Biomedicines

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Open AccessFeature PaperReview

Showing the Way: Oncolytic Adenoviruses as Chaperones of Immunostimulatory Adjuncts

by Jing Li Huang, Christopher J. LaRocca and Masato Yamamoto

Biomedicines 2016, 4(3), 23; https://doi.org/10.3390/biomedicines4030023 - 19 Sep 2016

Cited by 11 | Viewed by 4833

Oncolytic adenoviruses (OAds) are increasingly recognized as vectors for immunotherapy in the treatment of various solid tumors. The myriads of advantages of using adenovirus include targeted specificity upon infection and selective replication, which lead to localized viral burst, exponential spread of OAds, and [...] Read more.

Oncolytic adenoviruses (OAds) are increasingly recognized as vectors for immunotherapy in the treatment of various solid tumors. The myriads of advantages of using adenovirus include targeted specificity upon infection and selective replication, which lead to localized viral burst, exponential spread of OAds, and antitumor effect. OAds can also induce a strong immune reaction due to the massive release of tumor antigens upon cytolysis and the presence of viral antigens. This review will highlight recent advances in adenoviral vectors expressing immunostimulatory effectors, such as GM-CSF (granulocyte macrophage colony-stimulating factor), interferon-α, interleukin-12, and CD40L. We will also discuss the combination of OAds with other immunotherapeutic strategies and describe the current understanding of how adenoviral vectors interact with the immune system to eliminate cancer cells. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessFeature PaperArticle

An Abraded Surface of Doxorubicin-Loaded Surfactant-Containing Drug Delivery Systems Effectively Reduces the Survival of Carcinoma Cells

by Christian Schmidt, Fabiano Yokaichiya, Nurdan Doğangüzel, Margareth K. K. Dias Franco, Leide P. Cavalcanti, Mark A. Brown, Melissa I. Alkschbirs, Daniele R. De Araujo, Mont Kumpugdee-Vollrath and Joachim Storsberg

Biomedicines 2016, 4(3), 22; https://doi.org/10.3390/biomedicines4030022 - 15 Sep 2016

Cited by 4 | Viewed by 5364

Abstract

An effective antitumor remedy is yet to be developed. All previous approaches for a targeted delivery of anticancer medicine have relied on trial and error. The goal of this study was to use structural insights gained from the study of delivery systems and [...] Read more.

