WO2008106606A2

WO2008106606A2 - Carotenoid analogs and derivatives in the treatment of prostate cancer

Info

Publication number: WO2008106606A2
Application number: PCT/US2008/055334
Authority: WO
Inventors: Timothy J. King; Samuel F Lockwood; Andrew David Hieber; Nicholas J. Shubin; Henry J. Jackson; Geoffry T. Nadolski
Original assignee: Cardax Pharmaceuticals, Inc.
Priority date: 2007-02-28
Filing date: 2008-02-28
Publication date: 2008-09-04
Also published as: WO2008106606A3

Abstract

The presently described embodiments are directed to compositions that include one or more carotenoid analogs or derivatives for use in the treatment of prostate cancer, BPH or prostatitis. Certain embodiments provide for the use of said carotenoid analogs or derivatives in preparing compositions suitable for use in such treatments. Further embodiments provide for pharmaceutical compositions that include one or more carotenoid analogs or derivatives in combination with one or more additional compositions or medicaments suitable for the treatment of prostate cancer. Yet further embodiments provide for methods of treating prostate cancer that include administering to a subject who would benefit from such treatment pharmaceutical compositions suitable for inhibiting or reducing one or more components of NF-κB signaling in the subject undergoing said treatments, and that include carotenoid analogs or derivatives, optionally in combination with one or more additional compositions or medicaments suitable for the treatment of prostate cancer.

Description

CAROTENOID ANALOGS AND DERIVATIVES IN THE TREATMENT OF PROSTATE

CANCER

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally relates to the field of medicinal chemistry. More specifically, the present invention relates to the use of carotenoid analogs, derivatives and compositions made using same for the treatment of prostate cancer and/or prostatitis and/or BPH in a subject. 2. Description of the Relevant Art

Prostate cancer is a disease in which cancer develops in the prostate, a gland in the male reproductive system. Cancer occurs when cells of the prostate mutate and begin to multiply out of control. These cells may spread (metastasize) from the prostate to other parts of the body, especially the bones and lymph nodes. Prostate cancer may cause pain, difficulty in urinating, erectile dysfunction and other symptoms.

Rates of prostate cancer vary widely across the world. Although the rates vary widely between countries, it is least common in South and East Asia, more common in Europe, and most common in the United States. According to the American Cancer Society, prostate cancer is least common among Asian men and most common among black men with figures for European men in-between. However, these high rates may be affected by increasing rates of detection.

Prostate cancer develops most frequently in men over fifty. This cancer can occur only in men, as the prostate is exclusively of the male reproductive tract. It is the most common type of cancer in men in the United States, where it is responsible for more male deaths than any other cancer, except lung cancer. However, many men who develop prostate cancer never have symptoms, undergo no therapy, and eventually die of other causes. Many factors, including genetics and diet, have been implicated in the development of prostate cancer.

Prostate cancer is most often discovered by physical examination or by screening blood tests, such as the PSA (prostate specific antigen) test. There is some current concern about the accuracy of the PSA test and its usefulness. Suspected prostate cancer is typically confirmed by removing a piece of the prostate (biopsy) and examining it under a microscope. Further tests, such as X-rays and bone scans, may be performed to determine whether prostate cancer has spread.

Prostate cancer can be treated with surgery, radiation therapy, hormone therapy, occasionally chemotherapy, or some combination of these. The age and underlying health of the man as well as the extent of spread, appearance under the microscope, and response of the cancer to initial treatment are important in determining the outcome of the disease. Since prostate cancer is a disease of older men, many will die of other causes before the prostate cancer can spread or cause symptoms. This makes treatment selection difficult. The decision whether or not to treat localized prostate cancer (a tumor that is contained within the prostate) with curative intent is a patient trade-off between the expected beneficial and harmful effects in terms of patient survival and quality of life.

NF-κB, is a ubiquitous transcription factor and regulates the transcription of a number of genes involved in immune and inflammatory pathways such as various pro-inflammatory cytokines, adhesion molecules, and apoptosis and thus, is one of the central regulators of an organism's responses to various stress signals. Dysregulation of NF-κB contributes to a variety of pathological conditions such as septic shock, acute inflammation, viral replication, and some malignancies.

The most abundant and active forms of NF-κB are dimeric complexes of p50/relA (p50/p65). In unstimulated cells, these factors are held in the cytoplasm in a complex with inhibitory proteins (IKBS) that mask its nuclear localization signal. In response to an extracellular signal such as inflammatory cytokines, mitogens, bacterial products, or oxidative stress, IKB undergoes phosphorylation at specific serine residues, which then signals their ubiquitination and degradation by the proteosome pathway. Degradation of IKB allows an inhibitor-free NF-κB complex to translocate into the nucleus, bind DNA, and activate the transcription of specific genes. Because of its role in inflammation and carcinogenesis as well as other immunological disorders, it would follow that down modulators of NF-κB would have tremendous therapeutic implications. Furthermore, some downstream effects due to inhibition of NF-κB activity is a decrease in the levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression. Both iNOS and COX- 2 have critical roles in the response of tissues to inflammation, injury, and carcinogenesis. Thus, there is need in the art for regulators of NF-κB as well as iNOS and COX-2 as such compounds will provide antiinflammatory and chemopreventive effects.

Antioxidant Properties of Carotenoids

Carotenoids are a group of natural pigments produced principally by plants, yeast, and microalgae. The family of related compounds now numbers greater than 750 described members, exclusive of Z and E isomers. Humans and other animals cannot synthesize carotenoids de novo and must obtain them from their diet. All carotenoids share common chemical features, such as a polyisoprenoid structure, a long polyene chain forming the chromophore, and near symmetry around the central double bond. Tail-to-tail linkage of two C₂o geranyl-geranyl diphosphate molecules produces the parent C₄₀ carbon skeleton. Carotenoids without oxygenated functional groups are called "carotenes", reflecting their hydrocarbon nature; oxygenated carotenes are known as "xanthophylls." "Parent" carotenoids may generally refer to those natural compounds utilized as starting scaffold for structural carotenoid analog synthesis. Carotenoid derivatives may be derived from a naturally occurring carotenoid. Naturally occurring carotenoids may include lycopene, lycophyll, lycoxanthin, astaxanthin, beta-carotene, lutein, zeaxanthin, and/or canthaxanthin to name a few. Cyclization at one or both ends of the molecule yields 7 identified end groups (illustrative structures shown in FIG. 1). Examples of uses of carotenoid derivatives and analogs are illustrated in U.S. Patent Application Serial No. 10/793,671 filed on March 4, 2004, entitled "CAROTENOID ETHER ANALOGS OR DERIVATIVES FOR THE INHIBITION AND AMELIORATION OF DISEASE" by Lockwood et al. published on January 13, 2005, as Publication No. US -2005 -0009758 and PCT International Application Number PCT/US2003/023706 filed on July 29, 2003, entitled "STRUCTURAL CAROTENOID ANALOGS FOR THE INHIBITION AND AMELIORATION OF DISEASE" by

Lockwood et al. (International Publication Number WO 2004/011423 A2, published on February 5, 2004) both of which are incorporated by reference as though fully set forth herein.

Documented carotenoid functions in nature include light harvesting, photoprotection, and protective and sex-related coloration in microscopic organisms, mammals, and birds, respectively. A relatively recent observation has been the protective role of carotenoids against age-related diseases in humans as part of a complex antioxidant network within cells. This role is dictated by the close relationship between the physicochemical properties of individual carotenoids and their in vivo functions in organisms. The long system of alternating double and single bonds in the central part of the molecule (delocalizing the π-orbital electrons over the entire length of the polyene chain) confers the distinctive molecular shape, chemical reactivity, and light- absorbing properties of carotenoids. Additionally, isomerism around C=C double bonds yields distinctly different molecular structures that may be isolated as separate compounds (known as Z ("cis") and E ("trans"), or geometric, isomers). Of the more than 750 described carotenoids, an even greater number of the theoretically possible mono-Z and poly-Z isomers are sometimes encountered in nature. The presence of a Z double bond creates greater steric hindrance between nearby hydrogen atoms and/or methyl groups, so that Z isomers are generally less stable thermodynamically, and more chemically reactive, than the corresponding all-E form. The all-E configuration is an extended, linear, and rigid molecule. Z-isomers are, by contrast, not simple, linear molecules (the so-called "bent-chain" isomers). The presence of any Z in the polyene chain creates a bent- chain molecule. The tendency of Z-isomers to crystallize or aggregate is much less than all-E, and Z isomers are more readily solubilized, absorbed, and transported in vivo than their all-E counterparts. This has important implications for enteral (e.g., oral) and parenteral (e.g., intravenous, intra-arterial, intramuscular, and subcutaneous) dosing in mammals.

Carotenoids with chiral centers may exist either as the R (rectus) or S (sinister) configurations. As an example, astaxanthin (with 2 chiral centers at the 3 and 3' carbons) may exist as 4 possible stereoisomers: 3S, 3'S; 3R, 3'S and 3S, 3'R (identical meso forms); or 3R, 3'R. The relative proportions of each of the stereoisomers may vary by natural source. For example, Hαemαtococcus pluviαlis microalgal meal is 99% 3S, 3'S astaxanthin, and is likely the predominant human evolutionary source of astaxanthin. Krill (3R,3'R) and yeast sources yield different stereoisomer compositions than the microalgal source. Synthetic astaxanthin, produced by large manufacturers such as Hoffmann-LaRoche AG, Buckton Scott (USA), or BASF AG, are provided as defined geometric isomer mixtures of a 1:2:1 stereoisomer mixture [3S, 3'S; 3R, 3'S, 3'R,3S (meso); 3R, 3'R] of non-esterified, free astaxanthin. Natural source astaxanthin from salmonid fish is predominantly a single stereoisomer (3S,3'S), but does contain a mixture of geometric isomers. Astaxanthin from the natural source Haematococcus pluvialis may contain nearly 50% Z isomers. As stated above, the Z conformational change may lead to a higher steric interference between the two parts of the carotenoid molecule, rendering it less stable, more reactive, and more susceptible to reactivity at low oxygen tensions. In such a situation, in relation to the all-is form, the Z forms: (1) may be degraded first; (2) may better suppress the attack of cells by reactive oxygen species such as superoxide anion; and (3) may preferentially slow the formation of radicals. Overall, the Z forms may initially be thermodynamically favored to protect the lipophilic portions of the cell and the cell membrane from destruction. It is important to note, however, that the all-is form of astaxanthin, unlike β- carotene, retains significant oral bioavailability as well as antioxidant capacity in the form of its dihydroxy- and diketo-substitutions on the β-ionone rings, and has been demonstrated to have increased efficacy over β-carotene in most studies. The all-is form of astaxanthin has also been postulated to have the most membrane-stabilizing effect on cells in vivo. Therefore, it is likely that the all-is form of astaxanthin in natural and synthetic mixtures of stereoisomers is also extremely important in antioxidant mechanisms, and may be the form most suitable for particular pharmaceutical preparations. The antioxidant mechanism(s) of carotenoids, and in particular astaxanthin, includes singlet oxygen quenching, direct radical scavenging, and lipid peroxidation chain-breaking. The polyene chain of the carotenoid absorbs the excited energy of singlet oxygen, effectively stabilizing the energy transfer by derealization along the chain, and dissipates the energy to the local environment as heat. Transfer of energy from triplet-state chlorophyll (in plants) or other porphyrins and proto-porphyrins (in mammals) to carotenoids occurs much more readily than the alternative energy transfer to oxygen to form the highly reactive and destructive singlet oxygen (¹O₂). Carotenoids may also accept the excitation energy from singlet oxygen if any should be formed in situ, and again dissipate the energy as heat to the local environment. This singlet oxygen quenching ability has significant implications in cardiac ischemia, macular degeneration, porphyria, and other disease states in which production of singlet oxygen has damaging effects. In the physical quenching mechanism, the carotenoid molecule may be regenerated (most frequently), or be lost. Carotenoids are also excellent chain-breaking antioxidants, a mechanism important in inhibiting the peroxidation of lipids. Astaxanthin can donate a hydrogen (H ) to the unstable polyunsaturated fatty acid (PUFA) radical, stopping the chain reaction. Peroxyl radicals may also, by addition to the polyene chain of carotenoids, be the proximate cause for lipid peroxide chain termination. The appropriate dose of astaxanthin has been shown to completely suppress the peroxyl radical chain reaction in liposome systems. Astaxanthin shares with vitamin E this dual antioxidant defense system of singlet oxygen quenching and direct radical scavenging, and in most instances (and particularly at low oxygen tension in vivo) is superior to vitamin E as a radical scavenger and physical quencher of singlet oxygen. Carotenoids, and in particular astaxanthin, are potent direct radical scavengers and singlet oxygen quenchers and possess all the desirable qualities of such therapeutic agents for inhibition or amelioration of ischemia-reperfusion (I/R) injury. Synthesis of novel carotenoid derivatives with "soft-drug" properties (i.e. activity in the derivatized form), with physiologically relevant, cleavable linkages to pro-moieties, can generate significant levels of free carotenoids in both plasma and solid organs. This is critically important, for in mammals, diesters of carotenoids generate the non-esterified or "free" parent carotenoid, and may be viewed as elegant synthetic and novel delivery vehicles with improved properties for delivery of free carotenoid to the systemic circulation and ultimately to target tissue. In the case of non-esterified, free astaxanthin, this is a particularly useful embodiment (characteristics specific to non-esterified, free astaxanthin below):

Lipid soluble in natural form; may be modified to become more water soluble Molecular weight of 597 Daltons [size < 600 daltons (Da) readily crosses the blood brain barrier, or BBB]

Long polyene chain characteristic of carotenoids effective in singlet oxygen quenching and lipid peroxidation chain breaking

No pro-vitamin A activity in mammals (eliminating concerns of hypervitaminosis A and retinoid toxicity in humans). The administration of antioxidants that are potent singlet oxygen quenchers and direct radical scavengers, particularly of superoxide anion, should limit hepatic fibrosis and the progression to cirrhosis by affecting the activation of hepatic stellate cells early in the fibrogenetic pathway. Reduction in the level of ROS by the administration of a potent antioxidant can therefore be crucial in the prevention of the activation of both HSC and Kupffer cells. This protective antioxidant effect appears to be spread across the range of potential therapeutic antioxidants, including water-soluble (e.g., vitamin C, glutathione, resveratrol) and lipophilic (e.g., vitamin E, β-carotene, astaxanthin) agents. Therefore, a co-antioxidant derivative strategy in which water-soluble and lipophilic agents are combined synthetically is a particularly useful embodiment.

