulations containing the pentaaza macrocyclic ring complex (and optionally anti-cancer therapeutic agent) may take the form of solid, semi-solid, lyophilized powder, or liquid dosage forms such as, for instance, aerosols, capsules, creams, emulsions, foams, gels/jellies, lotions, ointments, pastes, powders, soaps, solutions, sprays, suppositories, suspensions, sustained-release formulations, tablets, tinctures, transdermal patches, and the like, preferably in unit dosage forms suitable for simple administration of precise dosages. If formulated as a fixed dose, such pharmaceutical compositions or formulation products employ the pentaaza macrocyclic ring complex (and optionally the anti-cancer therapeutic agent) within accepted dosage ranges.
[00206] In one embodiment, a formulation is provided that contains the pentaaza macrocyclic ring complex provided as a part of a sterile liquid dosage form suitable for injection, either in the same liquid dosage form with the anti-cancer therapeutic agent or as a separate dosage form. The liquid form can further comprise one or more further ingredients, such as edetate disodium (EDTA). In one embodiment, the liquid form can comprise EDTA in an amount suitable to act as a preservative and/or metal-chelating agent, such as an amount of about 0.025%. The liquid form can further comprise water, and may also comprise a pH adjuster, such as sodium bicarbonate, for pH adjustment in the range of pH 5.5 to 7.0.
[00207] Formulations for certain pentaaza macrocyclic ring complexes are also described in, for example, in U.S. Patent Nos. 5,610,293, 5,637,578, 5,874,421,
5,976,498, 6,084,093, 6,180,620, 6,204,259, 6,214,817, 6,245,758, 6,395,725, and
6,525,041 (each of which is hereby incorporated herein by reference in its entirety).
[00208] It is contemplated that formulations of the pentaaza macrocyclic ring complex, optionally with the anti-cancer therapeutic agent, may employ conventional formulation techniques for these components individually, or alternative formulation routes, subject to compatibility and efficacy of the various components, in combination.
[00209] The above-described pharmaceutical compositions including the pentaaza macrocyclic compound (optionally with the anti-cancer therapeutic agent) may additionally include one or more additional pharmaceutically active components. Suitable pharmaceutically active agents that may be included in the compositions according to aspects of the present invention include, for instance, antiemetics, anesthetics, antihypertensives, antianxiety agents, anticlotting agents, anticonvulsants, blood glucose-lowering agents, decongestants, antihistamines, antitussives, antineoplastics, beta blockers, anti-inflammatory agents, antipsychotic agents, cognitive enhancers, cholesterol-reducing agents, antiobesity agents, autoimmune disorder agents, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's Disease agents, antibiotics, antidepressants, and antiviral agents. The individual components of such compositions may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
[00210] In yet another embodiment, a kit may be provided that includes a pentaaza macrocyclic ring complex and optionally the anti-cancer therapeutic agent, for treatment of a condition such as cancer, and/or to reduce the likelihood of recurrence of cancer. For example, the kit may comprise a first vessel or container having therein a formulation comprising the pentaaza macrocyclic ring complex, such as an oral or injectable formulation of the pentaaza macrocyclic ring complex, and a second vessel or container having therein a formulation comprising the anti-cancer therapeutic agent, such as an injectable formulation of anti-cancer therapeutic agent. The kit may further comprise a label or other instructions for administration of the active agents, recommended dosage amounts, durations and administration regimens, warnings, listing of possible drug-drug interactions, and other relevant instructions, such as a label instructing therapeutic regimens (e.g., dosing, frequency of dosing, etc.) corresponding to any of those described herein.
Radiation Therapy
[00211] In one embodiment, the pentaaza macrocyclic ring complex (and optionally the anti-cancer therapeutic agent), is administered in combination with a radiation therapy treatment regime.
[00212] In general, the temporal aspects of the administration of the pentaaza macrocyclic ring complex (and optionally the anti-cancer therapeutic agent) may depend for example, on the particular radiation therapy that is selected, or the type, nature, and/or duration of the radiation exposure. Other considerations may include the disease or disorder being treated and the severity of the disease or disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the , administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors. For example, the pentaaza macrocyclic ring complex may be administered in various embodiments before, during, and/or after the administration of the radiation therapy (e.g., before, during or after exposure to and/or before, during or after a course of radiation therapy comprising multiple exposures and/or doses). By way of another example, the pentaaza macrocyclic ring complex may be administered in various embodiments before, during, and/or after an exposure to radiation. In one embodiment, the radiation therapy can comprise any selected from the group consisting of gamma irradiation, proton therapy, heavy ion therapy, brachytherapy, radionuclide therapy, conformal radiation therapy, intensity modulated radiation therapy, stereotactic body radiation therapy, stereoablative radiation therapy, and gamma knife therapy, whether delivered as standard fractionation, hypofractionation, accelerated fractionation or decelerated fractionation and variations thereof. [00213] If desired, the effective dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the dose. [00214] In one embodiment, for example, the pentaaza macrocyclic ring complex is administered to the patient prior to or simultaneous with the radiation exposure. In another embodiment, for example, the pentaaza macrocyclic ring complex is administered to the patient prior to, but not after, the radiation exposure. In yet another embodiment, the pentaaza macrocyclic ring complex is administered to the patient at least 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, 180 minutes, 0.5 days, 1 day, 3 days, 5 days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or longer, prior to the radiation exposure, such as an initial radiation exposure in a course of radiation treatment, or prior to another dose or dose fraction of radiation that is one of the doses or dose fractions of radiation in the course of treatment. In still other embodiments, for example, the pentaaza macrocyclic ring complex is administered to the patient after the radiation exposure; thus, for example, the compound may be administered up to 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, or 180 minutes, 0.5 days, 1 day, 3 days, 5 days, one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, nine weeks, ten weeks, eleven weeks, twelve weeks, or longer, after the radiation exposure, which may be a dose or dose fraction of radiation in a multi-dose course of radiation therapy, or may be the single or final dose or dose fraction of radiation in the radiation therapy.
[00215] In certain embodiments of radiation therapy, a patient receives a dose or dose fraction of ionizing radiation to kill or control the growth of cancerous cells. The dose or dose fraction of radiation may be directed at a specific part of the body, and the beam of radiation may also be shaped according to a predetermined treatment regimen, to reduce deleterious effects on parts of the body not afflicted with cancer. A typical course of radiation therapy may include one or a plurality of doses or dose fractions of radiation, which can be administered over the course of days, weeks and even months. A total “dose” of radiation given during a course of radiation therapy typically refers to the amount of radiation a patient receives during the entire course of radiation therapy, which doses may be administered as dose “fractions” corresponding to multiple radiation exposures in the case where the total dose is administered over several sessions, with the sum of the fractions administered corresponding to the overall dose.