An effective antitumor remedy is yet to be developed. All previous approaches for a targeted delivery of anticancer medicine have relied on trial and error. The goal of this study was to use structural insights gained from the study of delivery systems and malignant cells to provide for a systematic approach to the development of next-generation drugs. We used doxorubicin (Dox) liposomal formulations. We assayed for cytotoxicity via the electrical current exclusion method. Dialysis of the samples yielded information about their drug release profiles. Information about the surface of the delivery systems was obtained through synchrotron small-angle X-ray scattering (SAXS) measurements. SAXS measurements revealed that Dox-loading yielded an abraded surface of our Dox liposomal formulation containing soybean oil, which also correlated with an effective reduction of the survival of carcinoma cells. Furthermore, a dialysis assay revealed that a higher burst of Dox was released from soybean oil-containing preparations within the first five hours. We conclude from our results that an abraded surface of Dox-loaded drug delivery system increases their efficacy. The apparent match between surface geometry of drug delivery systems and target cells is suggested as a steppingstone for refined development of drug delivery systems. This is the first study to provide a systematic approach to developing next-generation drug carrier systems using structural insights to guide the development of next-generation drug delivery systems with increased efficacy and reduced side effects. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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Full article ">Figure 1
Freshly prepared carrier systems display a peak hydrodynamic particle size of approximately 200 nm. Freshly prepared particles (blank: top panel; doxorubicin (Dox)-loaded particles: bottom panel) were diluted 1:2500 in particle-free water and measured using a Malvern particle size reader. The distribution of the hydrodynamic particle size (in nm) is plotted against the intensity (in %). Individual preparations are denoted by black: soybean oil formulation with sodium tetradecyl sulfate (STS); red: soybean oil formulation without STS; green: Mygliol 812 formulations with STS; blue: Mygliol 812 formulations without STS. Full article ">Figure 2
Stable mean hydrodynamic particle size distribution of delivery systems after 7 months of storage at 4 °C in the dark. The same preparations that were measured in <a href="#biomedicines-04-00022-f001" class="html-fig">Figure 1</a> were stored for 7 months in the dark at 4 °C and subjected to a determination of the mean hydrodynamic particle size distribution, as described in <a href="#biomedicines-04-00022-f001" class="html-fig">Figure 1</a> and above. The distribution of the hydrodynamic particle size (in nm) is plotted against the intensity (in %). Individual preparations are denoted on the left side of each graph. Full article ">Figure 3
Uniform release characteristics of carrier systems tested. Equal amounts of Dox-loaded carriers were placed in a dialysis bag and dialyzed against a volume of 50 mL buffer under constant agitation (100 rpm). Optical densities of samples, corrected against dialysis medium were used to determine [Dox]. Full article ">Figure 4
The viability of HeLa and HCT-116 cells is reduced after exposure to Dox soybean oil-based carrier systems. Shown here are phase contrast images with focus on adherent cells of HeLa (top panel) and HCT116 cultures (bottom panel) before and after exposure to 1 µM of Dox delivered via soybean oil-based carriers without STS. These images were taken before cells were harvested for the determination of the survival using the Casy TT system, as described in the Methods section. Note the changed morphology in response of the treatment with Dox. The results of the quantification are shown in <a href="#biomedicines-04-00022-f005" class="html-fig">Figure 5</a>. Full article ">Figure 5
The survival of HeLa cells is reduced the strongest with Dox-loaded and STS-containing soybean oil-based carrier systems. Shown here are medium-corrected, relative survival rates of either HeLa or HCT116 cells in response to Dox. To account for the eventuality of cytotoxic properties of empty carrier systems, we added comparable amounts of empty carriers as were needed to the delivery of the concentration of Dox (not shown). Red bars indicate 1 µM free Dox, and violet bars indicate 1 µM Dox delivered via carrier systems. The results for soybean oil-derived formulations are shown in the top panel, whereas and the results for the corresponding Mygliol 812-derived formulations are shown in the bottom panel. Full article ">Figure 6
Loading with Dox abrades the surfaces of STS-containing soybean oil carriers. Shown here are the results of SAXS measurements using STS-containing Mygliol 812 (M) and Soybean (S) oil-based carriers with S0 and M0 denoting plain formulations, and Dox-loaded carriers labeled with the amounts of Dox loaded (M1: 180 µM; S1: 360 µM; M2 and S2: 540 µM; M3 and S3: 900 µM). The intensity of the scattering event I is plotted using arbitrary units against the scattering vector q in nm−1 with the approximated tangent of the graph denoted as red line in the respective plots. In addition, a graphical interpretation of the results obtained is provided. Both plain soybean oil and plain Mygliol 812-based systems display a smooth surface in accordance with [<a href="#B30-biomedicines-04-00022" class="html-bibr">30</a>]. Loading with Dox, regardless of the amounts loaded, roughens the surface in the case of soybean oil carriers. In stark contrast, Mygliol 812-based formulations yield a diffuse surface after loading with Dox. Full article ">

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Open AccessFeature PaperReview

Capitalizing on Cancer Specific Replication: Oncolytic Viruses as a Versatile Platform for the Enhancement of Cancer Immunotherapy Strategies

by Donald Bastin, Scott R. Walsh, Meena Al Saigh and Yonghong Wan

Biomedicines 2016, 4(3), 21; https://doi.org/10.3390/biomedicines4030021 - 24 Aug 2016

Cited by 11 | Viewed by 6633

Abstract

The past decade has seen considerable excitement in the use of biological therapies in treating neoplastic disease. In particular, cancer immunotherapy and oncolytic virotherapy have emerged as two frontrunners in this regard with the first FDA approvals for agents in both categories being [...] Read more.