Vitamin E is generally considered the reference antioxidant. When compared with vitamin E, carotenoids are more efficient in quenching singlet oxygen in homogeneous organic solvents and in liposome systems. They are better chain-breaking antioxidants as well in liposomal systems. They have demonstrated increased efficacy and potency in vivo. They are particularly effective at low oxygen tension, and in low concentration, making them extremely effective agents in disease conditions in which ischemia is an important part of the tissue injury and pathology. These carotenoids also have a natural tropism for the liver after oral administration. Therefore, therapeutic administration of carotenoids should provide a greater benefit in limiting fibrosis than vitamin E.

Problems related to the use of some carotenoids and structural carotenoid analogs include: (1) the complex isomeric mixtures, including non-carotenoid contaminants, provided in natural and synthetic sources leading to costly increases in safety and efficacy tests required by such agencies as the FDA; (2) limited bioavailability upon administration to a subject; and (3) the differential induction of cytochrome P450 enzymes (this family of enzymes exhibits species-specific differences which must be taken into account when extrapolating animal work to human studies). SUMMARY OF THE INVENTION

In some embodiments, uses of carotenoids, carotenoid analogs or derivatives, including pharmaceutically acceptable salts thereof, may include the formulation of pharmaceutical compositions suitable for the treatment of prostate cancer.

In some embodiments, pharmaceutical compositions suitable for use in the treatment of prostate cancer, BPH or prostatitismay include one or more carotenoid analogs or derivatives in an amount sufficient to at least partially inhibit the activity NF-κB in at least a portion of prostate cancer cells in a subject. Inhibition of NF-κB prostate cancer cells in a subject may be associated with reduced phosphorylation of IKB, with reduced IKB expression in the cells, or with the combination thereof. In an embodiment, pharmaceutical compositions formulated for use in the treatment of prostate cancer may include one or more carotenoid analogs or derivatives in an amount sufficient to affect one or more properties of prostate cancer cells, including but not limited to reducing the growth rate of the prostate cancer cells, inhibiting the progression of the prostate cancer cells through the cell cycle, suppressing prostate cancer cell invasiveness, or reducing the survival rate of the prostate cancer cells.

In an embodiment, pharmaceutical compositions formulated for use in the treatment of prostate cancer may include one or more carotenoid analogs or derivatives in an amount sufficient to affect one or more biochemical pathways in prostate cancer cells, including but not limited to reducing the level of phosphorylation of one or more proteins involved in NF-κB activation (e.g., IKB), reduce the accumulation of NF-κB in the nucleus of prostate cancer cells, and or reduce the level of expression of one or more NF-κB responsive gene products in prostate cancer cells, including but not limited to e.g., cyclin Dl, TNF-α, MMP-9, c-myc, and IKB.

In some embodiments, pharmaceutical compositions provided that may include one or more carotenoid analogs or derivatives in combination with one or more additional compositions or medicaments used in the treatment of prostate cancer, including but not limited to one or more chemotherapy agents, one or more hormonal therapy agent, or one or more chemotherapy agents in combination with one or more hormonal therapy agents.

In some embodiments, methods are provided for treating prostate cancer in a subject. Such methods may include administering to an individual who would benefit from such treatment a therapeutically effective amount of a pharmaceutical composition that includes one or more carotenoid analogs or derivatives. Methods are also provided for the treatment of prostate cancer comprising administering to an individual having need for such treatment a therapeutically effective amount of a pharmaceutical composition that includes one or more carotenoid analogs or derivatives.

In certain embodiments, the carotenoid analogs or derivatives may be administered to a subject concurrently with one or more additional compositions or medicaments used in the treatment of prostate cancer, including but not limited to one or more chemotherapy agents, one or more hormonal therapy agent, or one or more chemotherapy agents in combination with one or more hormonal therapy agents. In an embodiment, the one or more additional compositions or medicaments may be administered to the subject either as a co-formulation, or as separate pharmaceutical and/or nutraceutical formulation administered as part of a co-therapy regimen. In one such embodiment, carotenoid analogs or derivatives may be administered to the subject undergoing such treatment prior to the commencement of drug therapy with the one or more additional compositions or medicaments used in the treatment of prostate cancer. In another embodiment, carotenoids analogs or derivatives may be administered to the subject following the commencement of drug therapy with the one or more additional compositions or medicaments used in the treatment of prostate cancer.

Administration of the carotenoid analogs or derivatives to a subject in accordance with the preceding embodiments may be provided to a subject with the intention of at least partially inhibiting and/or influencing some of the negative or undesirable cellular and/or biochemical processes that occur in prostate cancer cells. Administering one or more carotenoid analogs or derivatives by one skilled in the art as provided for herein - including consideration of the pharmacokinetics and pharmacodynamics of therapeutic drug delivery - is expected to reduce and/or ameliorate at least a portion of the of the negative or undesirable cellular and/or biochemical processes that occur in prostate cancer cells.

In some of the foregoing embodiments, analogs or derivatives of carotenoids may be at least partially water-soluble. "Water-soluble" structural carotenoid analogs or derivatives are those analogs or derivatives that may be formulated in aqueous solution, either alone or with one or more excipients. Water-soluble carotenoid analogs or derivatives may include those compounds and synthetic derivatives that form molecular self-assemblies, and may be more properly termed "water dispersible" carotenoid analogs or derivatives. Water-soluble and/or "water-dispersible" carotenoid analogs or derivatives may be preferred in some embodiments.

Water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 1 mg/mL in some embodiments. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 5 mg/ml - 10 mg/mL. In certain embodiments, water- soluble carotenoid analogs or derivatives may have a water solubility of greater than about 20 mg/mL. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 25 mg/mL. In some embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 50 mg/mL. In some embodiments, water-soluble analogs or derivatives of carotenoids may be administered to a subject alone or in combination with additional carotenoids or structural analogs or derivatives thereof. In some embodiments, water-soluble analogs or derivatives of carotenoids may be administered to a subject alone or in combination with other antioxidants.

The uses, methods and compositions contemplated herein include the use of one or more carotenoid analogs or derivatives. In some embodiments, a carotenoid analogs or derivatives may have the structure:

where each R³ is independently hydrogen or methyl, and where R¹ and R² are each independently:

wherein R⁴ is independently hydrogen, -OH, -CH₂OH, or -OR⁶; where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; alkyl; aryl; -alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl- N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^~; -aryl-CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)- aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl- CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(O)-(NR⁷)-alkyl-N(R⁷)₂; -C(O)-(NR⁷)-aryl-N(R⁷)₂; -C(O)-(NR⁷)-alkyl-N⁺(R⁷)₃; - C(O)-(NR⁷)-aryl-N⁺(R⁷)₃; -C(O)-(NR⁷)-alkyl-CO₂R⁹; -C(O)-(NR⁷)-aryl-CO₂R⁹; -C(O)-(NR⁷)-alkyl-CO₂ ^"; - C(O)-(NR⁷)-aryl-CO₂ ^"; -C(O)-(NR⁷)-alkyl-N(R⁷)-alkyl-N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; - C(O)-[C₆-C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

In some embodiments, carotenoid analogs or derivatives suitable for use with the present compositions, methods and uses may have the structure

where each R¹ and R² are independently:

where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; alkyl; aryl; - alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; -aryl- CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl- CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(O)- (NR⁷)-alkyl-N(R⁷)₂; -C(O)- (NR⁷)- aryl-N(R⁷)₂; -C(O)- (NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)- (NR⁷)-aryl-N⁺(R⁷)₃; -C(O)- (NR⁷)-alkyl-CO₂R⁹; -C(O)- (NR⁷)-aryl-CO₂R⁹; -C(O)- (NR⁷)-alkyl-CO₂ ^~; -C(O)- (NR⁷)-aryl-CO₂ ^~; -C(O)- (NR⁷)-alkyl-N(R⁷)-alkyl- N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-amino acid; -C(NR⁷)-amino acid; -C(O)-[C₆-C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co- antioxidant.

In some embodiments, each -OR⁶ group may independently be

-(C(O)-CH₂-NHMe, -C(O)-NHMe-CH₂-CO₂R⁹, and pharmaceutically acceptable salts of any of these compounds, where each R is independently H, alkyl, aryl, benzyl, Group IA metal, or co-antioxidant.

where each R³ is independently hydrogen or methyl, and wherein each R¹ and R² are independently:

R I ³ R I ³ R I ³ R I ³ RR⁵⁰ RR³-³ RR³-³ RR³-³ R ψ⁵ R H³" RH³" RH³" 3 R π³ R π³ R π³ R π³

^o_^λ λ ΛAi _R5Λ_γJ_γLA_rt \ _R5\\\\|

R^a R^a R^a R³ R³ R³ R³ R³ R³ R³ R³ R³ R³ R³ R³ R³

where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; alkyl; aryl; -alkyl- N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^~; -aryl-CO₂ ^"; - C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; - C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(O)- (NR⁷)-alkyl-N(R⁷)₂; -C(O)- (NR⁷)-aryl- N(R⁷)₂; -C(O)- (NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)- (NR⁷)-aryl-N⁺(R⁷)₃; -C(O)- (NR⁷)-alkyl-CO₂R⁹; -C(O)- (NR⁷)- aryl-CO₂R⁹; -C(O)- (NR⁷)-alkyl-CO₂ ^~; -C(O)- (NR⁷)-aryl-CO₂ ^~; -C(O)- (NR⁷)-alkyl-N(R⁷)-alkyl-N(R⁷)₂; - C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-amino acid; -C(NR⁷)-amino acid; -C(O)-[C₆-C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co- antioxidant.

In some embodiments, carotenoid analogs or derivatives suitable for use with the present compositions, methods and uses may have the structure:

wherein each R6 is independently: H; alkyl; aryl; -alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl- N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^~; -aryl-CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; - C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)- aryl-CO₂ ^"; -C(O)- (NR⁷)-alkyl-N(R⁷)₂; -C(O)- (NR⁷)-aryl-N(R⁷)₂; -C(O)- (NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)- (NR⁷)-aryl-N⁺(R⁷)₃; -C(O)- (NR⁷)-alkyl-CO₂R⁹; -C(O)- (NR⁷)-aryl-CO₂R⁹; -C(O)- (NR⁷)-alkyl-CO₂ ^~; - C(O)- (NR⁷)-aryl-CO₂ ^~; -C(O)- (NR⁷)-alkyl-N(R⁷)-alkyl-N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; - C(O)-amino acid; -C(NR⁷)-amino acid; -C(O)-[C₆-C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

In some embodiments, a method of treating prostate cancer in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a synthetic analog or derivative of a carotenoid. The synthetic analog or derivative of the carotenoid may have the structure

wherein R⁴ is independently hydrogen, -OH, -CH₂OH, or -OR⁶; where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; alkyl; aryl; -alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl- N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; -aryl-CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)- aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl- CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(O)- (NR⁷)-alkyl-N(R⁷)₂; -C(O)- (NR⁷)-aryl-N(R⁷)₂; -C(O)- (NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)- (NR⁷)-aryl-N⁺(R⁷)₃; -C(O)- (NR⁷)-alkyl-CO₂R⁹; -C(O)- (NR⁷)-aryl-CO₂R⁹; -C(O)- (NR⁷)-alkyl- CO₂ ^"; -C(O)- (NR⁷)-aryl-CO₂ ^"; -C(O)- (NR⁷)-alkyl-N(R⁷)-alkyl-N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; - S(O)(OR⁸)₂; -C(O)-amino acid; -C(NR⁷)-amino acid; -C(O)-[C₆-C₂₄ saturated hydrocarbon] ; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

In some embodiments, a method of treating prostate cancer in a subject may include administering to the subject an effective amount of a pharmaceutically acceptable formulation including a synthetic analog or derivative of a carotenoid where each -OR⁶ group may independently be:

and pharmaceutically acceptable salts of any of these compounds, where each R is independently H, alkyl, aryl, benzyl, Group IA metal, or co-antioxidant.