[00216] In one embodiment, the pentaaza macrocyclic ring complex is administered within a predetermined time period before or after a radiation exposure, such as before or after a radiation dose or dose fraction. For example, the pentaaza macrocyclic ring complex may be administered within 1 week, 48 hours, 24 hours, 12 hours, 6, hours, 2 hours, 1 hour or even within 30 minutes of the patient receiving the radiation exposure, such as the dose or dose fraction (either before or after the radiation exposure corresponding to the radiation dose or dose fraction). Other durations between the radiation exposure and administration of the compound that result in the enhanced the killing of cancer cells may also be suitable. In one embodiment, one or more of the pentaaza macrocyclic ring complex and/or the optional anti-cancer therapeutic agent may be administered before the radiation exposure, and the remaining one or more of the pentaaza macrocyclic ring complex and/or the anti-cancer therapeutic agent can be administered after the radiation exposure. One or more of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent may also be administered both before and after administration of a radiation exposure. [00217] In one embodiment, a course of radiation therapy includes a plurality of radiation doses or dose fractions given over a predetermined period of time, such as over the course of hours, weeks, days and even months, with the plural doses or dose fractions being either of the same magnitude or varying. That is, a course of radiation therapy can comprise the administration of a series of multiple doses or dose fractions of radiation. In one embodiment, the pentaaza macrocyclic ring complex can be administered before one or more radiation doses or dose fractions in the series, such as before each radiation dose or dose fraction, or before some number of the radiation doses or dose fractions. Furthermore, the administration of the pentaaza macrocyclic ring complex and optional anti-cancer therapeutic agent during the course of radiation therapy can be selected to enhance the cancer treating effects of the radiation therapy, such as by sensitizing cancer cells to the radiation therapy. In one embodiment, the pentaaza macrocyclic ring complex is administered within a predetermined duration before or after of each dose or dose fraction, such as the predetermined duration discussed above. In another embodiment, the pentaaza macrocyclic ring complex is administered within a predetermined duration of time before or after only select doses or dose fractions. In yet another embodiment, at least one of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent is administered within a predetermined duration of time before the doses, while another of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent is administered within a predetermined duration of time after the doses or dose fraction. In a further embodiment, at least one of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent is administered only within the predetermined duration before or after select doses or dose fractions, while another of the pentaaza macrocyclic ring complex and the optional anti-cancer therapeutic agent is administered only within the predetermined duration before or after doses or dose fractions other than the select doses or dose fractions.
[00218] A suitable overall dose to provide during a course of therapy can be determined according to the type of treatment to be provided, the physical characteristics of the patient and other factors, and the dose fractions that are to be provided can be similarly determined. In one embodiment, a dose fraction of radiation that is administered to a patient may be at least 1.8 Gy, such as at least 2 Gy, and even at least 3 Gy, such as at least 5 Gy, and even at least 6 Gy. In yet another embodiment, a dose fraction of radiation that is administered to a patient may be at least 10 Gy, such as at least 12 Gy, and even at least 15 Gy, such as at least 18 Gy, and even at least 20 Gy, such as at least 24 Gy. In general, a dose fraction of radiation administered to a patient will not exceed 54 Gy. Furthermore, it should be noted that, in one embodiment, a dose fraction delivered to a subject may refer to an amount delivered to a specific target region of a subject, such as a target region of a tumor, whereas other regions of the tumor or surrounding tissue may be exposed to more or less radiation than that specified by the nominal dose fraction amount.
[ 00219 ] In yet another embodiment, the optional anti-cancer therapeutic agent comprises a chemotherapeutic agent. In chemotherapy, chemotherapeutic agents are administered to a patient to kill or control the growth of cancerous cells. A typical course of chemotherapy may include one or a plurality of doses of one or more chemotherapeutic agents, which can be administered over the course of days, weeks and even months. Chemotherapeutic agents can include at least one of: alkylating antineoplastic agents such as nitrogen mustards (e.g. cyclophosphamide, chlorambucil), nitrosoureas (e.g. n-nitroso-n-methylurea, carmustine, semustine), tetrazines (e.g. dacarbazine, mitozolimide), aziridines (e.g. thiotepa, mytomycin); antimetabolites such as anti-folates (e.g. methotrexate and pemetrexed), fluoropyrimidines (e.g., fluorouracil, capecitabine), anthracyclines (e.g. doxorubicin, daunorubicin, epirubicin), deoxynucleoside analogs (e.g. cytarabine, gemcitabine, decitabine) and thiopurines (e.g., thioguanine, mercaptopurine); anti microtubule agents such as taxanes (e.g. paclitaxel, docetaxel); topoisomerase inhibitors (e.g. etoposide, doxorubicin, mitoxantrone, teniposide); and antitumor antibiotics (e.g. bleomycin, mitomycin). For example, the chemotherapeutic agent may be selected from the group consisting of all-trans retinoic acid, arsenic trioxide, azacitidine, azathioprine, bleomycin, carboplatin, capecitabine, cisplatin, chlorambucil, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, epothilone, etoposide, fluorouracil, gemcitabine, hydroxyurea, idarubicin, imatinib, mechlorethamine, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, pemetrexed, teniposide, tiguanine, valrubicin, vinblastine, vincristine, vindesine, and vinorelbine. The administration of many of the chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR), e.g., 1996 edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA). [00220] In one embodiment, the optional anti-cancer therapeutic agent comprises a chemotherapeutic agent that is any of a platinum-containing chemotherapeutic agent and an anthracycline chemotherapeutic agent. For example, the chemotherapeutic agent can comprise any of a platinum-containing chemotherapeutic agent selected from the group consisting of cisplatin, oxaliplatin, carboplatin, nedaplatin, lobaplatin, heptaplatin, dicycloplation, lipoplatin, LA-12, phosphaplatin, phenanthriplatin, prolindac, triplatin tetranitrate, picoplatin, satraplatin and/or pharmaceutically acceptable salts thereof, and/or an anthracycline chemotherapeutic agent selected from the group consisting of doxorubicin, daunorubicin, epirubicin and idarubicin, and/or pharmaceutically acceptable salts thereof. Other chemotherapeutic agents described elsewhere herein may also be suitable. According to yet another embodiment, the anti-cancer therapeutic agent comprises a cell cycle inhibitor such as a CDK4/6 inhibitor, such as any selected from the group consisting of group of palbociclib, abemaciclib, ribociclib, and derivatives, salts and/or prodrugs thereof.