The past decade has seen considerable excitement in the use of biological therapies in treating neoplastic disease. In particular, cancer immunotherapy and oncolytic virotherapy have emerged as two frontrunners in this regard with the first FDA approvals for agents in both categories being obtained in the last 5 years. It is becoming increasingly apparent that these two approaches are not mutually exclusive and that much of the therapeutic benefit obtained from the use of oncolytic viruses (OVs) is in fact the result of their immunotherapeutic function. Indeed, OVs have been shown to recruit and activate an antitumor immune response and much of the current work in this field centers around increasing this activity through strategies such as engineering genes for immunomodulators into OV backbones. Because of their broad immunostimulatory functions, OVs can also be rationally combined with a variety of other immunotherapeutic approaches including cancer vaccination strategies, adoptive cell transfer and checkpoint blockade. Therefore, while they are important therapeutics in their own right, the true power of OVs may lie in their ability to enhance the effectiveness of a wide range of immunotherapies. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Immunostimulatory actions of oncolytic viruses converts non-inflamed tumors into inflamed tumors and induce an antitumor immune response. (A) Established tumors with a non-inflamed phenotype show a reduced inflammatory cytokine expression profile and a lack of T cell infiltration. A state of immune exclusion and ignorance is induced in these tumors by immunosuppression induced by inhibitory immune cells such as Treg and myeloid derived suppressor cells (MDSC) in the tumor microenvironment; (B) Infection of a tumor with an oncolytic virus leads to a variety of immunostimulatory actions which can convert a non-inflamed tumor into an inflamed tumor and promote an antitumor response. OV infection leads to the release of chemokines and cytokines from infected cells which recruit a variety of innate and adaptive immune effector cells. PAMPs (pathogen associated molecular patterns) associated with OVs and DAMPs (danger associated molecular patterns) released upon oncolysis provide maturation signals to antigen presenting cells within the tumor microenvironment which then phagocytose and cross-present these antigens in the secondary lymphoid organs to induce an adaptive anti-tumor response. Full article ">Figure 2
Left side: Enhanced anti-tumor response when using OV to boost a TAA prime. When boosting an anti-TAA response with an OV, two distinct viral vectors encoding a common tumor-associated antigen are employed. Priming with an empty adenoviral vector (Priming vector-no TAA) and boosting with a rhabdovirus expressing a TAA (Boosting OV vector-TAA) induces an anti-TAA response which is overshadowed by the anti-OV response; Right side: Priming with an adenoviral vector expressing a TAA (Priming vector-TAA) and boosting with a rhabdovirus expressing the same TAA (Boosting OV vector-TAA) induces a dramatically enhanced anti-TAA response and a reduced anti-OV response. Full article ">Figure 3
Rhabdovirus OVV boosting of TCM in the splenic follicle and the marginal zone as an anatomical barrier preventing TEFF recirculating back to the follicle. TAA-specific TCM cells induced by the priming vector reside in the splenic follicle which is maintained as an immunopriviliged site by the surrounding marginal zone and its resident marginal zone macrophages (MΦ). When administered by intravenous injection, VSV traffics to the splenic follicle and infects follicular B cells. Infected B cells produce and release TAA encoded by the rhabdovirus which is taken up by neighbouring DCs and presented to TCM cells. Stimulated TCM cells are converted into TEFF and are excluded from the follicle by the marginal zone so that they cannot eliminate TAA carrying DCs. Full article ">Figure 4
Combination of dual-specific ACT and OVV therapy. T cells with native TCR specificity for a TAA are engineered to express a recombinant TCR or CAR in order to generate dual specific T cells for ACT. Serial injection of dual specific T cells and an OVV serves to activate T cells through TCR stimulation and recruit them to the tumor where they can detect TAA positive cells and attack the tumor through either TCR or CAR binding of its target. In this way, tumors with heterogeneous TAA expression can be effectively targeted and destroyed with one combination therapy. Full article ">

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Open AccessReview

Emerging Therapeutic Potential of Nanoparticles in Pancreatic Cancer: A Systematic Review of Clinical Trials

by Minnie Au, Theophilus I. Emeto, Jacinta Power, Venkat N. Vangaveti and Hock C. Lai

Biomedicines 2016, 4(3), 20; https://doi.org/10.3390/biomedicines4030020 - 19 Aug 2016

Cited by 27 | Viewed by 7538

Abstract

Pancreatic cancer is an aggressive disease with a five year survival rate of less than 5%, which is associated with late presentation. In recent years, research into nanomedicine and the use of nanoparticles as therapeutic agents for cancers has increased. This article describes [...] Read more.