In some embodiments, a composition may include one or more carotenoids, carotenoid analogs, carotenoid derivatives, and pharmaceutically acceptable derivatives of carotenoids, carotenoid analogs, and carotenoid derivatives having the general structure:

Each R³ may be independently hydrogen or methyl. Each R¹ and R² may be independently:

wherein R⁴ is independently hydrogen, -OH, methyl,. -CH₂OH, or -OR⁵; wherein at least one R⁴ group in the carotenoid analog or derivative may be -OR⁵; wherein each R⁵ is independently: alkyl; aryl; -alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; - aryl-CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl- CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^~; -C(O)-aryl-CO₂ ^"; -C(O)- (NR⁷)-alkyl-N(R⁷)₂; -C(O)- (NR⁷)- aryl-N(R⁷)₂; -C(O)- (NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)- (NR⁷)-aryl-N⁺(R⁷)₃; -C(O)- (NR⁷)-alkyl-CO₂R⁹; -C(O)- (NR⁷)-aryl-CO₂R⁹; -C(O)- (NR⁷)-alkyl-CO₂ ^~; -C(O)- (NR⁷)-aryl-CO₂ ^~; -C(O)- (NR⁷)-alkyl-N(R⁷)-alkyl- N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-[C₆-C₂₄ saturated hydrocarbon] ; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

wherein R⁴ is independently hydrogen, -OH, methyl,. -CH₂OH, or -OR⁵; wherein at least one R⁴ group in the carotenoid analog or derivative may be -OR⁵; wherein each R⁵ is independently: alkyl; aryl; - alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; -aryl- CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl- CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(O)- (NR⁷)-alkyl-N(R⁷)₂; -C(O)- (NR⁷)- aryl-N(R⁷)₂; -C(O)- (NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)- (NR⁷)-aryl-N⁺(R⁷)₃; -C(O)- (NR⁷)-alkyl-CO₂R⁹; -C(O)- (NR⁷)-aryl-CO₂R⁹; -C(O)- (NR⁷)-alkyl-CO₂ ^"; -C(O)- (NR⁷)-aryl-CO₂ ^"; -C(O)- (NR⁷)-alkyl-N(R⁷)-alkyl- N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-[C₆-C₂₄ saturated hydrocarbon] ; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

Each R³ may be independently hydrogen or methyl, and where each R¹ and R² may be independently:

wherein R⁴ is independently hydrogen, -OH, methyl,. -CH₂OH, or -OR⁵; wherein at least one R⁴ group in the carotenoid analog or derivative may be -OR⁵; wherein each R⁵ is independently: alkyl; aryl; ■ alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; -aryl- CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl- CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(O)- (NR⁷)-alkyl-N(R⁷)₂; -C(O)- (NR⁷)- aryl-N(R⁷)₂; -C(O)- (NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)- (NR⁷)-aryl-N⁺(R⁷)₃; -C(O)- (NR⁷)-alkyl-CO₂R⁹; -C(O)- (NR⁷)-aryl-CO₂R⁹; -C(O)- (NR⁷)-alkyl-CO₂ ^~; -C(O)- (NR⁷)-aryl-CO₂ ^~; -C(O)- (NR⁷)-alkyl-N(R⁷)-alkyl- N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-[C₆-C₂₄ saturated hydrocarbon] ; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

wherein R⁴ is independently hydrogen, -OH, methyl,. -CH₂OH, or -OR⁵; wherein at least one R⁴ group in the carotenoid analog or derivative may be -OR⁵; wherein each R⁵ is independently: alkyl; aryl; -alkyl- N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; -aryl-CO₂ ^"; - C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; - C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(O)- (NR⁷)-alkyl-N(R⁷)₂; -C(O)- (NR⁷)-aryl- N(R⁷)₂; -C(O)- (NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)-(NR⁷)-aryl-N⁺(R⁷)₃; -C(O)-(NR⁷)-alkyl-CO₂R⁹; -C(O)-(NR⁷)- aryl-CO₂R⁹; -C(O)-(NR⁷)-alkyl-CO₂ ^"; -C(O)-(NR⁷)-aryl-CO₂ ^"; -C(O)-(NR⁷)-alkyl-N(R⁷)-alkyl-N(R⁷)₂; - C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-[C₆-C₂₄ saturated hydrocarbon] ; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄; a peptide; a carbohydrate; a nucleoside reside; or a co- antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co- antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

Each co-antioxidant may be independently Vitamin C, Vitamin C analogs, Vitamin C derivatives, Vitamin E, Vitamin E analogs, Vitamin E derivatives, flavonoids, flavonoid derivatives, or flavonoid analogs. Flavonoids include, but are not limited to, quercetin, xanthohumol, isoxanthohumol, or genistein. Selection of the co-antioxidant should not be seen as limiting for the therapeutic application of the current invention.

In some embodiments, pharmaceutical compositions are provided that may include one or more carotenoids ("a co-formulation" strategy), or synthetic derivatives or analogs thereof, in combination with one or more additional compositions or medicaments used in the treatment of prostate cancer. Certain embodiments may be further directed to pharmaceutical compositions that include combinations of two or more carotenoids or synthetic analogs or derivatives thereof.

In some embodiments, separate pharmaceutical compositions are provided, such that the one or more additional compositions or medicaments used in the treatment of prostate cancer is/are delivered separately from the carotenoid, or synthetic derivatives or analogs thereof (sometimes referred to in the art as a "co-administration" strategy). The pharmaceutical compositions may be adapted to be administered orally, or by one or more parenteral routes of administration. In an embodiment, the pharmaceutical composition may be adapted such that at least a portion of the dosage of the carotenoid or synthetic derivative or analog thereof is delivered prior to, during, or after at least a portion of the one or more additional compositions or medicaments used in the treatment of prostate cancer is/are delivered to the subject.

Embodiments directed to pharmaceutical compositions may further include appropriate vehicles for delivery of said pharmaceutical composition to a desired site of action (i.e., the site a subject's body where the biological effect of the pharmaceutical composition is most desired). Pharmaceutical compositions including carotenoids or analogs that may be administered orally or intravenously may be particularly advantageous for and suited to embodiments described herein. In yet a further embodiment, an injectable pharmaceutical composition may be prepared.

Each co-antioxidant may be independently Vitamin C, Vitamin C analogs, Vitamin C derivatives,

Vitamin E, Vitamin E analogs, Vitamin E derivatives, flavonoids, flavonoid derivatives, or flavonoid analogs. Flavonoids include, but are not limited to, quercetin, xanthohumol, isoxanthohumol, or genistein.

Selection of the co-antioxidant should not be seen as limiting for the therapeutic application of the current invention.

In some embodiments, separate pharmaceutical compositions are provided, such that the one or more additional compositions or medicaments used in the treatment of prostate cancer is/are delivered separately from the carotenoid, or synthetic derivatives or analogs thereof (sometimes referred to in the art as a "co-administration" strategy). The pharmaceutical compositions may be adapted to be administered orally, or by one or more parenteral routes of administration. In an embodiment, the pharmaceutical composition may be adapted such that at least a portion of the dosage of the carotenoid or synthetic derivative or analog thereof is delivered prior to, during, or after at least a portion of the one or more additional compositions or medicaments used in the treatment of prostate cancer is/are delivered to the subject. Embodiments directed to pharmaceutical compositions may further include appropriate vehicles for delivery of said pharmaceutical composition to a desired site of action (i.e., the site a subject's body where the biological effect of the pharmaceutical composition is most desired). Pharmaceutical compositions including xanthophyll carotenoids or analogs that may be administered orally or intravenously may be particularly advantageous for and suited to embodiments described herein. In yet a further embodiment, an injectable

A carotenoid formulation or a structural analog or derivative may be administered with a carotenoid tructural analog or derivative and/or other carotenoid structural analogs or derivatives, or in formulation with antioxidants and/or excipients that further the intended purpose. In some embodiments, one or more of the xanthophyll carotenoids or synthetic analogs or derivatives thereof may be at least partially water-soluble.

BRIEF DESCRIPTION OF THE DRAWINGS

The above brief description as well as further objects, features and advantages of the methods and apparatus of the present invention will be more fully appreciated by reference to the following detailed description of presently preferred but nonetheless illustrative embodiments in accordance with the present invention when taken in conjunction with the accompanying drawings.

FIG. 1 shows several examples of the structures of various synthetic carotenoid derivatives or analogs that may be used according to some embodiments. (A) lycophyll disuccinate; (B) lycophyll dilysinate; (C) disuccinate divitamin C astaxanthin; (D) disodium disuccinic acid ester astaxanthin salt; (E) dilysinate astaxanthin ester;

FIG. 2 is a depiction of the enzymatic hydrolysis of lycophyll dilysinate by esterases (e.g., in the intestine);

FIG. 3 is a bar graph depicting the uptake of lycophyll by PC-3 cells treated with 10^"5 M lycophyll in THF for the indicated amount of time, as measured by intracellular lycophyll concentration;

FIG. 4 is a representation of the effects of lycophyll dilysinate (LdiLys) on various cellular properties of prostate cancer cells;

FIG. 5 shows the biochemical effect on various components of the NF-κB signaling pathway of treating DU- 145 cells with 10 ng/ml TNF-α for 10 minutes and 10^"5 M LdiLys for the indicated amount of time;

FIG. 6 shows the effect of 10^"5 M LdiLys treatment for 30 min on IKB phosphorylation in various cell lines;

FIG. 7 shows the effect of 10^"5 M LdiLys treatment for 24 hr on steady-state expression of various NF-KB responsive gene products in various prostate tumor cell lines; FIG. 8 is a schematic representation of an in vitro assay to measure the effect of 72 hr LdiLys treatment and extracellular matrix (ECM) (e.g., MATRIGEL™) on PC-3 cell invasion through a porous polycarbonate membrane;

FIG. 9 is a bar graph depicting the results obtained in the assay depicted in FIG. 8; FIG. 10 shows bar graphs comparing the effect of the presence or absence of ECM

(MATRIGEL™) on the results obtained in the assay depicted in FIG. 9;

FIG. 11 is a bar graph depicting the results obtained in an in vitro MMP-9 inhibition assay; MMP- 9 is inhibited in vitro in a dose-dependent manner over the indicated concentration range;

FIG. 12 shows the effect LdiLys on NF-κB activity in TNF-α treated or untreated DU- 145 cells as measured by total cellular IKB expression;

FIG. 13 shows the effect on NF-κB activity in DU- 145 cells treated with 10^'5 M LdiLys for the indicated times up to 30 min as measured by (A) steady state total cellular IKB expression; and (B) IKB phosphorylation ;

FIG. 14 shows the effect on NF-κB activity in DU- 145 cells treated with 10 ng/ml TNF-α for 10 min or 10^"5 M LdiLys for 30 min, either alone or in combination as indicated, in various tumor cell lines;;

FIG. 15 is a bar graph showing the dose-dependent reduction in average tumor cell invasion as measured in the assay depicted in FIG. 8 in response to 72 hr pre-treatment of PC-3 cells with 10^"7 - 10^"5 M LdiLys as indicated, in the presence or absence of ECM (MATRIGEL™); and

FIG. 16 is a bar graph showing the dose-dependent reduction in tumor cell invasion as measured in the assay depicted in FIG. 8 in response to 72 hr pre-treatment of PC-3 cells with 10^"7 - 10^"5 M LdiLys as indicated, in the presence (light bars) or absence of ECM (MATRIGEL™) (dark bars).

While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof are shown by way of example in the drawings and will herein be described in detail. It should be understood, however, that the drawing and detailed description thereto are not intended to limit the invention to the particular form disclosed, but on the contrary, the intention is to cover all modifications, equivalents and alternatives falling within the spirit and scope of the present invention as defined by the appended claims.

DETAILED DESCRIPTION

It is to be understood that the present invention is not limited to particular devices or biological systems, which may, of course, vary. It is also to be understood that, as used in this specification and the appended claims, the singular forms "a", "an", and "the" include singular and plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a linker" includes one or more linkers. It is to be yet further understood that any terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. The terms used throughout this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner in describing the general embodiments of the invention, as well as how to make and use them. It will be readily appreciated that the same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed in greater detail herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification, including examples of any terms discussed herein, is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term.

As used herein, the term "xanthophyll carotenoid" generally refers to a naturally occurring or synthetic 40-carbon polyene chain with a carotenoid structure that contains at least one oxygen-containing functional group. The chain may include terminal cyclic end groups. Exemplary, though non-limiting, xanthophyll carotenoids include astaxanthin, zeaxanthin, lutein, echinenone, lycophyll, canthaxanthin, and the like. Non-limiting examples of carotenoids that are not xanthophyll carotenoids include β-carotene and lycopene.

As used herein, terms such as "carotenoid analog" and "carotenoid derivative" generally refer to chemical compounds or compositions derived from a naturally occurring or synthetic carotenoid. Terms such as carotenoid analog and carotenoid derivative may also generally refer to chemical compounds or compositions that are synthetically derived from non-carotenoid based parent compounds; however, which ultimately substantially resemble a carotenoid derived analog. Non-limiting examples of carotenoid analogs and derivatives that may be used according to some of the embodiments described herein are depicted schematically in FIG. 1. As used herein, the term "organ", when used in reference to a part of the body of an animal or of a human generally refers to the collection of cells, tissues, connective tissues, fluids and structures that are part of a structure in an animal or a human that is capable of performing some specialized physiological function. Groups of organs constitute one or more specialized body systems. The specialized function performed by an organ is typically essential to the life or to the overall well-being of the animal or human. Non-limiting examples of body organs include the heart, lungs, kidney, ureter, urinary bladder, adrenal glands, pituitary gland, skin, prostate, uterus, reproductive organs (e.g., genitalia and accessory organs), liver, gall-bladder, brain, spinal cord, stomach, intestine, appendix, pancreas, lymph nodes, breast, salivary glands, lacrimal glands, eyes, spleen, thymus, bone marrow. Non-limiting examples of body systems include the respiratory, circulatory, cardiovascular, lymphatic, immune, musculoskeletal, nervous, digestive, endocrine, exocrine, hepato-biliary, reproductive, and urinary systems. In animals, the organs are generally made up of several tissues, one of which usually predominates, and determines the principal function of the organ.

As used herein, the term "tissue", when used in reference to a part of a body or of an organ, generally refers to an aggregation or collection of morphologically similar cells and associated accessory and support cells and intercellular matter, including extracellular matrix material, vascular supply, and fluids, acting together to perform specific functions in the body. There are generally four basic types of tissue in animals and humans including muscle, nerve, epithelial, and connective tissues.

As used herein the terms "reducing," "inhibiting" and "ameliorating," when used in the context of modulating a pathological or disease state, generally refers to the prevention and/or reduction of at least a portion of the negative consequences of the disease state. When used in the context of the biochemical activity .

The terms "androgen independent" or "androgen insensitive" as used herein generally refers to. The term "androgen dependent" or "androgen sensitive" as used herein generally refers to. Abnormal Proliferation is defined as a series of genetically determined changes that occur in mammalian cells in the pathological state known as cancer. This process eventually results in the loss of control of apoptosis in cancer cells. This can occur in steps, generally referred to as 1. initiation, which is defined as the stage when an external agent or stimulus triggers a genetic change in one or more cells, and 2. promotion, which is defined as the stage involving further genetic and metabolic changes, which can include inflammation. During the "promotion stage," cells begin a metabolic transition to a stage of cellular growth in which apoptosis is blocked.

As used herein, the terms "malignant cells," "tumorigenic cells," and the like, generally refer to cancer cells that have escapeed normal growth control mechanisms through a series of metabolic changes during the initiation and promotion stages of the onset of malignancy. These changes are a consequence of genetic alterations in the cells (either activating mutations and/or increased expression of protooncogenes— and/or inactivating mutations and/or decreased expression of one or more tumor suppressor genes). Most oncogene and tumor suppressor gene products are components of signal transduction pathways that control cell cycle entry or exit, promote differentiation, sense DNA damage and initiate repair mechanisms, and/or regulate cell death programs. Cells employ multiple parallel mechanisms to regulate cell growth, differentiation, DNA damage control, and apoptosis. Nearly all tumor and malignant cells have mutations in multiple oncogenes and tumor suppressor genes.