[00221] In one embodiment, the optional anti-cancer therapeutic agent comprise a chemotherapeutic agent selected from the group consisting of cisplatin, doxorubicin, bleomycin, and paclitaxel. Furthermore, in one embodiment, the chemotherapeutic agent may be selected from the group consisting of a taxane, an anticancer antibiotic, and an anthracycline. Other chemotherapeutic agents can include arsenic trioxide and 5-FU, which agents can also be used in the methods and compositions described herein. (Alexandre et al., Cancer Res. 67: (8), 3512-3517 (2007); Yen etal., J. Clin. Invest. 98 (5), 1253-1260 (1996); Masuda etal., Cancer Chemother. Pharmacol. 47(2), 155-160 (2001)).
[00222] According to yet another embodiment, the chemotherapeutic agent can include at least one of an antimetabolite anti-cancer agents and antimitotic anti-cancer agents, and combinations thereof, which may include some of the agents described above and well as other agents described further herein. Various antimetabolite and antimitotic agents may be employed in the methods and compositions described herein.
[00223] Antimetabolic agents typically structurally resemble natural metabolites, which are involved in normal metabolic processes of cancer cells such as the synthesis of nucleic acids and proteins. The antimetabolites, however, differ enough from the natural metabolites such that they interfere with the metabolic processes of cancer cells. In the cell, antimetabolites are mistaken for the metabolites they resemble, and are processed by the cell in a manner analogous to the normal compounds. The presence of the “decoy” metabolites prevents the cells from carrying out vital functions and the cells are unable to grow and survive. For example, antimetabolites may exert cytotoxic activity by substituting these fraudulent nucleotides into cellular DNA, thereby disrupting cellular division, or by inhibition of critical cellular enzymes, which prevents replication of DNA.
[00224 ] In one embodiment, therefore, the antimetabolite agent is a nucleotide or a nucleotide analog. In certain embodiments, for example, the antimetabolite agent may comprise purine (e.g., guanine or adenosine) or analogs thereof, or pyrimidine (cytidine or thymidine) or analogs thereof, with or without an attached sugar moiety.
[00225] Suitable antimetabolite agents for use in the present disclosure may be generally classified according to the metabolic process they affect, and can include, but are not limited to, analogues and derivatives of folic acid, pyrimidines, purines, and cytidine. Thus, in one embodiment, the antimetabolite agent(s) is selected from the group consisting of cytidine analogs, folic acid analogs, purine analogs, pyrimidine analogs, and combinations thereof.
[00226] In one particular embodiment, for example, the antimetabolite agent is a cytidine analog. According to this embodiment, for example, the cytidine analog may be selected from the group consisting of cytarabine (cytosine arabinodside), azacitidine (5-azacytidine), and salts, analogs, and derivatives thereof.
[00227] In another particular embodiment, for example, the antimetabolite agent is a folic acid analog. Folic acid analogs or antifolates generally function by inhibiting dihydrofolate reductase (DFIFR), an enzyme involved in the formation of nucleotides; when this enzyme is blocked, nucleotides are not formed, disrupting DNA replication and cell division. According to certain embodiments, for example, the folic acid analog may be selected from the group consisting of denopterin, methotrexate (amethopterin), pemetrexed, pteropterin, raltitrexed, trimetrexate, and salts, analogs, and derivatives thereof.
[00228] In another particular embodiment, for example, the antimetabolite agent is a purine analog. Purine-based antimetabolite agents function by inhibiting DNA synthesis, for example, by interfering with the production of purine containing nucleotides, adenine and guanine which halts DNA synthesis and thereby cell division. Purine analogs can also be incorporated into the DNA molecule itself during DNA synthesis, which can interfere with cell division. According to certain embodiments, for example, the purine analog may be selected from the group consisting of acyclovir, allopurinol, 2-aminoadenosine, arabinosyl adenine (ara-A), azacitidine, azathiprine, 8- aza-adenosine, 8-fluoro-adenosine, 8-methoxy-adenosine, 8-oxo-adenosine, cladribine, deoxycoformycin, fludarabine, gancylovir, 8-aza-guanosine, 8-fluoro-guanosine, 8- methoxy-guanosine, 8-oxo-guanosine, guanosine diphosphate, guanosine diphosphate- beta-L-2-aminofucose, guanosine diphosphate-D-arabinose, guanosine diphosphate-2 - fluorofucose, guanosine diphosphate fucose, mercaptopurine (6-MP), pentostatin, thiamiprine, thioguanine (6-TG), and salts, analogs, and derivatives thereof.
[00229] In yet another particular embodiment, for example, the antimetabolite agent is a pyrimidine analog. Similar to the purine analogs discussed above, pyrimidine-based antimetabolite agents block the synthesis of pyrimidine-containing nucleotides (cytosine and thymine in DNA; cytosine and uracil in RNA). By acting as “decoys,” the pyrimidine-based compounds can prevent the production of nucleotides, and/or can be incorporated into a growing DNA chain and lead to its termination. According to certain embodiments, for example, the pyrimidine analog may be selected from the group consisting of ancitabine, azacitidine, 6-azauridine, bromouracil (e.g., 5- bromouracil), capecitabine, carmofur, chlorouracil (e.g. 5-chlorouracil), cytarabine (cytosine arabinoside), cytosine, dideoxyuridine, 3'-azido-3'-deoxythymidine, 3'-dideoxycytidin-2'-ene, 3'-deoxy-3'-deoxythymidin-2'-ene, dihydrouracil, doxifluridine, enocitabine, floxuridine, 5-fluorocytosine, 2-fluorodeoxycytidine, 3-fluoro-3'- deoxythymidine, fluorouracil (e.g., 5-fluorouracil (also known as 5-FU), gemcitabine, 5- methylcytosine, 5-propynylcytosine, 5-propynylthymine, 5-propynyluracil, thymine, uracil, uridine, and salts, analogs, and derivatives thereof. In one embodiment, the pyrimidine analog is other than 5-fluorouracil. In another embodiment, the pyrimidine analog is gemcitabine or a salt thereof.
[00230] In certain embodiments, the antimetabolite agent is selected from the group consisting of 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof. In other embodiments, the antimetabolite agent is selected from the group consisting of capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, and salts, analogs, derivatives, and combinations thereof. In one particular embodiment, the antimetabolite agent is other than 5- fluorouracil. In a particularly preferred embodiment, the antimetabolite agent is gemcitabine or a salt or thereof ( e.g ., gemcitabine HCI (Gemzar®)).