Pancreatic cancer is an aggressive disease with a five year survival rate of less than 5%, which is associated with late presentation. In recent years, research into nanomedicine and the use of nanoparticles as therapeutic agents for cancers has increased. This article describes the latest developments in the use of nanoparticles, and evaluates the risks and benefits of nanoparticles as an emerging therapy for pancreatic cancer. The Preferred Reporting Items of Systematic Reviews and Meta-Analyses checklist was used. Studies were extracted by searching the Embase, MEDLINE, SCOPUS, Web of Science, and Cochrane Library databases from inception to 18 March 2016 with no language restrictions. Clinical trials involving the use of nanoparticles as a therapeutic or prognostic option in patients with pancreatic cancer were considered. Selected studies were evaluated using the Jadad score for randomised control trials and the Therapy CA Worksheet for intervention studies. Of the 210 articles found, 10 clinical trials including one randomised control trial and nine phase I/II clinical trials met the inclusion criteria and were analysed. These studies demonstrated that nanoparticles can be used in conjunction with chemotherapeutic agents increasing their efficacy whilst reducing their toxicity. Increased efficacy of treatment with nanoparticles may improve the clinical outcomes and quality of life in patients with pancreatic cancer, although the long-term side effects are yet to be defined. The study registration number is CRD42015020009. Full article

(This article belongs to the Section Immunology and Immunotherapy)

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Open AccessFeature PaperReview

Recombinant Poxvirus and the Tumor Microenvironment: Oncolysis, Immune Regulation and Immunization

by Daniel W. Sharp and Edmund C. Lattime

Biomedicines 2016, 4(3), 19; https://doi.org/10.3390/biomedicines4030019 - 12 Aug 2016

Cited by 24 | Viewed by 7680

Abstract

Oncolytic viruses (OVs) are being extensively studied for their potential roles in the development of cancer therapy regimens. In addition to their direct lytic effects, OVs can initiate and drive systemic antitumor immunity indirectly via release of tumor antigen, as well as by [...] Read more.

Oncolytic viruses (OVs) are being extensively studied for their potential roles in the development of cancer therapy regimens. In addition to their direct lytic effects, OVs can initiate and drive systemic antitumor immunity indirectly via release of tumor antigen, as well as by encoding and delivering immunostimulatory molecules. This combination makes them an effective platform for the development of immunotherapeutic strategies beyond their primary lytic function. Engineering the viruses to also express tumor-associated antigens (TAAs) allows them to simultaneously serve as therapeutic vaccines, targeting and amplifying an immune response to TAAs. Our group and others have shown that vaccinating intratumorally with a poxvirus that encodes TAAs, in addition to immune stimulatory molecules, can modulate the tumor microenvironment, overcome immune inhibitory pathways, and drive both local and systemic tumor specific immune responses. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Graphical abstract

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Schematic diagram showing how recombinant oncolytic viruses (OV) therapy can overcome the immunosuppressive effects of the Tumor Microenvironment (TME): (a) Tumor cell secretion of a variety of cytokines and other factors can inhibit productive immune response by dendritic cells (DC), cytolytic T-cells (CTL) and type-1 helper T-cells (TH1) and generate protective immunosuppressive cell populations such as tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC) and regulatory T-cells (Treg); (b) Intratumoral treatment with OV therapy can overcome the immunosuppressive TME by lysing tumor cells (releasing inflammatory signals), expressing immunostimulatory molecules within the TME (reversing the inhibition by tumor cells and removing the stimuli for immunosuppressive cells), and over-expressing tumor-associated-antigens (TAAs) for DC uptake and T-cell activation. Full article ">Figure 2
Neutralization of Tregs enhances the tumor growth-inhibiting effects of both systemic and intratumoral TAA vaccination. Combination treatment with the anti-CD25 monoclonal antibody PC61 and either systemic or intratumoral VV-HY (a cocktail of two rVVs encoding genes coding for two immunodominant tumor antigens) inhibits tumor growth (a) and results in prolonged survival (b) compared to treatment with either systemic or intratumoral VV-HY alone. Reprinted from [<a href="#B91-biomedicines-04-00019" class="html-bibr">91</a>], with permission from Elsevier. Full article ">Figure 3
Vaccination into the tumor microenvironment with recombinant VV-neu leads to tumor regression, increased systemic CTL response, and reverses the systemic elevation in MDSC. (a) In a mouse HER2+ breast cancer mode, vaccination into the tumor microenvironment with recombinant vaccinia expressing the HER2/neu TAA (i.t. VV-neu + VV-GMCSF + KLH) results in a tumor specific CTL response; (b) regression of the primary tumor; (c) and a decrease in systemic MDSCs, whereas systemic treatment (s.c. VV-neu + VV-GMCSF + KHL) is not effective. Reprinted from [<a href="#B91-biomedicines-04-00019" class="html-bibr">91</a>], with permission from Elsevier. Full article ">