The term "cell line," as used herein generally refers to a permanently established, ex vivo, cell culture that will proliferate indefinitely given appropriate fresh medium and space.

The term "PC-3" (ATCC^® Number: CRL-1435™) as used herein generally refers to a human prostate cancer cell line derived from a grade IV adenocarcinoma bone metastasis from a 62 year old Caucasian male. PC-3 cells are generally adherent epithelial in nature, are able to grow in semi-solid suspension, and are highly tumorigenic after about 20 days in nude mice. PC-3 cells are androgen- independent and exhibit low acid phosphatase and testosterone-5-α reductase activities. The line is near- triploid with a modal number of 62 chromosomes. There are nearly 20 marker chromosomes commonly found in each cell; and normal N2, N3, N4, N5, N12, and N15 are not found. No normal Y chromosomes are detectable. The line expresses HLA Al, A9 and has the following genetic markers: Amelogenin: X; CSFlPO: 11; D13S317: 11; D16S539: 11; D5S818: 13; D7S820: 8,11; THOl: 6,7; TPOX: 8,9; vWA: 17.

The term "DU-145" (ATCC^® Number: HTB-81™) as used herein generally refers to a human prostate cancer cell line derived from a brain metastasis carcinoma of a 69 year old Caucasian male. DU- 145 cells are generally adherent epithelial in nature, and are can form grade II adenocarcinomas in nude mice. The line is not detectably hormone sensitive, is only weakly positive for acid phosphatase and isolated cells form colonies in soft agar. The cells express Blood type O; Rh⁺ antigens, and do not express prostate antigen.

The term "LNCaP" (ATCC^® Number: CRL-1740™) as used herein generally refers to a human prostate carcinoma cell line derived from a left supraclavicular lymph node metastasis of a 50 year old Caucasian male. LNCaP cells are generally adherent epithelial in nature, are tumorigenic in nude mice, and form colonies in soft agar. Unlike PC-3 and DU-145 cells, LNCaP cells express both the androgen and estradiol receptors, making them responsive androgens (growth modulation and acid phosphatase production).

The term "HT-1080" (ATCC^® Number: CCL- 121™) as used herein generally refers to a human fibrosarcoma cell line of connective tissue (non-prostate) origin isolated from a 35 year old Caucasian male. The cells are tumorigenic in nude mice, express the activated N-ras oncogene, and are insensitive to androgens for their growth.

The term "NF-κB" or "Nuclear Factor kappaB" as used herein generally refers to a protein complex that functions broadly as a transcription factor. NF-κB is found in all cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Consistent with this role, incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development, among others. Members of the NF-κB family share structural homology with the retroviral oncoprotein v-Rel, resulting in their classification as NF-κB/Rel proteins. There are five proteins in the mammalian NF-κB family: NF-κBl (also called p50); NF-κB2 (also called p52); ReIA (also named p65); ReIB; and c-Rel. Unlike ReIA, ReIB, and c-Rel; p50 and p52 do not contain trans-activation domains in their C-termini. Nevertheless, these two NF-κB members play critical roles in modulating the specificity of NF-κB function. Although homodimers of p50 and p52 are generally repressors of KB transcription, both p50 and p52 participate in target gene transactivation by forming heterodimers with ReIA, ReIB or c-Rel. Additionally, the p50 and p52 homodimers also bind to the nuclear protein Bcl-3, forming potent transcriptional activators. Part of NF-KB'S importance in regulating cellular responses is that it generally belongs in the category of "rapid-acting" primary transcription factors-i.e., transcription factors which are present in cells in an inactive state and do not require new protein synthesis to be activated (other members of this family include transcription factors such as c-Jun, STATs and nuclear hormone receptors). This allows NF-kB to act as a "first responder" to harmful cellular stimuli. Stimulation of a wide variety of cell-surface receptors leads directly to NF-κB activation and fairly rapid changes in gene expression.

NF-κB is widely used by eukaryotic cells as a regulator of genes that control cell proliferation and cell survival. As such, many different types of human tumors have misregulated NF-κB : that is, NF-κB is constitutively active. Active NF-κB turns on the expression of genes that keep the cell proliferating and protect the cell from conditions that would otherwise cause it to die. In tumor cells, NF-κB is active either due to mutations in genes encoding the NF-κB transcription factors themselves or in genes that control NF-κB activity (such as IkB genes); in addition, some tumor cells secrete factors that cause NF-κB to become active. Blocking NF-κB can cause tumor cells to stop proliferating, to die, or to become more sensitive to the action of anti-tumor agents. Thus, NF-κB is the subject of much active research among pharmaceutical companies as a target for anti-cancer therapy.

Because NF-κB controls many genes involved in inflammation, it is not surprising that NF-κB is found to be chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, sepsis, among others. Many natural products (including anti-oxidants) that have been promoted to have anti-cancer and anti-inflammatory activity have also been shown to inhibit NF-κB. Recent work by Karin, Ben-Neriah and others has highlighted the importance of the connection between NF-κB, inflammation and cancer and underscored the value of therapies that regulate the activity of NF-κB.

In unstimulated cells, the NF-κB dimers are sequestered in the cytoplasm by a family of inhibitors, called IKBS (Inhibitor of kappa B), which are proteins that contain multiple copies of a sequence called ankyrin repeats. By virtue of their ankyrin repeat domains, the IKB proteins mask the nuclear localization signals (NLS) of NF-κB proteins and keep them sequestered in an inactive state in the cytoplasm.

The term "IKB" is generally used herein to refer to a family of related proteins that funtion in regulating the NF-κB pathway in cells. IKB ' S typivally have an N-terminal regulatory domain, followed by six or more ankyrin repeats and a PEST domain in their C -terminus. Activation of the NF-κB complexes occurs primarily via activation of a kinase called the IKB kinase (IKK). When activated by signals, usually coming from the outside of the cell (e.g., TNF-α), the IKB kinase phosphorylates two serine residues located in an IKB regulatory domain. When phosphorylated on these serines (e.g., serines 32 and 36 in human IκBα), the IKB inhibitor molecules are modified by a process called "ubiquitination" which then leads them to be degraded by a cell structure called the proteasome.

With the degradation of the IKB inhibitor, the NF-κB complex is then freed to enter the nucleus where it can 'turn on' the expression of specific genes that have DNA-binding sites for NF-κB nearby. The activation of these genes by NF-κB then leads to the given physiological response, for example, an inflammatory or immune response, a cell survival response, or cellular proliferation. NF-κB turns on expression of its own repressor, IκBα. The newly-synthesized IκBα then re-inhibits NF-κB and thus forms an auto feedback loop, that results in oscillating levels of NF-κB activity.

As used herein, the phrases "inhibit the activity of NF-κB," "inhibit one or more components of NF-κB signaling" and the like, generally refer to a process, drug or molecule that inhibits the function of at least one component of a functional NF-κB signal cascade (as described above), which may include, though is not limited to, affecting the expression of one or more NF-κB subunits (e.g., p50, p65 etc.), affecting expression of IKB, affecting IKB phosphorylation, affecting the expression and/or activity of IKK, affecting the signaling efficiency of a membrane receptor that stimulates NF-κB (such as, e.g., TNF- α and/or one of its receptors), affecting nuclear translocation of an active NF-κB complex, or any combinations of the above.

The term "Benign prostatic hyperplasia" or "BPH" generally refers to a common disease of elderly men and a risk factor for developing prostate cancer later in life. BPH affects around 50% of men in their 50s with increasing prevalence up to 90% of men in their 80s and older (see, e.g., Schwarz, S. et al, Journal of Nutrition 138:49-53, 2008). It has been shown that BPH patients exhibit increased oxidative stress compared to normal patients particularly elevated lipid peroxidation (TBARS and MDA measured) and decreased glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities [Aydin, A. et al., Clinical Biochemistry 39:176-179, 2006 ; Sikka, S.C., Curr. Med. Chem. 10(24):2679- 92, 2003; and Aryal, M. et al., J. Nepal Med. Assoc. 46(167):103-6, 2007]. Towards the goal of amelioration of this disease, treatment with a natural antioxidant that is structurally almost identical to lycophyll, lycopene, patients exhibited decreased PSA levels and decreased prostate enlargement progression [Schwartz et al.]. Additionally, there was a significant decrease in symptom estimates [Schwartz et al.]. Therefore, due to the similarity of structure and function between lycophyll and lycopene and due to the implication of increased oxidative stress in the development of BPH, we would predict possible amelioration of disease progression and symptoms following lycophyll administration to BPH patients.

The term "prostatitis" refers to an extremely common condition in men worldwide; 2-10% of men experience it during their lifetime [Habermacher, G.M. et al., Annu. Rev. Med. 57:195-206, 2006; Nickel, J.C., Rev. Utol. l(3):160-169, 1999). It is the most common presenting diagnosis for men under 50 years of age in the outpatient urologic clinic setting. This diagnosis is comprised of four separate classifications (NIH category MV). Category III, Chronic Pelvic Pain Syndrome (CPPS), which accounts for 90-95% of prostatitis cases is of unknown etiology and is marked by a mixture of pain, urinary, and ejaculatory symptoms with no uniformly effective therapy. Due to the paucity of therapeutics, many urologists recommend increased consumption of antioxidants and antioxidant containing supplements to ameliorate disease symptoms. Mechanisms of disease pathology include growth factors, inflammatory infiltrates and hormonal influence [Habermacher et al. And Nickel et al.]. One study utilized quercetin, a bioflavonoid with antioxidant properties, in patients with CPPS and found 82% of patients had at least a 25% improvement in symptom score measured with a quality of life questionnaire currently recognized by the NIH as the only measurement of efficacy in treating CPPS [Shoskes, D.A. et al., Urology 54:960-963, 1999]. Quercetin, in addition to being an antioxidant, has been shown to decrease inflammatory pathways including the NF-κB pathway [Shoskes, D. A., Transplant. 66:147-152, 1998] which we present data herein showing our compound lycophyll and its derivatives also suppress. We therefore predict that treatment of CPPS patients with similar antioxidants, lycophyll or its derivatives, that lowers inflammation and NF-κB pathway activation may have similar ameliorative benefits on disease symptoms.

The term "MATRIGEL™" as used herein generally refers to a gelatinous protein mixture that is secreted by mouse tumor cells and resembles the complex extracellular matrix environment found in many tissues. MATRIGEL™ is used in cell biology resrach as a substrate for cell culture. Cells cultured on MATRIGEL™ demonstrate complex cellular behavior that is otherwise impossible to observe under laboratory conditions. In some instances researchers may prefer to use greater volumes of Matrigel to produce thick three-dimensional gels. The utility of thick gels is that they induce cells to migrate from the surface to the interior of the gel. Conversely, MATRIGEL™ may be applied to a porous membrane through which the migration of cancer cells may be observed and measured. This migratory behavior is studied by researchers as a model of tumor cell metastasis.

In the pharmaceutical arts, MATRIGEL™ ^{may beused} to screen drug molecules. A typical experiment may include adding a test molecule to MATRIGEL™ and observing cellular behavior thereafter. In the case of metastasis studies, test molecules that inhibit tumor cell migration may also have potential as anticancer drugs.

The ability of MATRIGEL™ to stimulate complex cell behavior is a consequence of its heterogeneous composition. The chief components of Matrigel are structural proteins such as laminin and collagen which present cultured cells with the adhesive peptide sequences that they would encounter in their natural environment. Also present are growth factors that promote differentiation and proliferation of many cell types. Matrigel contains numerous other proteins in small amounts and its exact composition is unknown.

The terms "LDL," "LdiLys," "XANCOR™,"or "Prostax," "LLys2" collectively refer to the synthetic carotenoid derivative "lycophyll dilysinate" or pharmaceutically acceptable salts derivatives thereof.

As used herein, phrases such as "one or more additional medicaments or compositions suitable for the treatment of prostate cancer in a subject," generally refer to a pharmaceutical composition that contains at least one pharmaceutically active compound that is used for the treatment of prostate cancer, but which is distinct from the carotenoid analogs or derivatives which for the basis of the presently described embodiments. Typically one or more additional medicaments or compositions suitable for the treatment of prostate cancer in a subject as presently described may include, though are not limited to, compositions or agents suitable for use in cancer chemotherapy and/or agents suitable for use in hormonal therapy, particularly, hormonal therapy relating to the prostate. Which of these options to employ, if at al, depends on a number of situation-specific variables, such as, by way of non-limiting example, the stage of the disease, the Gleason score, and the PSA level, all of will be readily appreciated by the skilled practitioner. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable acid addition salts of the compounds of the invention include salts derived form inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorus, and the like, as well as the salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like. Also contemplated are the salts of amino acids such as arginate, gluconate, galacturonate, and the like; see, for example, Berge et al., "Pharmaceutical Salts," J. of Pharmaceutical Science, 1977; 66:1 19. The acid addition salts of the basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base, and isolating the free base in the conventional manner. The free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention. Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metal hydroxides, or of organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine, and procaine; see, for example, Berge et al., supra., 1977. The base addition salts of acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

The phrase "combination therapy" (or "co-therapy"), as used herein embraces the administration of one or more carotenoid analogs or derivatives, and of one or more metalloproteinase inhibitors, as part of a specific treatment regimen intended to provide a beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents. Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected). The term is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner. Substantially simultaneous administration can be accomplished, for example, by administering to the subject a pharmaceutical preparation having a fixed ratio of each therapeutic agent or in multiple preparations for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents can be administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection. The sequence in which the therapeutic agents are administered is not narrowly critical. "Combination therapy" also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients (such as, but not limited to, additional pharmacologic agents) and non-drug therapies (such as, but not limited to, surgery or radiation treatment).