[00231] Other antimetabolite agents may be selected from, but are not limited to, the group consisting of acanthifolic acid, aminothiadiazole, brequinar sodium, Ciba- Geigy CGP-30694, cyclopentyl cytosine, cytarabine phosphate stearate, cytarabine conjugates, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMDC, Wellcome EHNA, Merck & Co. EX-015, fazarabine, fludarabine phosphate, N-(2'-furanidyl)-5-fluorouracil, Daiichi Seiyaku FO- 152, 5-FU-fibrinogen, isopropyl pyrrolizine, Lilly LY-188011; Lilly LY-264618, methobenzaprim, Wellcome MZPES, norspermidine, NCI NSC-127716, NCI NSC- 264880, NCI NSC-39661, NCI NSC-612567, Warner-Lambert PALA, pentostatin, piritrexim, plicamycin, Asahi Chemical PL-AC, Takeda TAC-788, tiazofurin, Erbamont TIF, tyrosine kinase inhibitors, Taiho LIFT and uricytin, among others.
[00232] In one embodiment, the chemotherapeutic agent comprises an antimitotic agent that is a microtubule inhibitor or a mictrotubule stabilizer. In general, microtubule stabilizers, such as taxanes (some of which are also described above) and epothilones, bind to the interior surface of the beta-microtubule chain and enhance microtubule assembly by promoting the nucleation and elongation phases of the polymerization reaction and by reducing the critical tubulin subunit concentration required for microtubules to assemble. Unlike mictrotubule inhibitors, such as the vinca alkaloids, which prevent microtubule assembly, the microtubule stabilizers, such as taxanes, decrease the lag time and dramatically shift the dynamic equilibrium between tubulin dimers and microtubule polymers towards polymerization. In one embodiment, therefore, the microtubule stabilizer is a taxane or an epothilone. In another embodiment, the microtubule inhibitor is a vinca alkaloid.
[00233] One element of the therapy described herein may include the use of a taxane or derivative or analog thereof, some of which have also been discussed above. In one embodiment, the taxane may be a naturally derived compound or a related form, or may be a chemically synthesized compound or a derivative thereof, with antineoplastic properties. The taxanes are a family of terpenes, including, but not limited to paclitaxel (Taxol®) and docetaxel (Taxotere®), which are derived primarily from the Pacific yew tree, Taxus brevifolia, and which have activity against certain tumors, particularly breast and ovarian tumors. In one embodiment, the taxane is docetaxel or paclitaxel. Paclitaxel is a preferred taxane and is considered an antimitotic agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions.
[00234 ] Also included are a variety of known taxane derivatives, including both hydrophilic derivatives, and hydrophobic derivatives. Taxane derivatives include, but are not limited to, galactose and mannose derivatives described in International Patent Application No. WO 99/18113; piperazino and other derivatives described in WO 99/14209; taxane derivatives described in WO 99/09021, WO 98/22451, and U.S.
Patent No. 5,869,680; 6-thio derivatives described in WO 98/28288; sulfenamide derivatives described in U.S. Patent No. 5,821,263; deoxygenated paclitaxel compounds such as those described in U.S. Patent No. 5,440,056; and taxol derivatives described in U.S. Patent No. 5,415,869. As noted above, it further includes prodrugs of paclitaxel including, but not limited to, those described in WO 98/58927; WO 98/13059; and U.S. Patent No. 5,824,701. The taxane may also be a taxane conjugate such as, for example, paclitaxel-PEG, paclitaxel-dextran, paclitaxel-xylose, docetaxel-PEG, docetaxel-dextran, docetaxel-xylose, and the like. Other derivatives are mentioned in "Synthesis and Anticancer Activity of Taxol Derivatives," D. G. I. Kingston et al., Studies in Organic Chemistry, vol. 26, entitled "New Trends in Natural Products Chemistry" (1986), Atta-ur-Rabman, P. W. le Quesne, Eds. (Elsevier, Amsterdam 1986), among other references. Each of these references is hereby incorporated by reference herein in its entirety.
[00235] Various taxanes may be readily prepared utilizing techniques known to those skilled in the art (see also WO 94/07882, WO 94/07881 , WO 94/07880, WO 94/07876, WO 93/23555, WO 93/10076; U.S. Pat. Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; and EP 590,267) (each of which is hereby incorporated by reference herein in its entirety), or obtained from a variety of commercial sources, including for example, Sigma-Aldrich Co., St. Louis, MO. [00236] Alternatively, the antimitotic agent can be a microtubule inhibitor; in one preferred embodiment, the microtubule inhibitor is a vinca alkaloid. In general, the vinca alkaloids are mitotic spindle poisons. The vinca alkaloid agents act during mitosis when chromosomes are split and begin to migrate along the tubules of the mitosis spindle towards one of its poles, prior to cell separation. Under the action of these spindle poisons, the spindle becomes disorganized by the dispersion of chromosomes during mitosis, affecting cellular reproduction. According to certain embodiments, for example, the vinca alkaloid is selected from the group consisting of vinblastine, vincristine, vindesine, vinorelbine, and salts, analogs, and derivatives thereof.
[00237] The antimitotic agent can also be an epothilone. In general, members of the epothilone class of compounds stabilize microtubule function according to mechanisms similar to those of the taxanes. Epothilones can also cause cell cycle arrest at the G2-M transition phase, leading to cytotoxicity and eventually apoptosis. Suitable epithiolones include epothilone A, epothilone B, epothilone C, epothilone D, epothilone E, and epothilone F, and salts, analogs, and derivatives thereof. One particular epothilone analog is an epothilone B analog, ixabepilone (Ixempra™).
[00238] In certain embodiments, the antimitotic anti-cancer agent is selected from the group consisting of taxanes, epothilones, vinca alkaloids, and salts and combinations thereof. Thus, for example, in one embodiment the antimitotic agent is a taxane. More preferably in this embodiment the antimitotic agent is paclitaxel or docetaxel, still more preferably paclitaxel. In another embodiment, the antimitotic agent is an epothilone (e.g., an epothilone B analog). In another embodiment, the antimitotic agent is a vinca alkaloid.
[00239] In one embodiment, the pentaaza macrocyclic ring complex may be administered within 1 week, 48 hours, 24 hours, 12 hours, 6, hours, 2 hours, 1 hour or even within 30 minutes of the patient receiving the dose of the chemotherapeutic agent (either before or after the dose of chemotherapeutic agent). Other durations between the additional chemotherapeutic agent dose and administration of the pentaaza macrocyclic ring complex that result in the enhanced the killing of cancer cells may also be suitable.