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Open AccessFeature PaperReview

From Benchtop to Bedside: A Review of Oncolytic Virotherapy

by Audrey H. Choi, Michael P. O’Leary, Yuman Fong and Nanhai G. Chen

Biomedicines 2016, 4(3), 18; https://doi.org/10.3390/biomedicines4030018 - 2 Aug 2016

Cited by 55 | Viewed by 8479

Abstract

Oncolytic viruses (OVs) demonstrate the ability to replicate selectively in cancer cells, resulting in antitumor effects by a variety of mechanisms, including direct cell lysis and indirect cell death through immune-mediate host responses. Although the mechanisms of action of OVs are still not [...] Read more.

Oncolytic viruses (OVs) demonstrate the ability to replicate selectively in cancer cells, resulting in antitumor effects by a variety of mechanisms, including direct cell lysis and indirect cell death through immune-mediate host responses. Although the mechanisms of action of OVs are still not fully understood, major advances have been made in our understanding of how OVs function and interact with the host immune system, resulting in the recent FDA approval of the first OV for cancer therapy in the USA. This review provides an overview of the history of OVs, their selectivity for cancer cells, and their multifaceted mechanism of antitumor action, as well as strategies employed to augment selectivity and efficacy of OVs. OVs in combination with standard cancer therapies are also discussed, as well as a review of ongoing human clinical trials. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessArticle

In Vitro Anti-Oxidant and Anti-Microbial Potentiality Investigation of Different Fractions of Caryota urens Leaves

by Shofiul Azam, Md. Kayes Mahmud, Md. Hamza Naquib, Saad Mosharraf Hossain, Mohammad Nazmul Alam, Md. Josim Uddin, Irfan Sajid, Muhammad Sazzad Hossain, Md. Salimul Karim and Md. Ali Hasan

Biomedicines 2016, 4(3), 17; https://doi.org/10.3390/biomedicines4030017 - 27 Jul 2016

Cited by 9 | Viewed by 5393

Abstract

Background: Caryota urens is a member of the Arecaceae family and a common plant in the Southeast Asian region. This plant has been reported as an anti-microbial agent in recent years. Thus, we aimed to find out the MIC (minimum inhibitory concentration) against [...] Read more.

Background: Caryota urens is a member of the Arecaceae family and a common plant in the Southeast Asian region. This plant has been reported as an anti-microbial agent in recent years. Thus, we aimed to find out the MIC (minimum inhibitory concentration) against different pathogenic microorganism. Methods: The leaves of C. urens were extracted and fractioned using different reagents (chloroform, n-hexane and carbon tetrachloride). Disc diffusion method was implemented for the assessment of in vitro anti-microbial potency (500 and 250 µg/disc). Result: The entire fraction showed good effect (with the zone of inhibition 19–25 mm) against both gram positive (Bacillus subtilis, Bacillus megaterium, Bacillus cereus, Sarina lutea) and gram negative (Vibrio mimicus, Shigella boydii, Escherichia coli, Pseudomonas aeruginosa) bacterial pathogens and fungal strains (Aspergillus niger, Saccharomyces cerevisiae). The plants also possess effective free radical scavenging potency with an IC₅₀ of 130.32 µg/mL. Conclusion: This finding reflects a link between the presence of anti-oxidative material and a substantial anti-microbial activity, and substantiates all previous claims against C. urens. Full article

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Open AccessFeature PaperReview

Fifty Years of Clinical Application of Newcastle Disease Virus: Time to Celebrate!

by Volker Schirrmacher

Biomedicines 2016, 4(3), 16; https://doi.org/10.3390/biomedicines4030016 - 20 Jul 2016

Cited by 68 | Viewed by 7890

Abstract

This review provides an overview of 50 years of basic and clinical research on an oncolytic avian virus, Newcastle Disease Virus (NDV), which has particular anti-neoplastic and immune stimulatory properties. Of special interest is the fact that this biological agent induces immunogenic cell [...] Read more.