As used herein, the term "inhibitor," when used in the context of an enzyme, as in "enzyme inhibitors," generally refers to molecules that bind to enzymes and decrease their catalytic acivity activity by at least 5%, at least 15%, at least 30%, at least 50% or at least 75%. Since blocking the activity of an enzyme can kill a pathogen or correct a metabolic imbalance, many drugs are designed as enzyme inhibitors. The binding of an inhibitor can stop a substrate from entering the active site of an enzyme and/or hinder the enzyme from catalyzing its reaction. Inhibitor binding is either reversible or irreversible. Irreversible inhibitors usually react with the enzyme and change it chemically. These inhibitors modify key amino acid residues needed for enzymatic activity. In contrast, reversible inhibitors bind non-covalently and different types of inhibition are produced depending on whether these inhibitors bind the enzyme, the enzyme-substrate complex, or both.

Many drug molecules are enzyme inhibitors so their discovery and improvement is an active area of research in biochemistry and pharmacology. A medicinal enzyme inhibitor is often judged by its specificity (its lack of binding to other proteins) and its potency (its dissociation constant, which indicates the concentration needed to inhibit the enzyme). A high specificity and potency ensure that a drug will have few side effects and thus low toxicity.

As used herein the terms "administration," "administering," or the like, when used in the context of providing a pharmaceutical or nutraceutical composition to a subject generally refers to providing to the subject one or more pharmaceutical, "over-the-counter" (OTC) or nutraceutical compositions in combination with an appropriate delivery vehicle by any means such that the administered compound achieves one or more of the intended biological effects for which the compound was administered. By way of non-limiting example, a composition may be administered parenteral, subcutaneous, intravenous, intracoronary, rectal, intramuscular, intra-peritoneal, transdermal, or buccal routes of delivery.

Alternatively, or concurrently, administration may be by the oral route. The dosage administered will be dependent upon the age, health, weight, and/or disease state of the recipient, kind of concurrent treatment, if any, frequency of treatment, and/or the nature of the effect desired. The dosage of pharmacologically active compound that is administered will be dependent upon multiple factors, such as the age, health, weight, and/or disease state of the recipient, concurrent treatments, if any, the frequency of treatment, and/or the nature and magnitude of the biological effect that is desired.

As used herein, terms such as "pharmaceutical composition," "pharmaceutical formulation," "pharmaceutical preparation," or the like, generally refer to formulations that are adapted to deliver a prescribed dosage of one or more pharmacologically active compounds to a cell, a group of cells, an organ or tissue, an animal or a human. Methods of incorporating pharmacologically active compounds into pharmaceutical preparations are widely known in the art. The determination of an appropriate prescribed dosage of a pharmacologically active compound to include in a pharmaceutical composition in order to achieve a desired biological outcome is within the skill level of an ordinary practitioner of the art. A pharmaceutical composition may be provided as sustained-release or timed-release formulations. Such formulations may release a bolus of a compound from the formulation at a desired time, or may ensure a relatively constant amount of the compound present in the dosage is released over a given period of time. Terms such as "sustained release," "controlled release," or "timed release" and the like are widely used in the pharmaceutical arts and are readily understood by a practitioner of ordinary skill in the art. Pharmaceutical preparations may be prepared as solids, semi-solids, gels, hydrogels, liquids, solutions, suspensions, emulsions, aerosols, powders, or combinations thereof. Included in a pharmaceutical preparation may be one or more carriers, preservatives, flavorings, excipients, coatings, stabilizers, binders, solvents and/or auxiliaries that are, typically, pharmacologically inert. It will be readily appreciated by an ordinary practitioner of the art that, included within the meaning of the term are pharmaceutically acceptable salts of compounds. It will further be appreciated by an ordinary practitioner of the art that the term also encompasses those pharmaceutical compositions that contain an admixture of two or more pharmacologically active compounds, such compounds being administered, for example, as a combination therapy.

As used herein the terms "subject" generally refers to a mammal, and in particular to a human. The terms "in need of treatment," "in need thereof," "who would benefit from such treatment," or the like when used in the context of a subject being administered a pharmacologically active composition, generally refers to a judgment made by an appropriate healthcare provider that an individual or animal requires or will benefit from a specified treatment or medical intervention. Such judgments may be made based on a variety of factors that are in the realm of expertise of healthcare providers, but include knowledge that the individual or animal is ill, will be ill, or is at risk of becoming ill, as the result of a condition that may be ameliorated or treated with the specified medical intervention.

The phrases "therapeutically effective amount" and "effective amount" are synonymous unless otherwise indicated, and mean an amount of a compound of the present invention that is sufficient to improve the condition, disease, or disorder being treated. Determination of a therapeutically effective amount, as well as other factors related to effective administration of a compound of the present invention to a patient in need of treatment, including dosage forms, routes of administration, and frequency of dosing, may depend upon the particulars of the condition that is encountered, including the patient and condition being treated, the severity of the condition in a particular patient, the particular compound being employed, the particular route of administration being employed, the frequency of dosing, and the particular formulation being employed. Determination of a therapeutically effective treatment regimen for a patient is within the level of ordinary skill in the medical or veterinarian arts. In clinical use, an effective amount may be the amount that is recommended by the U.S. Food and Drug Administration, or an equivalent foreign agency. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the mammalian host treated and the particular mode of administration.

By "prophylactically effective amount" is meant an amount of a pharmaceutical composition that will substantially prevent, delay or reduce the risk of occurrence of the biological or physiological event in a cell, a tissue, a system, animal or human that is being sought by a researcher, veterinarian, physician or other caregiver.

The term "pharmacologically inert," as used herein, generally refers to a compound, additive, binder, vehicle, and the like, that is substantially free of any pharmacologic or "drug-like" activity.

A "pharmaceutically or nutraceutically acceptable formulation," as used herein, generally refers to a non-toxic formulation containing a predetermined dosage of a pharmaceutical and/or nutraceutical composition, wherein the dosage of the pharmaceutical and/or nutraceutical composition is adequate to achieve a desired biological outcome. The meaning of the term may generally include an appropriate delivery vehicle that is suitable for properly delivering the pharmaceutical composition in order to achieve the desired biological outcome.

As used herein the term "antioxidant" may be generally defined as any of various substances (as beta-carotene, vitamin C, and α-tocopherol) that inhibit oxidation or reactions promoted by Reactive Oxygen Species (ROS) and other radical and non-radical species.

As used herein the term "co-antioxidant" may be generally defined as an antioxidant that is used and that acts in combination with another antioxidant (e.g., two antioxidants that are chemically and/or functionally coupled, or two antioxidants that are combined and function with each another in a pharmaceutical preparation). The effects of co-antioxidants may be additive (i.e., the anti-oxidative potential of one or more anti-oxidants acting additively is approximately the sum of the oxidative potential of each component anti-oxidant) or synergistic (i.e., the anti-oxidative potential of one or more antioxidants acting synergistically may be greater than the sum of the oxidative potential of each component anti-oxidant).

Compounds described herein embrace isomers mixtures, racemic, optically active, and optically inactive stereoisomers and compounds.

Prostate Cancer:

NF-κB in Cancer:

The eukaryotic nuclear factor KB (NF-KB) plays an important role in inflammation, autoimmune response, cell proliferation, and apoptosis by regulating the expression of genes involved in these processes. Five members of the NF-κB family have been identified: NF-KB I (p5O/plO5), NF-κB2

(p52/pl00), ReIA (p65), ReIB, and c-Rel. They share a highly conserved ReI homology domain (RHD), which is responsible for DNA binding, dimerization, and interaction with IKB. The p50/RelA(p65) heterodimer is the major Rel/NF-κB complex in most cells. ReIB can act as both a transcriptional activator as well as a repressor of NF-κBdependent gene expression. It acts as an activator when it associates with p50 or p52. However, its inhibitory effect has been attributed to the formation of the RelA(p65):RelB heterodimer that does not bind to KB sites. Studies on NIH 3T3 cells have also shown that RelA(p65):RelB heterodimers are not regulated by IKB and are located in both the cytoplasm and the nucleus.

The activity of NF-κB is tightly regulated by its interaction with inhibitory IKB proteins. In most resting cells, NF-κB is sequestered in the cytoplasm in an inactive form associated with inhibitory molecules such as IKB α, IKB β, IκBε, pi 05, and pi 00. This interaction blocks the ability of NF-κB to bind to DNA and results in the NF-κB complex being primarily localized to the cytoplasm due to a strong nuclear export signal in IκBα. Following exposure to inflammatory cytokines, UV light, reactive oxygen species, or bacterial and viral toxins, the NF-κB signaling cascade is activated, leading to the complete degradation of IKB. This allows the translocation of unmasked NF-κB to the nucleus where it binds to the enhancer or promoter regions of target genes and regulates their transcription. In the nucleus, acetylation of NF-KB determines its active or inactive state. p300 and CBP acetyltransferases play a major role in the acetylation of RelA(p65), principally targeting Lys²¹⁸' ^{221> 310} for modification. Acetylated NF-κB is active and is resistant to the inhibitory effects of IKB. However, when histone deacetylase 3 (HD AC3) deacetylates NF-κB, IKB readily binds to NF-κB and causes its translocation into the cytoplasm. Here HDAC3 serves as an intranuclear molecular switch that turns off the biological processes triggered by NF- KB. One of the target genes activated by NF-κB is that encoding IκBα. Newly synthesized IκBα can enter the nucleus, remove NF-κB from DNA, and export the complex back to the cytoplasm to restore its original latent state.

As mentioned above, the activation of NF-κB by extracellular inducers depends on the phosphorylation and subsequent degradation of IKB proteins. Activation of NF-κB is achieved through the action of a family of serine/threonine k (IKK). The IKK contains two catalytic subunits (IKKα and IKKβ) and a regulatory/adapter protein NEMO (also known as IKKγ). IKKα and IKKβ phosphorylate IKB proteins and the members of the NF-κB family. All IKB proteins contain two conserved serine residues within their N-terminal area, which are phosphorylated by IKK. IKKα and IKKβ share about 50% sequence homology and can interchangeably phosphorylate Ser^32/36 of IκBα, and Ser^19/23 of IκBβ. These phosphorylation events lead to the immediate polyubiquitination of IKB proteins and rapid degradation by the 26S proteasome.

The Rel/NF-κB signal transduction pathway is misregulated in a variety of human cancers, especially those of lymphoid cell origin. Several human lymphoid cancer cells are reported to have mutations or amplifications of genes encoding NF-κB transcription factors. In most cancer cells NF-κB is constitutively active and resides in the nucleus. In some cases, this may be due to chronic stimulation of the IKK pathway, while in others the gene encoding IKB α may be defective. Such continuous nuclear NF- KB activity not only protects cancer cells from apoptotic cell death, but may even enhance their growth activity. Designing anti-tumor agents to block NF-κB activity or to increase their sensitivity to conventional chemotherapy may have great therapeutic value.

Therefore, in accordance with the disclosure set forth above, it is an object of the embodiments set forth herein to provide a use for carotenoid analogs and derivatives in applications directed to treating prostate cancer in a subject.

In one embodiment, uses of carotenoid analogs or derivatives, including pharmaceutically acceptable salts thereof, in applications directed to treating prostate cancer in a subject may include the preparation of a pharmaceutical composition suitable for such treatment. The pharmaceutical compositions may typically include one or more carotenoid analogs or derivatives in an amount sufficient to affect one or more aspects of NF-κB function in prostate cancer cells, including but not limited to reducing the growth rate of prostate cancer cells, reducing the survival rate of prostate cancer cells, inhibiting the progression of prostate cancer cells through one or more phases of the cell cycle,at least partially inhibiting or reducing the invasiveness of prostate cancer cells through reducing extracellular matrix, inhibiting the activity of MMP-9, reducing the expression of IKB in prostate cancer cells, reducing the phosphorylation of IKB in prostate cancer cells, reducing the expression of cyclin Dl in prostate cancer cells, reducing the expression of c-myc in prostate cancer cells, reducing the expression of TNF-α in prostate cancer cells, reducing the accumulation of NF-κB in the nucleus of prostate cancer cells, or any combinations of one or more of the above.

In one embodiment, uses of carotenoid analogs or derivatives, including pharmaceutically acceptable salts thereof, in applications directed to treating prostate cancer in a subject may include methods of treating a disorder characterized by dysregulated NF-κB activity in at least a portion of cells comprising a prostate tumor in the subject comprising administering to a subject who would benefit from such treatment a therapeutically effective amount of a pharmaceutically acceptable composition comprising a carotenoid analog or derivative.

In an embodiment, uses of carotenoid analogs or derivatives, including pharmaceutically acceptable salts thereof, in applications directed to directed treating prostate cancer in a subject may include the preparation of pharmaceutical compositions for use with additional pharmaceutical compositions which, when co-administered, act as prostate cancer therapy.

In one embodiment, uses of carotenoid analogs or derivatives, including pharmaceutically acceptable salts thereof, in applications directed to treating prostate cancer in a subject may include the preparation of pharmaceutical compositions having at least one carotenoid analog or derivative, in addition to at least one additional composition or medicament suitable for use as a prostate cancer treatment, including but not limited to one or more hormonal therapy compositions and/or one or more chemotherapeutic agents.

In an embodiment, carotenoids or synthetic derivatives or analogs thereof may be administered to a subject concurrently with at least one additional composition or medicament suitable for use as a prostate cancer treatment. In alternate embodiments, carotenoids or synthetic derivatives or analogs thereof may be administered to a subject prior to the commencement of drug therapy with the one or more additional compositions or medicaments suitable for use as a prostate cancer treatment. In yet further embodiments, xanthophyll carotenoids or synthetic derivatives or analogs thereof may be administered to a subject following the commencement of therapy with the one or more additional compositions or medicaments suitable for use as a prostate cancer treatment. The carotenoids or synthetic derivatives or analogs thereof may be provided in a single pharmaceutical preparation together with at least one additional composition or medicament suitable for use as a prostate cancer treatment. Alternatively, the carotenoids or synthetic derivatives or analogs thereof may be provided to a subject in a pharmaceutical preparation that is distinct from that which includes the one or more additional compositions or medicaments suitable for use as a prostate cancer treatment. The suitability of any particular composition or medicament for use as a prostate cancer treatment can be readily determined by evaluation of its potency and selectivity using methods known to those skilled in the art, followed by evaluation of its toxicity, absorption, metabolism, pharmacokinetics: eic in accordance with standard pharmaceutical practice. Chemotherapeutic Combinations and Treatment:

As described above, the presently contemplated treatment methods and compositions are not limited solely to the administration of a formulation containing synthetic carotenoid analogs and derivatives as the sole medically active component. On the contrary, equally contemplated are compositions and methods in which the subject carotenoid analogs or derivatives may be administered in conjunction with one or more additional compositions or medicament suitable for the treatment of prostate cancer. Typically, such agents may be divided into one of two non-mutually exclusive categories: chemotherapeutic agents, and hormonal therapy agents.