[00240] In one embodiment, a course of chemotherapy includes a singular dose of the additional chemotherapeutic agent. In another embodiment, a course of chemotherapy includes a plurality of doses of the additional chemotherapeutic agent given over a predetermined period of time, such as over the course of hours, weeks, days and even months. The plural doses may be either of the same magnitude or varying, and can include doses of the same or different chemotherapeutic agents and/or a combination of chemotherapeutic agents.
Examples
[00241] The following examples illustrate examples of the methods and compositions of treatment described herein.
[00242 ] In the examples, the following cell lines were used: M20 (Dermal firboblasts (20 yr old male); HT1080 (fibrosarcoma); SW872 (liposarcoma); SKLMS1 (leiomyosarcoma)
[00243] Example 1
[00244] Increased levels of dihydroethidium (DHE) oxidation in sarcoma cell lines. Steady-state levels of ROS were assessed in M20 (normal human dermal fibroblasts), HT1080 (fibrosarcoma), SW872 (liposarcoma) and SKLMS1 (leiomyosarcoma) cells at 3 hours (see Fig. 1 A), and at 24 hours (see Fig. 1 B). Cells were treated with 5 mM of manganese pentaazamacrocycle (MnPAM) dismutase mimetic GC441924 hours prior to radiation with 4 Gy. Following DFIE staining, the cells were analyzed using a LSR-UV in flow cytometry. All experiments are n=2, **=p<0.05 versus M20 control group as determined by two-way ANOVA, post-hoc Tukey test using GraphPad prism software. The results as shown in Figs. 1A-1B demonstrate that sarcoma cells have increased levels of reactive oxygen species relative to non- malignant cells.
[00245] Example 2
[00246] Increasing concentrations of ascorbate (up to 10 pMol/cell) is toxic to sarcoma cell lines. Sarcoma lines HT 1080, SW872 and SKLMS1 were tested to demonstrate the toxicity of increasing concentrations of ascorbate (up to 10 pMol/cell pharmacological ascorbate (P-AscFI-)). 10 pMol/cell of ascorbate resulted in significant toxicity to FIT1080 compared to SW872 and SKLMS-1 cells. All cells were treated with an ascorbate titration using picomole/cell with concentrations adjusted to maintain 2 mM ascorbate. 10 pMol per cell resulted in almost 100-fold clonogenic cell killing in SKLMS- 1 cells. Error bars indicate the standard error of the mean of n=3 per group. * indicates p<0.05. Statistical analysis was analyzed using GraphPad Prism. Accordingly, it was shown that sarcoma cells demonstrate a dose dependent increase in clonogenic cell killing following treatment with ascorbate PAscH- (see Fig. 2). [00247] Example 3
[00248] Combined treatment with GC4419 and P-AscH' Enhance Sarcoma Response to Radiation. Sarcoma cells lines, HT1080, SW872, and SKLMS-1, were treated with 4 Gy of ionizing radiation (IR) , 5 mM of a MnPAM dismutase mimetic (GC4419) (24 hours prior) or 10 pM/cell of ascorbate (see Fig. 3A). To determine if the combined treatment of ascorbate (PAscH-) and GC4419 enhanced sarcoma cell killing, cells were exposed to 4 Gy IR, 5 pM of GC4419 (24 hours prior to IR) and 10 pM/cell ascorbate (1 hr prior to IR) and plated for clonogenic cell survival. The combination of P- AscH- and GC4419 enhanced IR-induced cell killing compared to the IR alone group in both FIT1080 and SW872 cells (see Fig. 3B). All experiments are at least n=2, *=p<0.01 versus the respective IR alone group as determined by one-way ANOVA, post-hoc Tukey test using GraphPad prism software. Accordingly, it was shown that treatment with dismutase mimetic kills at least some sarcoma cell lines, that combination with P- AscH- kills all sarcoma cell lines tested, and further exacerbates IR-included killing of sarcoma cells.
[00249] Example 4
[00250] GC4419 decreases migration of fibrosarcoma cells. Relative migration was assessed using transwell migration chambers from BD Falcon™ (8 pM pore size, 353097; BD Biosciences) in M20 and FIT1080 cells treated with 5 uM of a MnPAM dismutase mimetic (GC4419) 24 hours prior to 4 Gy IR exposure, alone and in combination with 15 U/ml catalase. The experiment consisted of one biological replicate and 3 technical replicates. Treatment with GC4419 alone increased migration of M20 normal fibroblasts relative to FIT1080 sarcoma cells, while migration of both was decreased somewhat following exposure to IR. Treatment with GC4419 and IR substantially increased migration of M20 cells and decreased migration of FIT1080 cells, (see Fig.4). Data represent relative migration compared to controls. Accordingly, it was shown that dismutase mimetic increases migration of normal fibroblasts (M20) including after IR exposure, which should support more rapid and appropriate repopulation and repair of injured tissues. Importantly, dismutase mimetic also decreases relative migration of cancer (HT1080) cells including following IR which should support maintaining or even increasing the anti-cancer efficacy of IR.
[0025]] Example 5
[00252] Treatment with GC4419 accelerates radiation-induced wound closure in a murine wound healing model. C57BI6/NHsd mice were pre-treated with 10mg/kg MnPAM dismutase mimetic (GC4419) I.P. daily starting 3 days prior to a single dose of 15 Gy IR using SARRP (Small Animal Radiation Research Platform) and up to two weeks following IR. 60 days following IR exposure, wounds were created on the dorsal side of mice using 5 mm biopsy punches and wound closure was measured using calipers until complete closure in the control group (see Fig. 5A). There were 3 mice per group. Wound measurements taken at day 0, 7, and 11 showed that radiation alone delayed wound healing and resulted in a larger percentage of the wound staying open. Treatment with 10 mg/kg GC4419 in combination with IR resulted in faster and more complete wound closure compared to IR treated mice and at least as fast as control sham-irradiated mice (see Fig. 5B). Fig 5C is a schematic showing the timeline and experimental design used to obtain the results illustrated in Figs 5A-5B.
Accordingly, it was shown that treatment with dismutase mimetic enhances (i.e. enables and accelerates) wound healing following IR exposure.