This review provides an overview of 50 years of basic and clinical research on an oncolytic avian virus, Newcastle Disease Virus (NDV), which has particular anti-neoplastic and immune stimulatory properties. Of special interest is the fact that this biological agent induces immunogenic cell death and systemic anti-tumor immunity. Furthermore, localized oncolytic virotherapy with NDV was shown to overcome systemic tumor resistance to immune checkpoint blockade immunotherapy. Clinical experience attests to low side effects and a high safety profile. This is due among others to the strong virus-induced type I interferon response. Other viral characteristics are lack of interaction with host cell DNA, lack of genetic recombination and independence of virus replication from cell proliferation. In this millennium, new recombinant strains of viruses are being produced with improved therapeutic properties. Clinical applications include single case observations, case series studies and Phase I to III studies. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Open AccessArticle

Design, Synthesis and Biochemical Evaluation of Novel Selective Estrogen Receptor Ligand Conjugates Incorporating an Endoxifen-Combretastatin Hybrid Scaffold

by Niall O. Keely, Miriam Carr, Bassem Yassin, Gloria Ana, David G. Lloyd, Daniela Zisterer and Mary J. Meegan

Biomedicines 2016, 4(3), 15; https://doi.org/10.3390/biomedicines4030015 - 20 Jul 2016

Cited by 16 | Viewed by 6245

Abstract

Nuclear-receptors are often overexpressed in tumours and can thereby be used as targets when designing novel selective chemotherapeutic agents. To date, many conjugates incorporating an estrogen receptor (ER) ligand have been synthesised in order to direct chemical agents to tissue sites containing ERs. [...] Read more.

Nuclear-receptors are often overexpressed in tumours and can thereby be used as targets when designing novel selective chemotherapeutic agents. To date, many conjugates incorporating an estrogen receptor (ER) ligand have been synthesised in order to direct chemical agents to tissue sites containing ERs. A series of ER ligand conjugates were synthesised incorporating an antagonistic ER ligand scaffold based on endoxifen, covalently-bound via an amide linkage to a variety of combretastatin-based analogues, which may act as antimitotic agents. These novel endoxifen-combretastatin hybrid scaffold analogues were biochemically evaluated in order to determine their antiproliferative and cytotoxicity effects in both the ER-positive MCF-7 and the ER-negative MDA-MB-231 human breast cancer cell lines. ER competitive binding assays were carried out to assess the binding affinity of the lead conjugate 28 towards both the ERα and ERβ isoforms. In results from the NCI 60-cell line screen, the lead conjugate 28 displayed potent and highly selective antiproliferative activity towards the MCF-7 human cancer cell line (IC₅₀ = 5 nM). In the ER-binding assays, the lead conjugate 28 demonstrated potent ER competitive binding in ERα (IC₅₀ value: 0.9 nM) and ERβ (IC₅₀ value: 4.7 nM). Preliminary biochemical results also demonstrate that the lead conjugate 28 may exhibit pure antagonism. This series makes an important addition to the class of ER antagonists and may have potential applications in anticancer therapy. Full article

(This article belongs to the Special Issue Development, Manufacture and Clinical Application of Drug Conjugates in Cancer Therapy)