With regard first to chemotherapeutic agents, in certain embodiments, it may be desirable to administer the synthetic carotenoid analog and derivative compositions in combination with one or more other agents having anti-tumor activity including chemo therapeutics, radiation, and therapeutic proteins or genes. This may enhance the overall anti- tumor activity achieved by therapy with the compounds of the invention alone, or may be used to prevent or combat multi-drug tumor resistance.

Cancer is the uncontrolled growth of cells due to damage to DNA (mutations) and, occasionally, due to an inherited propensity to develop certain tumours. Therefore, broadly speaking, the majority of chemotherapeutic drugs work by impairing or otherwise inhibiting some aspect of mitosis (cell division), effectively targeting fast-dividing cells. As these drugs cause damage to cells they are termed cytotoxic. Some drugs cause cells to undergo apoptosis (so-called "cell suicide").

As chemotherapy affects cell division, tumours with high growth fractions (such as acute myelogenous leukemia and the lymphomas, including Hodgkin's disease) are more sensitive to chemotherapy, as a larger proportion of the targeted cells are undergoing cell division at any time.

Chemotherapeutic drugs affect "younger" tumours (i.e. more differentiated) more effectively, because mechanisms regulating cell growth are usually still preserved. With succeeding generations of tumour cells, differentiation is typically lost, growth becomes less regulated, and tumours become less responsive to most chemotherapeutic agents. Near the center of some solid tumours, cell division has effectively ceased, making them insensitive to chemotherapy. Another problem with solid tumours is the fact that the chemotherapeutic agent often does not reach the core of the tumour. Solutions to this problem include radiation therapy (both brachytherapy and teletherapy) and surgery.

The majority of chemotherapeutic drugs can be divided in to: alkylating agents, antimetabolites, anthracyclines, plant alkaloids, topoisomerase inhibitors, monoclonal antibodies, and other antitumour agents. All of these drugs affect cell division or DNA synthesis and function in some way. Some newer agents don't directly interfere with DNA. These include the new tyrosine kinase inhibitor imatinib mesylate (GLEEVEC® or GLIVEC®), which directly targets a molecular abnormality in certain types of cancer (chronic myelogenous leukemia, gastrointestinal stromal tumors).

Alkylating agents (LOlA): Akylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. Cisplatin and carboplatin, as well as oxaliplatin are alkylating agents. Other agents are mechloethamine, cyclophosphamide, chlorambucil. They work by chemically modifying a cell's DNA.

Anti-metabolites (LOlB): Anti-metabolites masquerade as purine ((azathioprine, mercaptopurine)) or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. They also affect RNA synthesis. Due to their efficiency, these drugs are the most widely used cytostatics.

Plant alkaloids and terpenoids (LOlC): These alkaloids are derived from plants and block cell division by preventing microtubule function. Microtubules are vital for cell division and without them it can not occur. The main examples are vinca alkaloids and taxanes. Vinca alkaloids (LOlCA): Vinca alkaloids bind to specific sites on tubulin, inhibiting the assembly of tubulin into microtubules (M phase of the cell cycle). They are derived from the Madagascar periwinkle, Catharanthus roseus (formerly known as Vinca rosea). The vinca alkaloids include: Vincristine, Vinblastine, Vinorelbine, and Vindesine.

Podophyllotoxin (LOlCB): Podophyllotoxin is a plant-derived compound used to produce two other cytostatic drugs, etoposide and teniposide. They prevent the cell from entering the Gl phase (the start of DNA replication) and the replication of DNA (the S phase). The exact mechanism of its action still has to be elucidated.

The substance has been primarily obtained from the American Mayapple {Podophyllum peltatum). Recently it has been discovered that a rare Himalayan Mayapple {Podophyllum hexandrum) contains it in a much greater quantity, but as the plant is endangered, its supply is limited. Studies have been conducted to isolate the genes involved in the substance's production, so that it could be obtained recombinantively.

Taxanes (LOlCD): Taxanes are derived from the Yew Tree. Paclitaxel is derived from the bark of the European Yew Tree while Docetaxel is derived from the pine needle of the Pacific Yew Tree. Taxanes enhance stability of microtubules, preventing the separation of chromosomes during anaphase. Taxanes include: Paclitaxel and Docetaxel.

Topoisomerase inhibitors (LOlCB and LOlXX): Topoisomerases are essential enzymes that maintain the topology of DNA. Inhibition of type I or type II topoisomerases interferes with both transcription and replication of DNA by upsetting proper DNA supercoiling. Some type I topoisomerase inhibitors include camptothecins: irinotecan and topotecan. Examples of type II inhibitors include amsacrine, etoposide, etoposide phosphate, and teniposide. These are semisynthetic derivatives of epipodophyllotoxins, alkaloids naturally occurring in the root of mayapple {Podophyllum peltatum). Antitumour antibiotics (LOlD): The most important immunosuppressant from this group is dactinomycin, which is used in kidney transplantations.

Monoclonal antibodies: These work by targeting tumour specific antigens, thus enhancing the host's immune response to tumour cells to which the agent attaches itself. Examples are trastuzumab (Herceptin) and rituximab (Rituxan).

In addition, some drugs may be used which modulate tumor cell behaviour without directly attacking those cells. Hormone treatments fall into this category of adjuvant therapies.

Hormonal therapies that may be particularly advantageous in the context of the present disclosure include those therapies that make use of one or more hormone antagonists. Particularly contemplated for for use as an additional medicament for the treatment of prostate cancer are those hormonal therapies that make use of antiandrogens to suppress androgenic hormones, which are required for the growth and survival of androgen-dependent prostate tumors.

An "antiandrogen," or "androgen antagonist," as used herein, generally refers to any of a group of hormone receptor antagonist compounds that are capable of preventing or inhibiting the biologic effects of androgens, male sex hormones, on normally responsive tissues in the body (such as, e.g., androgen- sesitive prostate cancer cells). Antiandrogens usually work by blocking the appropriate receptors, competing for binding sites on the cell's surface, obstructing the pathway by which androgens exert their function in vivo.

Medical indications for antiandrogens include, though are not limited to, treatment of benign prostatic hyperplasia (prostate enlargement) and use as an antineoplastic agent and palliative, adjuvant or neoadjuvant hormonal therapy in prostate cancer. The term antiandrogen withdrawal response (AAWR) describes the medical course taken when cancer cells adapt to feed on the antiandrogens rather than androgen, so that treatment must be halted in order to starve those cells thriving on the antiandrogens. Currently available antiandrogen drugs (brand names in parentheses) include: Spironolactone (Aldactone, Spiritone), a synthetic 17-spirolactone corticosteroid, which is a renal competitive aldosterone antagonist in a class of pharmaceuticals called potassium-sparing diuretics, used primarily to treat low-renin hypertension, hypokalemia, and Conn's syndrome.

Cyproterone acetate (Androcur, Climen, Diane 35, Ginette 35), a synthetic steroid, a potent antiandrogen that also possesses progestational properties. Flutamide (Eulexin), nilutamide (Anandron, Nilandron) and bicalutamide (Casodex), nonsteroidal, pure antiandrogens. Flutamide is the oldest and has more unwanted side effects than the others. Bicalutamide is the newest and has the least side effects. Ketoconazole (Nizoral), an imidazole derivative used as a broad-spectrum antifungal agent effective against a variety of fungal infections, side effects include serious liver damage and reduced levels of androgen from both the testicles and adrenal glands. Ketoconazole is a relatively weak antiandrogen. Finasteride (Proscar, Propecia) and dutasteride (Avodart), inhibitors of the 5-α-reductase enzyme that prevent the conversion of testosterone into dihydrotestosterone (DHT). Finasteride blocks only 5-α- reductase type II, dutasteride also blocks type I. They are not general antiandrogens in that they don't counteract the effects or production of other androgens than DHT.

To use the present invention in combination with the administration of a second chemotherapeutic agent, one would simply administer to a subject a carotenoid analog or derivative composition in combination with the second chemotherapeutic or hormonal therapy agent in a manner effective to result in their combined anti-tumor actions within the subject. These agents would, therefore, be provided in an amount effective and for a period of time effective to result in their combined presence within the tumor vasculature and their combined actions in the tumor environment. To achieve this goal, the carotenoid analog or derivative composition and chemotherapeutic or hormonal therapy agents may be administered to the subject simultaneously, either in a single composition, or as two distinct compositions using different administration routes.

Alternatively, the triterpene composition treatment may precede or follow the chemotherapeutic agent, radiation or protein or gene therapy treatment by intervals ranging from minutes to weeks. In embodiments where the second agent and carotenoid analog or derivative composition are administered separately to the animal, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the additional agent and carotenoid analog or derivative composition would still be able to exert an advantageously combined effect on the tumor. In such instances, it is contemplated that one would contact the tumor with both agents within about 5 minutes to about one week of each other and, more preferably, within about 12-72 hours of each other, with a delay time of only about 24-48 hours being most preferred. In some situations, it may be desirable to extend the time period for treatment significantly, where several days (2, 3, 4, 5, 6 or 7) or even several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations. It also is conceivable that more than one administration of either the carotenoid analog or derivative glycoside or the second agent will be desired. To achieve tumor regression, both agents are delivered in a combined amount effective to inhibit its growth, irrespective of the times for administration.

A variety of agents are suitable for use in the combined treatment methods disclosed herein. Chemotherapeutic agents contemplated as exemplary include, e.g., etoposide (VP-16), adriamycin, 5- fluorouracil (5-FU), camptothecin, actinomycin-D, mitomycin C, and cisplatin (CDDP).

As will be understood by those of ordinary skill in the art, the appropriate doses of chemotherapeutic agents will be generally around those already employed in clinical therapies wherein the chemotherapeutics are administered alone or in combination with other chemotherapeutics. By way of example only, agents such as cisplatin, and other DNA alkylating agents may be used. Cisplatin has been widely used to treat cancer, with efficacious doses used in clinical applications of 20 mg/m² for 5 days every three weeks for a total of three courses. Cisplatin is not absorbed orally and must therefore be delivered via injection intravenously, subcutaneously, intratumorally or intraperitoneally.

Further useful agents include compounds that interfere with DNA replication, mitosis and chromosomal segregation. Such chemotherapeutic compounds include adriamycin, also known as doxorubicin, etoposide, verapamil, podophyllotoxin, and the like. Widely used in a clinical setting for the treatment of neoplasms, these compounds are administered through bolus injections intravenously at doses ranging from 25-75 mg/m² at 21 day intervals for adriamycin, to 35-50 mg/m² for etoposide intravenously or double the intravenous dose orally. Agents that disrupt the synthesis and fidelity of polynucleotide precursors also may be used.

Particularly useful are agents that have undergone extensive testing and are readily available. As such, agents such as 5-fluorouracil (5-FU) are preferentially used by neoplastic tissue, making this agent particularly useful for targeting to neoplastic cells. Although quite toxic, 5-FU is applicable in a wide range of carriers, including topical, with intravenous administration in doses ranging from 3 to 15 mg/kg/day being commonly used.

Exemplary chemotherapeutic agents that are useful in connection with combined therapy are listed in Table 5. Each of the agents listed therein are exemplary and by no means limiting. In this regard, the skilled artisan is directed to "Remington's Pharmaceutical Sciences" 15th Edition, chapter 33, in particular pages 624-652. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards. Chemotherapeutic Agents Useful In Neoplastic Disease may include, though are not limited to: Alkylating Nitrogen Mustards, Mechlorethamine (HN₂), Cyclophosphamide, Ifosfamide, Melphalan (L-sarcolysin), Chlorambucil, Ethylenimenes, Hexamethylmelamine, Methylmelamines, Thiotepa, , Alkyl Sulfonates, Busulfan, , Carmustine, Nitrosoureas Lomustine, Semustine, methyl-CCNU, Streptozocin streptozotocin Dacarbazine dimethyltriazenoimidazolecarboxamide Methotrexate amethopterin Fluouracil (5- fluorouracil; 5-FU) Floxuridine fluorode-oxyuridine; FUdR Cytarabine arabinoside Mercaptopurine 6- mercaptopurine; 6-MP Thioguanine 6-thioguanine; TG Pentostatin deoxycoformycin Vinblastine Vincristine Epipodophyllotoxins Etoposide Tertiposide Dactinomycin (actinomycin D) Daunorubicin

(daunomycin; rubidomycin) Doxorubicin Bleomycin Plicamycin (mithramycin) Mitomycin (mitomycin C) L-Asparaginase Interferon-α Cisplatin (cis-DDP) Carboplatin Anthracenedione Mitoxantrone Hydroxyurea Methyl Hydrazine Procarbazine Derivative (N-methylhydrazine, MIH) Adrenocortical Mitotane (o, p'-DDD) Aminoglutethimide Adrenocorticosteroids Prednisone Hydroxyprogesterone, caproate Medroxyprogesterone acetate Megestrol acetate Diethylstilbestrol Breast, prostate Ethinyl estradiol (other preparations available) Tamoxifen Testosterone propionate Fluoxymesterone (other preparations available) Antiandrogens Flutamide Leuprolide

Other factors that cause DNA damage and have been used extensively include what are commonly known as γ-rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells. Other forms of DNA damaging factors also are contemplated such as microwaves and UV-irradiation. It is most likely that all of these factors affect a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes. Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 wk), to single doses of 2000 to 6000 roentgens. Dosage ranges for radioisotopes vary widely, and depend on the half -life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells. Salts encompassed within the term ''pharmaceutically acceptable salts^'' refer to non-toxic salts of the compounds which are generally prepared by reacting a free base with a suitable organic or inorganic acid or by reacting the acid with a suitable organic or inorganic base. Particular mention may be made of the pharmaceutically acceptable inorganic and organic acids customarily used in pharmacy. Those suitable are in particular wafεr-solublε and water-insoiuble acid addition salts with acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric add, nitric acid, sulfuric acid, acetic acid, citric acid, D- gluconic acid, benzoic acid,

acid, butyric acid, sulfosalicylic acid, maleic acid, lauiϊc acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric add. embonic add. stearic add. toluenesulfonic acid, meihanesulfonic acid or i-hydroxy-2-naphihoic add, the adds being employed in salt preparation— depending on whether it is a mono- or polybasic acid and depending on which salt is desired-in an equimolar quantitative ratio or one differing therefrom.