[00253] Example 6
[00254 ] Pancreatic Cancer Trial
[00255] Figs. 6-8 described the parameters and timeline for a randomized, placebo controlled trial of a MnPAM dismutase mimetic (GC4419) + stereotactic body radiation therapy (SBRT) in patients with locally advanced pancreatic cancer. As described in the figures, either 90 mg dismutase mimetic or placecbo were administered as a 60-minute intravenous infusion before each of five daily doses of 10 Gy IR delivered as SBRT. Patients treated in this study were judged to either be “unresectable” or “borderline” as to the resectability of the tumor before treatment, as detailed in the figures. At a period of approximately 6 weeks after treatment with SBRT, patients were re-evaluated for tumor resectability, and as judged medically appropriate underwent surgical resection of their tumor with approximately 2 weeks. Figs. 9-10 show some of the surgical results from the trial of Figs. 6-8. The results show that more patients treated with dismutase mimetic + SBRT were resected (5 of 24) than with placebo + SBRT (2 of 18), and that surgical outcomes in terms of absence of observable cancer in the edges of the resected tumor-containing tissue (negative margins, or Ro) were better with dismutase mimetic + SBRT (5 of 5) than with placebo + SBRT (1 of 2). These surgical results did not appear closely related to response of the tumor in terms of size, with several of the positive surgical results occurring in tumors which were not observed by radiographic imaging to shrink. Importantly, dismutase mimetic +SBRT did not decrease, and in fact appeared to increase, anti-cancer efficacy versus placebo + SBRT. Accordingly, it was shown that in this pilot study, more patients with LAPC in the arm treated with dismutase mimetic were resected following IR exposure for treatment of pancreatic cancer.
INCORPORATION BY REFERENCE
[00256] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
EQUIVALENTS
[00257] While specific embodiments have been discussed, the above specification is illustrative, and not restrictive. Many variations will become apparent to those skilled in the art upon review of this specification. The full scope of the embodiments should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
[00258] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained.

Claims

WHAT IS CLAIMED IS: 1. A method of enhancing wound healing after a radiation exposure in a mammalian subject in need thereof, the method comprising: selecting the mammalian subject from among a population of mammalian subjects that has been or will be exposed to radiation, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after the radiation exposure:
Figure imgf000085_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and Rio attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
2. A method of enhancing surgical outcome in a mammalian subject that has received or will receive radiation therapy, the method comprising: selecting the mammalian subject from among a population of mammalian subjects that has been or will be exposed to radiation, performing surgery on the mammalian subject, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after the radiation exposure,
Figure imgf000087_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
3. A method of enhancing wound healing in a mammalian subject following radiation therapy for treatment of a tumor, the method comprising: selecting the mammalian subject from among a population of mammalian subjects afflicted with a tumor that is treatable by radiation therapy, and administering to the subject the radiation therapy in combination with a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy:
Figure imgf000088_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and R1 and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent; X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
4. A method of enhancing wound healing in a mammalian subject afflicted with a tumor that is treatable by surgery and radiation therapy, the method comprising: selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and surgery, and administering to the subject radiation therapy in combination with a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy:
Figure imgf000090_0001
wherein
M is Mn2+ or Mn3+;
R1, R2, R'2, R3, R4, R5, R'5, R6, R'6, R7, R8, R9, R'9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(ORii)(Ri2), -P(0)(ORii)(ORi2), -P(0)(ORH)(RI2), and -OP(0)(ORII)(ORI2), wherein Rn and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and Rio attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
5. A method of enhancing an outcome of tumor treatment in a mammalian subject, the method comprising: selecting a predetermined period of time in which to perform surgery following an exposure to radiation administered as a part a radiation therapy of the tumor to the mammalian subject, in relation to whether or not the mammalian subject has received or will receive administration of a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, and performing surgery on the mammalian subject within the selected predetermined period of time,
Figure imgf000092_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
6. A method of enhancing an outcome of tumor treatment in a mammalian subject, the method comprising: selecting a predetermined period of time following surgery to expose the mammalian subject radiation administered as a part a radiation therapy of the tumor to the mammalian subject, in relation to whether or not the mammalian subject has received or will receive administration of a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, and exposing the mammalian subject to radiation within the selected predetermined period of time following surgery,
Figure imgf000093_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and R1 and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent; X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
7. The method according to claim 5, wherein in a case where the patient has received or will receive a pentaaza macrocyclic ring complex of Formula (I), performing the surgical resection within a first predetermined period of time, and in a case where the patient does not receive the pentaaza macrocyclic ring complex of Formula (I), performing the surgical resection within a second predetermined period of time that is longer than the first predetermined period of time.
8. The method according to claim 6, wherein in a case where the patient has received or will receive a pentaaza macrocyclic ring complex of Formula (I), exposing to radiation within a first predetermined period of time, and in a case where the patient does not receive the pentaaza macrocyclic ring complex of Formula (I), exposing to radiation within a second predetermined period of time that is longer than the first predetermined period of time.
9. The method according to any of claims 5-8, wherein the first period of time is within 1 day, 2 days, 3 day, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, of a last radiation exposure of the mammalian subject.
10. A method of preparing a mammalian subject for surgery following radiation therapy, the method comprising: administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to Formula (I) below, prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy:
Figure imgf000096_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and Rio attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
11. A method of enhancing wound healing following tissue resection and radiation therapy for treatment of a tumor in a mammalian subject, the method comprising: exposing the mammalian subject to radiation as a part of radiation therapy; resecting a region of tissue at a location of the tumor in the mammalian subject; and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after the radiation exposure:
Figure imgf000097_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and R1 and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent; X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
12. A method of enhancing wound healing in a mammalian subject afflicted with a tumor that is treatable by tissue resection and radiation therapy, the method comprising: selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and resection of the tumor, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy:
Figure imgf000099_0001
wherein
M is Mn2+ or Mn3+;
R1, R2, R'2, R3, R4, R5, R'5, R6, R6, R7, R8, R9, R'9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(ORii)(Ri2), -P(0)(ORii)(ORi2), -P(0)(ORH)(RI2), and -OP(0)(ORII)(OR12), wherein Rn and R12 are independently hydrogen or alkyl;
U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and Rio attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
13. The method of any preceding claim, wherein the method selectively increases the migration of normal (non-malignant) cells at a wound site, relative to the migration of malignant cells.
14. A method of selectively increasing the migration of normal cells relative to the migration of malignant cells following surgery and radiation therapy for treatment of a tumor in a mammalian subject, the method comprising: exposing the mammalian subject to radiation as a part of the radiation therapy; performing surgery on the mammalian subject; and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after the radiation exposure received as a part of the radiation therapy:
Figure imgf000101_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
15. A method of selectively increasing the migration of normal cells relative to the migration of malignant cells following surgery in a mammalian subject afflicted with a tumor that is treatable by surgery and radiation therapy, the method comprising: selecting the mammalian subject from among a population of mammalian subjects afflicted with the tumor that is treatable by radiation therapy and surgery, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after a radiation exposure received as a part of the radiation therapy:
Figure imgf000102_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and R1 and R10 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent; X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
16. A method of selectively increasing the migration migration of malignant cells in a mammalian subject following radiation therapy, the method comprising: selecting the mammalian subject from among a population of mammalian subjects in need of enhanced wound healing following radiation therapy, and administering to the mammalian subject a therapeutically effective amount of a pentaaza macrocyclic ring complex corresponding to the Formula (I) below, prior to, concomitantly with, or after radiation exposure received as a part of the radiation therapy:
Figure imgf000104_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms;
W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and Rio attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese.