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Estradiol, Tamoxifen, 4-Hydroxytamoxifen, Endoxifen and Combretastatin A-4. Full article ">Figure 2
Effect on alkaline phosphatase activity of conjugate 28 and tamoxifen in Ishikawa cells. Full article ">Figure 3
Predicted binding mode of compound 28 in the ligand binding domain of ERα. Highest-ranking docking orientation and predicted receptor interactions for 28 (ball-and-stick representation) in ERα compared to the crystal solution for 4-hydroxytamoxifen (yellow); pdb 3ERT [<a href="#B41-biomedicines-04-00015" class="html-bibr">41</a>]. (H-bond interactions are illustrated as broken lines). Full article ">Figure 4
Predicted binding mode of compound 28 in the ligand binding domain of ERβ. Highest-ranking docking orientation and predicted receptor interactions for 28 (ball-and-stick representation) in ERβ compared to the crystal solution for 4-hydroxytamoxifen (yellow) (pdb 1QKN) [<a href="#B42-biomedicines-04-00015" class="html-bibr">42</a>]. (H-bond interactions are illustrated as broken lines). Full article ">Scheme 1
Synthesis of endoxifen 11 and hydroxyendoxifen derivative 12. Reagents and conditions: (i) TBDMS-Cl, Imidazole, DMF; (ii) Zn, TiCl4, THF; (iii) BrCH2CH2Br, NaOH (aq.), (nBu)4NHSO3; (iv) CH3NH2, sealed tube, 60 °C; (v) TBAF, THF. (TBDMS = tert-Butyldimethylsilyl). Full article ">Scheme 2
Synthesis of combretastatin acrylic acid analogues. Reagents and conditions: (i) (CH3CO)2O, Et3N, reflux, 3 h followed by conc HCl. Full article ">Scheme 3
Synthesis of endoxifen-combretastatin hybrid conjugates 27–46 and amides 47–55. Reagents and conditions: (i) DCC, HOBt, CH2Cl2, 20 °C, 24–48 h; (ii) TBAF, THF, 20 °C, 24 h (R1–R8: see <a href="#biomedicines-04-00015-t002" class="html-table">Table 2</a>); (iii) Pyrrolidine or piperidine, 2-chloro-1-methylpyridinium iodide, CH2Cl2, Et3N, 20 °C, 1 h; (iv) Fe, HCl, CH3CO2H, EtOH, reflux, 12 h. Full article ">

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Open AccessReview

Antibody–Drug Conjugates for Cancer Therapy

by Adam C. Parslow, Sagun Parakh, Fook-Thean Lee, Hui K. Gan and Andrew M. Scott

Biomedicines 2016, 4(3), 14; https://doi.org/10.3390/biomedicines4030014 - 11 Jul 2016

Cited by 81 | Viewed by 14189

Abstract

Antibody–drug conjugates (ADCs) take advantage of the specificity of a monoclonal antibody to deliver a linked cytotoxic agent directly into a tumour cell. The development of these compounds provides exciting opportunities for improvements in patient care. Here, we review the key issues impacting [...] Read more.

Antibody–drug conjugates (ADCs) take advantage of the specificity of a monoclonal antibody to deliver a linked cytotoxic agent directly into a tumour cell. The development of these compounds provides exciting opportunities for improvements in patient care. Here, we review the key issues impacting on the clinical success of ADCs in cancer therapy. Like many other developing therapeutic classes, there remain challenges in the design and optimisation of these compounds. As the clinical applications for ADCs continue to expand, key strategies to improve patient outcomes include better patient selection for treatment and the identification of mechanisms of therapy resistance. Full article

(This article belongs to the Special Issue Development, Manufacture and Clinical Application of Drug Conjugates in Cancer Therapy)

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Open AccessFeature PaperReview

Tumor-Associated Macrophages in Oncolytic Virotherapy: Friend or Foe?

by Nicholas L. Denton, Chun-Yu Chen, Thomas R. Scott and Timothy P. Cripe

Biomedicines 2016, 4(3), 13; https://doi.org/10.3390/biomedicines4030013 - 7 Jul 2016

Cited by 39 | Viewed by 8004

Abstract

Cancer therapy remains a challenge due to toxicity limitations of chemotherapy and radiation therapy. Oncolytic viruses that selectively replicate and destroy cancer cells are of increasing interest. In addition to direct cell lysis, these vectors stimulate an anti-tumor immune response. A key regulator [...] Read more.

Cancer therapy remains a challenge due to toxicity limitations of chemotherapy and radiation therapy. Oncolytic viruses that selectively replicate and destroy cancer cells are of increasing interest. In addition to direct cell lysis, these vectors stimulate an anti-tumor immune response. A key regulator of tumor immunity is the tumor-associated macrophage population. Macrophages can either support oncolytic virus therapy through pro-inflammatory stimulation of the anti-tumor response at the cost of hindering direct oncolysis or through immunosuppressive protection of virus replication at the cost of hindering the anti-tumor immune response. Despite similarities in macrophage interaction between adult and pediatric tumors and the abundance of research supporting macrophage modulation in adult tumors, there are few studies investigating macrophage modulation in pediatric cancers or modulation of immunotherapy. We review the current state of knowledge regarding macrophages in cancers and their influence on oncolytic virotherapy. Full article

(This article belongs to the Special Issue Oncolytic Viruses as a Novel Form of Immunotherapy for Cancer)

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Biomedicines, Volume 4, Issue 3 (September 2016) – 11 articles

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