As examples of salts with bases are mentioned the lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium; meglumine or guanidiniυm salts, here, too, the bases being employed in salt preparation in an equimolar quantitative ratio or one differing therefrom.

It is understood that the active compounds and their pharmaceutically acceptable salts mentioned can also be present, for example, in the foim of their pharmaceutically acceptable solvates, in particular in the form of their hydrates,

The pharmaceutical preparation may be administered orally, in the form of a tablet, a capsule, an emulsion, a liquid, or the like. Alternatively, the pharmaceutical preparation may be administered via a parenteral route. A more detailed description of the types of pharmaceutical preparations that are suitable for some embodiments is described in detail below. Some embodiments may be particularly suited timed or sustained release pharmaceutical preparations, in which the preparation is adapted to deliver a known dosage of carotenoids or synthetic derivatives or analogs thereof at or over a predetermined time. In an embodiment, a pharmaceutical preparation may be a "soft drug", in that the compound is active in the derivatized state, and may yield a known carotenoid after metabolic conversion in vivo. In an embodiment, a pharmaceutical preparation may be adapted to one drug, or a portion thereof, before delivering the second drug. For example, a pharmaceutical preparation may be adapted in such a way that at least a portion of the xanthophyll carotenoid or structural analog or derivative thereof is released into the body of a subject before the additional prostate cancer treatment compositions or medicaments are released. One or more of the additional prostate cancer treatment compositions or medicaments for the uses presently contemplated may be formulated as a separate pharmaceutical composition to be administered in conjunction with the subject carotenoid analogs or derivatives as part of a therapeutic regimen, or may be formulated in a single preparation together with the one or more carotenoid analogs or derivatives. Such a composition may be administered orally, parenterally, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral generally embraces non-oral routes of administration, including but not limited to, subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Formulation of drugs is discussed in, for example, Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975. Another discussion of drug formulations can be found in Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980. Therapeutic kits:

Therapeutic kits comprising the carotenoid analogs or derivatives, either alone or in combination with an additional composition suitable for the treatment of prostate cancer are also contemplated herein. Such kits will generally contain, in suitable container means, a pharmaceutically acceptable formulation of at least one carotenoid analog or derivative compound. The kits also may contain other pharmaceutically acceptable formulations, such as those containing components to target the carotenoid analog or derivative compounds to distinct regions of a patient where treatment is needed, or any one or more of a range of drugs which may work in concert with the carotenoid analog or derivative compounds, for example, chemotherapeutic agents as described above. The kits may have a single container means that contains the carotenoid analog or derivative compounds, with or without any additional components, or they may have distinct container means for each desired agent. When the components of the kit are provided in one or more liquid solutions, the liquid solution is an aqueous solution, with a sterile aqueous solution being particularly preferred. However, the components of the kit may be provided as dried powder(s). When reagents or components are provided as a dry powder, the powder can be reconstituted by the addition of a suitable solvent. It is envisioned that the solvent also may be provided in another container means. The container means of the kit will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which the monoterpene/triterpene glycoside, and any other desired agent, may be placed and, preferably, suitably aliquoted. Where additional components are included, the kit will also generally contain a second vial or other container into which these are placed, enabling the administration of separated designed doses. The kits also may comprise a second/third container means for containing a sterile, pharmaceutically acceptable buffer or other diluent.

The kits also may contain a means by which to administer the monoterpene/triterpene compositions to an animal or patient, e.g., one or more needles or syringes, or even an eye dropper, pipette, or other such like apparatus, from which the formulation may be injected into the animal or applied to a diseased area of the body. The kits of the present invention will also typically include a means for containing the vials, or such like, and other component, in close confinement for commercial sale, such as, e.g., injection or blow-molded plastic containers into which the desired vials and other apparatus are placed and retained.

Targeted Cancer Therapy:

The carotenoid analogs or derivatives described herein may be linked to one or more, molecules which target the compounds to specific cells for example, inflamed cells, tumor cells etc. Targeting is beneficial in that it can be used to increase the overall levels of a drug at the site of treatment, for example, at sites of inflammation or tumor sites, while minimizing systemic exposure to the drug.

In common with the chemotherapeutic agents discussed above, it is possible that the use of a targeted carotenoid analog or derivative may be used in combination with a second agent, such as a chemotherapeutic agent, as provided for above. Both the carotenoid analog or derivative and the second agent may be directed to the same or different targets within the tumor environment. This should result in additive, greater than additive or even markedly synergistic results.

Exemplary targeting agents employed in combination with the carotenoid analogs or derivatives will be those targeting agents that are capable of delivering carotenoid analog or derivative molecules to the afflicted region, i.e., capable of localizing to a tumor site. Similarly desired will be those agents that target the vasculature of a tumor region. The targeting of the carotenoid analog or derivative compounds is specifically contemplated to allow for greater effective concentrations in afflicted regions without or with the minimization of potential side effects which could be observed with a somewhat wider or systemic distribution of the compounds. Turing now to the drawings, FIG. 1 depicts several examples of the structures of various synthetic carotenoid analogs and derivatives that may be used in accordance with one or more of the embodiments provided for herein. (A) lycophyll disuccinate; (B) lycophyll dilysinate; (C) disuccinate divitamin C astaxanthin; (D) disodium disuccinic acid ester astaxanthin salt (Cardax™); (E) dilysinate astaxanthin ester. Of course, it will be readily appreciated by a practitioner having ordinary skill in the art that suitable carotenoid analogs are not limited to those shown in FIG. 1. On the contrary, these are merely provided for the purpose of providing exemplary compounds suitable for the present purpose, and other, including but not limited to pharmaceutically acceptable salts thereof, may be employed for use with the presently described embodiments, without departing from the spirit and scope thereof.

FIG. 2 is a depiction of the enzymatic hydrolysis of lycophyll dilysinate by esterases (e.g., in the intestine), which may be administered to a subject for the purposes of the present embodiments. By virtue of enzymes such as e.g., esterases present in the digestive tract and in solid organs of subject administered such compounds, as well as by virtue of the endogenous esterase activity of soluble blood proteins (e.g., serum albumins), which bind to and transport the subject carotenoid analogs and derivatives, at least a portion of the functional side groups (in this non-limiting example, lysines coupled via ester linkage to the terminal OH of lycophyll) may be hydrolyzed from the synthetic carotenoid analog or derivative. Thus, while an individual may be administered a carotenoid analog or derivative having various functional groups (at least in part for the purpose of increasing the solubility of carotenoids in aqueous solvents) are described below in greater detail, once ingested, said analogs or derivatives are metabolized in vivo as shown in the example represented in FIG. 2.

The parent carotenoid analog or derivative, as well as its hydrolyzed "naked" xanthophyll carotenoid may be taken up by target cells, including but not limited to target cells such as prostate cancer cells. Turning to FIG. 3, a bar graph is shown depicting the uptake of lycophyll by PC-3 cells treated with 10^~5 M lycophyll in THF for the indicated amount of time. Data are represented as intracellular lycophyll concentration.

FIG. 4is a representation of the effects of lycophyll dilysinate (LdiLys) on various cellular properties of prostate cancer cells. (A) is a depiction of the uptake of LdiLys visualized by colour, of cell pellets consisting of DU- 145 cells cultured for 24 hr in the presence of the indicated amount of LdiLys;

(B) is a graphical representation showing the percentage of the cells shown in (A) that are in Gl phase of the cell cycle after being treated for 24 hr as indicated; (C) is a graph showing the growth kinetics of DU- 145 cells treated with 10^~5 M LdiLys over a period of 96 hr; and (D) is a bar graph showing the percent survival of DU-145 cells and LNCaP cells treated with 10^~5 M LdiLys or vehicle alone for either 24 hr or 48 hr as indicated;

FIG. 5 shows the biochemical effect on various components of the NF-κB signaling pathway of treating DU-145 cells with 10 ng/ml TNF-α for 10 minutes and 10^"5 M LdiLys for the indicated amount of time. (A) TNF-α induced IKB phosphorylation of IKB in cells pre-treated with 10^"5 M LdiLys for 24 hr is reduced by about 80%; (B) IKB phosphorylation in cells treated with 10^"5 M LdiLys for 5, 10, or 30 min is reduced by 2%, by 16% and by 55% respectively; (C) TNF-α induced IKB phosphorylation in cells pre- treated with 10^"5 M LdiLys for 30 min or for 2 hr is reduced by about 46% and by about 98%, respectively; (D) TNF-α induced accumulation of NF-κB in the nucleus of cells is about 60% lower in cells treated for 2 hr with 10^"5 M LdiLys vs. vehicle treated control cells;

FIG. 6 shows the effect of 10^"5 M LdiLys treatment for 30 min on IKB phosphorylation in various cell lines (A) in LNCaP cells, 30 min LdiLys treatment reduced steady-state and TNF-α-induced IKB phosphorylation by about 55% and about 54%, respectively; (B) in PC-3 cells, 30 min LdiLys treatment reduced steady-state and TNF-α-induced IKB phosphorylation by about 11% and about 27%, respectively;

(C) in a human fibrosarcoma tumor cell line (HT-1080), 30 min LdiLys treatment reduced steady-state and TNF-α-induced IKB phosphorylation by about 33% and about 41%, respectively; FIG. 7 shows the effect of 10^"5 M LdiLys treatment for 24 hr on steady-state expression of various

NF-κB responsive gene products in various prostate tumor cell lines. (A) Treatment of DU-145 cells for 24 hr with 10^"5 M LdiLys results in a 67% decrease in the steady state expression of cyclin Dl, and a 67% decrease in the steady state expression of c-myc; (B) Treatment of LNCaP cells for 24 hr with 10^"5 M LdiLys results in a 51% decrease in the steady state expression of cyclin Dl, and a 21% decrease in the steady state expression of TNF-α; (C) Treatment of PC-3 cells for 24 hr with 10^'5 M LdiLys results in a 86% decrease in the steady state expression of cyclin Dl, and a 21% decrease in the steady state expression of TNF-α;

FIG. 8 is a schematic representation of an in vitro assay to measure the effect of 72 hr LdiLys treatment and extracellular matrix (ECM) (e.g., MATRIGEL™) on PC-3 cell invasion through a porous polycarbonate membrane;

FIG. 9 is a bar graph depicting the results obtained in the assay depicted in FIG. 8, in which PC-3 cells were treated with 10^~5 M LdiLys for 72 hr or were left untreated; in the presence of LdiLys, average PC-3 cell invasion was reduced by about 18%;

FIG. 10 shows bar graphs comparing the effect of the presence or absence of ECM (MATRIGEL™) on the results obtained in the assay depicted in FIG. 9; the inhibitory effect of LdiLys on PC-3 cell transmembrane invasion is more pronounced in the presence of ECM (A) than in its absence (B);

FIG. 11 is a bar graph depicting the results obtained in an in vitro MMP-9 inhibition assay; MMP-

9 is inhibited in vitro in a dose-dependent manner over the indicated concentration range; FIG. 12 shows the effect LdiLys on NF-κB activity in TNF-α treated or untreated DU- 145 cells as measured by total cellular IKB expression: (A) steady state IKB expression in DU-145 cells treated for 24 hr with 10^"5 M LdiLys is reduced by about 71% (compare lane 1 with lane 2). When treated for 10 min with 10 ng/ml TNF-α only as a control (compare lane 3 with lane 4), IKB levels are reduced by about 90%. When treated for 10 min with 10 ng/ml TNF-α and for 24 hr with 10^"5 M LdiLys, IKB expression is reduced a further 82% than when treated with LdiLys alone (compare lane 5 with lane 6, and these two lanes with lane 3); (B) steady state IKB expression in DU-145 cells treated for the indicated time intervals with 10^"5 M LdiLys. IKB expression is reduced by about 31% and about 47% in DU-145 cells treated with LdiLys for 30 min or 120, respectively (compare lanes 3 and 4 with lane 1); When treated for 10 min with

10 ng/ml TNF-α only as a control as above (compare lane 3 with lane 4), IKB levels are reduced by about 80%. When treated for 10 min with 10 ng/ml TNF-α and with 10^'5 M LdiLys for 30 min, IKB expression is reduced a further 38% than when treated with TNF-α alone (compare lane 6 with lane 5) and a further 73% when treated with LdiLys for 120 min than when treated with TNF-α alone (compare lane 7 with lane 5); (C) steady state IKB expression in DU-145 cells treated for the indicated time intervals with 10^"5 M LdiLys either alone or in combination with 10 ng/ml TNF-α for 10 min. When treated for 10 min with 10 ng/ml TNF-α only as a control as above (compare lane 2 with lane 1), IKB levels are reduced by about 80%. When pre-treated with 10^'5M LdiLys for 30 min (lanes 3 and 4) or for 120 min (lanes 5 and 6), IKB expression is reduced by 81% and 89%, respectively, in response to TNF-α;