17. A kit for therapeutic treatment of a mammalian subject, the kit comprising: the pentaaza macrocyclic ring complex corresponding to Formula (I) below:
Figure imgf000106_0001
wherein M is Mn2+ or Mn3+; R1, R2, R′2, R3, R4, R5, R′5, R6, R′6, R7, R8, R9, R′9, and R10 are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO2NR11R 12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl; U, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; V, together with the adjacent carbon atoms of the macrocycle, forms a fused substituted or unsubstituted, saturated, partially saturated or unsaturated, cycle or heterocycle having 3 to 20 ring carbon atoms; W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and Ri and Rio attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent;
X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof;
Z is a counterion; n is an integer from 0 to 3; and the dashed lines represent coordinating bonds between the nitrogen atoms of the macrocycle and the transition metal, manganese; optionally, a further anti-cancer agent; and instructions for administering the therapeutically effective amount of the pentaaza macrocyclic ring complex to perform a method according to any of the preceding claims.
18. The method or kit according to any preceding claim, wherein the method accelerates wound healing following surgery.
19. The method or kit according to any preceding claim, wherein the mammalian subject is suffering from a tumor or complications associated therewith that are treatable by surgery.
20. The method or kit according to any preceding claim, wherein surgery is performed on the mammalian subject to remove all or part of the tumor by tissue resection.
21. The method or kit according to any preceding claim, wherein surgery is performed on the mammalian subject for diagnostic purposes and/or to perform a biopsy.
22. The method or kit according to any preceding claim, wherein surgery is performed on the mammalian subject for treatment of complications associated with the tumor.
23. The method or kit according to any preceding claim, wherein surgery is performed on the mammalian subject to make improvements in cosmetic appearance.
24. The method or kit according to any preceding claim, wherein would healing is sufficiently enhanced so as to make surgery feasible.
25. The method or kit according to any preceding claim, wherein would healing is sufficiently enhanced so as to make surgery to resect a tumor more accurate.
26. The method or kit according to any preceding claim, wherein would healing is sufficiently enhanced so as to make surgery to resect a tumor more efficient.
27. The method or kit according to any preceding claim, wherein would healing is sufficiently enhanced so as to improve the surgical outcome of the mammalian subject.
28. The method or kit according to any preceding claim, wherein wound healing is sufficiently enhanced so as to improve the recovery of the mammalian subject from surgery.
29. The method or kit according to any preceding claim, wherein administration of the pentaaza macrocyclic ring complex of Formula (I) preserves the condition of normal tissue subjected to radiation exposure sufficiently such that normal tissue can be differentiated from malignant tissue for purposes of tissue resection.
30. The method or kit of any preceding claim, wherein the method reduces the development of fibrotic and/or abnormal tissue post-irradiation.
31. The method or kit according to any preceding claim, wherein the mammalian subject has been exposed to radiation.
32. The method or kit according to any preceding claim, wherein the mammalian subject is selected for exposure to radiation.
33. The method or kit according to any preceding claim, wherein the mammalian subject has been exposed to radiation within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day as administration of the pentaaza macrocyclic ring complex of Formula (I).
34. The method or kit according to any preceding cl , subject is selected to be exposed to radiation within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day as administration of the pentaaza macrocyclic ring complex of Formula (I).
35. The method or kit according to any preceding claim, wherein the mammalian subject has been exposed to radiation within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that surgery is performed on the mammalian subject.
36. The method or kit according to any preceding claim, wherein the mammalian subject is selected to be exposed to radiation within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that surgery is performed on the mammalian subject.
37. The method or kit according to any preceding claim, wherein the mammalian subject is administered the pentaaza macrocyclic ring complex of Formula (I) within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that surgery is performed on the mammalian subject.
38. The method or kit according to any preceding claim, wherein the mammalian subject is selected to have surgery within 6 months, 3 months, 2 months, 1 month, 2 weeks, 1 week, 5 days, 3 days, 2 days, 1 day, and/or on the same day that the pentaaza macrocyclic ring complex of Formula (I) is administered.
39. The method or kit of any preceding claim, the method comprising performing surgery on the mammalian subject after exposure to radiation.
40. The method or kit of any preceding claim, the method comprising subjecting the mammalian subject to radiation exposure before performing a surgical procedure, and subjecting the mammalian subject to a further radiation exposure after performing the surgical procedure.
41. The method or kit of any preceding claim, the method comprising performing a surgical procesure on the mammalian subject before a first exposure to radiation as a part of a course of radiation therapy.
42. The method or kit according to any preceding claim, the method comprising administering the pentaaza macrocyclic ring complex according to Formula (I) before subjecting the mammalian subject to radiation exposure.
43. The method or kit according to any preceding claim, the method comprising administering the pentaaza macrocyclic ring complex according to Formula (I) after subjecting the mammalian subject to radiation exposure.
44. The method or kit according to any preceding claim, the method comprising administering the pentaaza macrocyclic ring complex according to Formula (I) concomitantly with subjecting the mammalian subject to radiation exposure.
45. The method or kit according to any preceding claim, the method comprising administering the pentaaza macrocyclic ring complex according to Formula (I) on a same day as subjecting the mammalian subject to radiation exposure.
46. The method or kit according to any preceding claim, the method comprising administering the pentaaza macrocyclic ring complex according to Formula (I) before performing surgery on the mammalian subject.
47. The method or kit according to any preceding claim, the method comprising administering the pentaaza macrocyclic ring complex according to Formula (I) after performing surgery on the mammalian subject.
48. The method or kit according to any preceding claim, the method comprising administering the pentaaza macrocyclic ring complex according to Formula (I) concomitantly with performing surgery on the mammalian subject.
49. The method or kit according to any preceding claim, the method comprising administering the pentaaza macrocyclic ring complex according to Formula (I) on a same day as performing surgery on the mammalian subject.
50. The method or kit according to any preceding claim, wherein the radiation therapy comprises administration of a plurality of radiation exposures to the mammalian subject, and wherein each of the plurality of radiation exposures comprises a dose fraction of an overall dosing regimen.
51. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex according to Formula (I) is administered prior to, concomitantly with, or after administration of a dose fraction of the overall dosing regimen.
52. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex according to Formula (I) is administered on a same day as a dose fraction of the overall dosing regimen.
53. The method or kit according to any preceding claim, wherein surgery is performed prior to, concomitantly with, or after administration of a dose fraction of the overall dosing regimen.
54. The method or kit according to any preceding claim, wherein surgery is performed on a same day as administration of a dose fraction of the overall dosing regimen.
55. The method or kit according to any preceding claim, wherein the radiation therapy comprises administration of a plurality of doses of radiation, with each dose optionally comprising a plurality of dose fractions.
56. The method or kit according to any preceding claim, wherein the radiation exposure is administered as part of aa course of radiation therapy comprising any selected from the group consisting of gamma irradiation, proton therapy, heavy ion therapy, brachytherapy, radionuclide therapy, conformal radiation therapy, intensity modulated radiation therapy, stereotactic body radiation therapy, stereoablative radiation therapy, and gamma knife therapy, whether delivered as standard fractionation, hypofractionation, accelerated fractionation or decelerated fractionation and variations thereof.
57. The method or kit according to any preceding claim, wherein the radiation therapy comprises one or more radiation exposures comprising at least 4 Gy of radiation, at least 8 Gy of radiation, at least 10 Gy of radiation, at least 12 Gy of radiation, at least 16 Gy of radiation, at least 18 Gy of radiation, at least 20 Gy of radiation, at least 25 Gy of radiation, at least 30 Gy of radiation, at least 35 Gy of radiation, at least 40 Gy of radiation, at least 45 Gy of radiation, at least 50 Gy of radiation, at least 55 Gy of radiation, or at least 60 Gy of radiation.
58. The method or kit according to any of preceding claim, the method further comprising administering to the subject a therapeutically effective amount of a chemotherapeutic agent.
59. The method or kit according to any preceding claim, wherein the mammalian subject is afflicted with a tumor comprising a cancer selected from the group consisting of soft tissue sarcoma, breast cancer, prostate cancer, testicular cancer, glioma, glioblastoma, head and neck cancer, ovarian cancer, endometrial cancer, hepatocellular carcinoma, desmoid tumors, pancreatic carcinoma, melanoma, and renal cell carcinoma.
60. The method or kit of claim 56, wherein the cancer and/or tumor comprises a soft tissue sarcoma or pancreatic carcinoma.
61. The method or kit according to any preceding claim, wherein the mammalian subject is a human subject.
62. The method or kit according to any preceding claim, wherein R1, R2, R'2, R3, R4,
R5, R'5, R6, Re, R7, Re, R9, R'9, and R10 are each hydrogen.
63. The method or kit according to any preceding claim, wherein W is an unsubstituted pyridine moiety.
64. The method or kit according to any preceding claim, wherein U and V are transcyclohexanyl fused rings.
65. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is represented by Formula (II)
Figure imgf000113_0001
wherein X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; and RA, RB, RC, and RD are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO 2NR11R12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl.
66. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is represented by Formula (III) or Formula (IV):
Figure imgf000114_0001
wherein X and Y represent suitable ligands which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof; and RA, RB, RC, and RD are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, heterocyclyl, an amino acid side chain moiety, or a moiety selected from the group consisting of -OR11, -NR11R12, -COR11, -CO2R11, -CONR11R12, -SR11, -SOR11, -SO2R11, -SO 2NR11R12, -N(OR11)(R12), -P(O)(OR11)(OR12), -P(O)(OR11)(R12), and -OP(O)(OR11)(OR12), wherein R11 and R12 are independently hydrogen or alkyl.
67. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is a compound represented by a formula selected from the group consisting of Formulae (V)-(XVI):
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
68. The method or kit according to any preceding claim, wherein X and Y are independently selected from substituted or unsubstituted moieties of the group consisting of halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid, aryl carboxylic acid, urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinous acid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate, aryl thiocarbamate, alkylaryl thiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkylaryl dithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite, tetrahalomanganate, tetrafluoroborate, hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate, citrate, ascorbate, saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions of ion exchange resins, or the corresponding anions thereof; or X and Y correspond to -0-C(0)-Xi, where each Xi is -C(X2)(X3)(X4), and each X1 is independently substituted or unsubstituted phenyl or -C(-X2)(-
X3X-X4); each X2 is independently substituted or unsubstituted phenyl, methyl, ethyl or propyl; each X3 is independently hydrogen, hydroxyl, methyl, ethyl, propyl, amino, -X5C(=0)Ri3 where X% is NH or O, and R13 is C1-C18 alkyl, substituted or unsubstituted aryl or C1-C18 aralkyl, or -OR14, where R14 is C1-C18 alkyl, substituted or unsubstituted aryl or C1 -C18 aralkyl, or together with X4 is (=0); and each X4 is independently hydrogen or together with X3 is (=0); or X and Y are independently selected from the group consisting of charge-neutralizing anions which are derived from any monodentate or polydentate coordinating ligand and a ligand system and the corresponding anion thereof; or X and Y are independently attached to one or more of R1, R2, R'2, R3, R4, Rs, R'5, R6, Re, R7, Re, R9, R'9, and R10.
69. The method or kit according to any preceding claim, wherein X and Y are independently selected from the group consisting of fluoro, chloro, bromo, and iodo anions.
70. The method or kit according to any preceding claim, wherein X and Y are independently selected from the group consisting of alkyl carboxylates, aryl carboxylates and arylalkyl carboxylates.
71. The method or kit according to any preceding claim, wherein X and Y are independently amino acids.
72. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is a compound represented by the formula:
Figure imgf000119_0001
73. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is a compound represented by the formula:
Figure imgf000119_0002
74. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is a compound represented by the formula:
Figure imgf000120_0001
75. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is represented by the formula:
Figure imgf000120_0002
76. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is represented by the formula:
Figure imgf000120_0003
77. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is represented by the formula:
Figure imgf000121_0001
.
78. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is represented by the formula:
Figure imgf000121_0002
79. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is administered to the subject in a dose in a range of from 0.2 mg/kg to 40 mg/kg.
80. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is administered to the subject in a dose in a range of from 0.2 mg/kg to 24 mg/kg.
81. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is administered to the subject in a dose in a range of from 0.2 mg/kg to 10 mg/kg.
82. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is administered via at least one of parenteral route and oral route.
83. The method or kit according to any preceding claim, wherein the pentaaza macrocyclic ring complex is administered intraperitoneally or intravenously.
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