FIG. 13 shows the effect on NF-κB activity in DU-145 cells treated with 10^'5 M LdiLys for the indicated times up to 30 min as measured by (A) steady state total cellular IKB expression; and (B) IKB phosphorylation; FIG. 14 shows the effect on NF-κB activity in DU- 145 cells treated with 10 ng/ml TNF-α for 10 min or 10^"5 M LdiLys for 30 min, either alone or in combination as indicated, in various tumor cell lines as measured by ; (A) in LNCaP cells, steady state IKB expression is reduced by about 78% in response to TNF-α stimulation as a control (compare lane 2 with lane 1). When treated for 30 min with LdiLys as indicated, IKB expression is reduced about 15% below the steady state IKB expression in un-induced (i.e., TNF-untreated) cells (compare lane 3 with lane 1), and 15% below the expression of IKB expression in induced (i.e., TNF-α treated) cells (compare lane 4 with lane 2); (B) in PC-3 cells, steady state IKB expression is reduced by about 58% in response to TNF-α stimulation as a control (compare lane 2 with lane 1). When treated for 30 min with LdiLys as indicated, IKB expression is reduced about 26% below steady state IKB expression in un-induced (i.e., TNF-untreated) cells (compare lane 3 with lane 1), and 65% below the expression of IKB expression in induced (i.e., TNF-α treated) cells (compare lane 4 with lane 2); (C) in fibrosarcoma (non-prostate) HT-1080 tumor cells, steady state IKB expression is reduced by about 85% in response to TNF-α stimulation as a control (compare lane 2 with lane 1). When treated for 30 min with LdiLys as indicated, IKB expression is increased about 13% above the steady state IKB expression in un-induced (i.e., TNF-untreated) cells (compare lane 3 with lane 1), and only 3.5% below the expression of IKB expression in induced (i.e., TNF-α treated) cells (compare lane 4 with lane 2), indicating that LdiLys does not appear to have an appreciable effect on IKB expression in non-prostate cells, despite reducing TNF-α induced IKB phosphorylation by about 41% (compare, e.g., FIG. 6, lane 2 with lane 4); (D) in DU-145 cells, steady state IKB expression (upper panel) is reduced by about 37% in response to TNF-α stimulation as a control (compare upper panel lane 2 with lane 1). When treated for 30 min with LdiLys as indicated, IKB expression is reduced about 26% below steady state IKB expression in un-induced (i.e., TNF-untreated) cells (compare upper panel lane 3 with lane 1), and 81% below the expression of IKB expression in induced (i.e., TNF-α treated) cells (compare upper panel lane 4 with lane 2). In DU-145 cells, IKB phosphorylation (lower panel) is increased by about 3.7-fold in response to TNF- α stimulation as a control (compare lower panel lane 2 with lane 1). When treated for 30 min with LdiLys as indicated, steady state IKB phosphorylation is reduced about 17% below the level of steady state IKB phosphorylation in un-induced (i.e., TNF-untreated) cells (compare lower panel lane 3 with lane 1), and 46% below the level of IKB phosphorylation in induced (i.e., TNF-α treated) cells (compare lower panel lane 4 with lane 2); FIG. 15 is a bar graph showing the dose-dependent reduction in average tumor cell invasion as measured in the assay depicted in FIG. 8 in response to 72 hr pre-treatment of PC-3 cells with 10^"7 - 10^"5 M LdiLys as indicated, in the presence or absence of ECM (MATRIGEL™);

FIG. 16 is a bar graph showing the dose-dependent reduction in tumor cell invasion as measured in the assay depicted in FIG. 8 in response to 72 hr pre-treatment of PC-3 cells with 10^"7 - 10^"5 M LdiLys as indicated, in the presence (light bars) or absence of ECM (MATRIGEL™) (dark bars); Dosage of compositions or medicament suitable for use in prostate cancer treatment

Dosage levels of additional prostate cancer treatment compositions or medicaments may be on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 1.0 mg to about 1 ,000 mg. The amount of active ingredient that may be combined with other anticancer agents to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

It is understood, however, that a specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the severity of the particular disease being treated and form of administration.

Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage- effect relationships from in vitro initially can provide useful guidance on the proper doses for patient administration. Studies in animal models also generally may be used for guidance regarding effective dosages for treatment of cancers in accordance with the present invention. In terms of treatment protocols, it should be appreciated that the dosage to be administered will depend on several factors, including the particular agent that is administered, the route administered, the condition of the particular patient, etc. Generally speaking, one will desire to administer an amount of the compound that is effective to achieve a serum level commensurate with the concentrations found to be effective in vitro. Thus, where a compound is found to demonstrate in vitro activity at, e.g., 10 μM, one will desire to administer an amount of the drug that is effective to provide about a 10 μM concentration in vivo. Determination of these parameters is well within the skill of the art.

These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.

CAROTENOIDS AND THE PREPARATION AND USE THEREOF In some embodiments, a composition may include one or more carotenoid analogs or derivatives, optionally in combination with one or more additional compositions or medicaments suitable for the treatment of a neurodegenerative disorders or conditions associated with oxidative stress. Carotenoid analogs and derivative suitable for use in accordance with the may include carotenoids having the general structure:

wherein R⁴ is independently hydrogen, -OH, -CH₂OH, or -OR⁶; where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; alkyl; aryl; -alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl- N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^~; -aryl-CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)- aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl- CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(NR⁷)-alkyl-N(R⁷)₂; -C(NR⁷)-aryl-N(R⁷)₂; -C(NR⁷)-alkyl-N⁺(R⁷)₃; -C(NR⁷)-aryl- N⁺(R⁷)₃; -C(NR⁷)-alkyl-CO₂R⁹; -C(NR⁷)-aryl-CO₂R⁹; -C(NR⁷)-alkyl-CO₂ ^"; -C(NR⁷)-aryl-CO₂ ^"; -C(NR⁷)- alkyl-N(R⁷)-alkyl-N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-[C₆-C₂₄ saturated hydrocarbon]; - C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, - S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

where each R¹ and R² are independently:

where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; alkyl; aryl; - alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; -aryl- CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl- CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(NR⁷)-alkyl-N(R⁷)₂; -C(NR⁷)-aryl- N(R⁷)₂; -C(NR⁷)-alkyl-N⁺(R⁷)₃; -C(NR⁷)-aryl-N⁺(R⁷)₃; -C(NR⁷)-alkyl-CO₂R⁹; -C(NR⁷)-aryl-CO₂R⁹; - C(NR⁷)-alkyl-CO₂ ^"; -C(NR⁷)-aryl-CO₂ ^"; -C(NR⁷)-alkyl-N(R⁷)-alkyl-N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; - S(O)(OR⁸)₂; -C(O)-amino acid; -C(NR⁷)-amino acid; -C(O)-[C₆-C₂₄ saturated hydrocarbon] ; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

In some embodiments, each -OR⁶ group may independently be

where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; alkyl; aryl; -alkyl- N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; -aryl-CO₂ ^"; - C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; - C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(NR⁷)-alkyl-N(R⁷)₂; -C(NR⁷)-aryl-N(R⁷)₂; - C(NR⁷)-alkyl-N⁺(R⁷)₃; -C(NR⁷)-aryl-N⁺(R⁷)₃; -C(NR⁷)-alkyl-CO₂R⁹; -C(NR⁷)-aryl-CO₂R⁹; -C(NR⁷)-alkyl- CO₂ ^"; -C(NR⁷)-aryl-CO₂ ^"; -C(NR⁷)-alkyl-N(R⁷)-alkyl-N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; - C(O)-amino acid; -C(NR⁷)-amino acid; -C(O)-[C₆-C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

wherein each R6 is independently: H; alkyl; aryl; -alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl- N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^~; -aryl-CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; - C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)- aryl-CO₂ ^"; -C(NR⁷)-alkyl-N(R⁷)₂; -C(NR⁷)-aryl-N(R⁷)₂; -C(NR⁷)-alkyl-N⁺(R⁷)₃; -C(NR⁷)-aryl-N⁺(R⁷)₃; - C(NR⁷)-alkyl-CO₂R⁹; -C(NR⁷)-aryl-CO₂R⁹; -C(NR⁷)-alkyl-CO₂ ^"; -C(NR⁷)-aryl-CO₂ ^"; -C(NR⁷)-alkyl-N(R⁷)- alkyl-N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-amino acid; -C(NR⁷)-amino acid; -C(O)-[C₆- C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co- antioxidant.

In some embodiments, carotenoid analogs or derivatives may be employed in "self-formulating" aqueous solutions, in which the compounds spontaneously self-assemble into macromolecular complexes. These complexes may provide stable formulations in terms of shelf life. The same formulations may be parenterally administered, upon which the spontaneous self-assembly is overcome by interactions with serum and/or tissue components in vivo.

Some specific embodiments may include phosphate derivatives, succinate derivatives, co- antioxidant derivatives (e.g., Vitamin C, Vitamin C analogs, Vitamin C derivatives, Vitamin E, Vitamin E analogs, Vitamin E derivatives, flavonoids, flavonoid analogs, or flavonoid derivatives), or combinations thereof derivatives or analogs of carotenoids. Flavonoids may include, for example, quercetin, xanthohumol, isoxanthohumol, or genistein. Vitamin E may generally be divided into two categories including tocopherols having a general structure

A/p/ω-tocopherol is used to designate when R¹ = R² = CH₃. βeto-tocopherol is used to designate when R¹ = CH₃ and R² = H. Gαraraα-tocopherol is used to designate when R¹ = H and R² = CH₃. De/to-tocopherol is used to designate when R = R = H.

The second category of Vitamin E may include tocotrienols having a general structure

Alpha- tocotrienol is used to designate when R¹ = R² = CH₃. Beta- tocotrienol is used to designate when R¹ = CH₃ and R² = H. Gamma- tocotrienol is used to designate when R¹ = H and R² = CH₃. Delta- tocotrienol is used to designate when R¹ = R² = H. Quercetin, a flavonoid, has the structure

In some embodiments, one or more co-antioxidants may be coupled to a carotenoid or carotenoid derivative or analog. Derivatives of one or more carotenoid analogues may be formed by coupling one or more free hydroxy groups of the co-antioxidant to a portion of the carotenoid.

Derivatives or analogs may be derived from any known carotenoid (naturally or synthetically derived). Specific examples of naturally occurring carotenoids which compounds described herein may be derived from include for example zeaxanthin, lutein, lycophyll, astaxanthin, and lycopene.

In some embodiments, carotenoid analogs or derivatives may have increased water solubility and/or water dispersibility relative to some or all known naturally occurring carotenoids. Contradictory to previous research, improved results are obtained with derivatized carotenoids relative to the base carotenoid, wherein the base carotenoid is derivatized with substituents including hydrophilic substituents and/or co-antioxidants.

In some embodiments, the carotenoid derivatives may include compounds having a structure including a polyene chain (i.e., backbone of the molecule). The polyene chain may include between about 5 and about 15 unsaturated bonds. In certain embodiments, the polyene chain may include between about 7 and about 12 unsaturated bonds. In some embodiments a carotenoid derivative may include 7 or more conjugated double bonds to achieve acceptable antioxidant properties.

In some embodiments, decreased antioxidant properties associated with shorter polyene chains may be overcome by increasing the dosage administered to a subject or patient.

In some embodiments, a chemical compound including a carotenoid derivative or analog may have the general structure:

Each R¹¹ may be independently hydrogen or methyl. R⁹ and R¹⁰ may be independently H, an acyclic alkene with one or more substituents, or a cyclic ring including one or more substituents. y may be 5 to 12. In some embodiments, y may be 3 to 15. In certain embodiments, the maximum value of y may only be limited by the ultimate size of the chemical compound, particularly as it relates to the size of the chemical compound and the potential interference with the chemical compound's biological availability as discussed herein. In some embodiments, substituents may be at least partially hydrophilic. These carotenoid derivatives may be included in a pharmaceutical composition.

In some embodiments, methods of treating a neurodegenerative disorders or conditions associated with oxidative stress in a subject may include administering to a subject who would benefit from such treatment a therapeutically effective amount of a pharmaceutically acceptable composition comprising a carotenoid analog or derivative having the structure

wherein R⁴ is independently hydrogen, -OH, -CH₂OH, or -OR⁶; where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; alkyl; aryl; -alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl- N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^~; -aryl-CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)- aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl- CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(NR⁷)-alkyl-N(R⁷)₂; -C(NR⁷)-aryl-N(R⁷)₂; -C(NR⁷)-alkyl-N⁺(R⁷)₃; -C(NR⁷)-aryl- N⁺(R⁷)₃; -C(NR⁷)-alkyl-CO₂R⁹; -C(NR⁷)-aryl-CO₂R⁹; -C(NR⁷)-alkyl-CO₂ ^"; -C(NR⁷)-aryl-CO₂ ^"; -C(NR⁷)- alkyl-N(R⁷)-alkyl-N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-amino acid; -C(NR⁷)-amino acid; -C(O)-[C₆-C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

In some embodiments, a method of treating neurodegenerative disorders or conditions associated with oxidative stress in a subject may include administering to a subject who would benefit from such treatment a therapeutically effective amount of a pharmaceutically acceptable composition comprising a carotenoid analog or derivative. The carotenoid analog or derivative of the carotenoid may have the structure

where each R¹ and R² are independently:

In some embodiments, each -OR⁶ group may independently be

5 H H

Jj ^NH2

O ; and pharmaceutically acceptable salts of any of these compounds, where each R is independently H, alkyl, aryl, benzyl, Group IA metal, or co-antioxidant.

When R⁶ is an amino acid derivative or a peptide, coupling of the amino acid or the peptide is accomplished through an ester linkage or a carbamate linkage. Specifically, an ester linked amino acid group -OR⁶ has the general structures:

Depending on if the free form of the salt form is desired. A carbamate linked amino acid group - OR⁶ will have the general structure:

Depending on if the free form of the salt form is desired. For both ester linked and carbamate linked amino acids, the group R¹⁴ represents an amino acid side chain. Specifically, R¹⁴ can be:

-H (glycine); -CH₃ (alanine); -CH(CH₃)-CH₃ (valine); -CH₂-CH(CH₃)-CH₃ (leucine);

-CH(CH₃)-CH₂-CH₃ (isoleucine); -CH₂-Ph (phenylalanine); -CH₂-CH₂-S-CH₃ (methionine);

-CH₂-OH (serine); -CH(CH₃)-OH (threonine); -CH₂-SH (cysteine); -CH₂-Ph-OH (tyrosine);

-CH₂-C(O)-NH₂ (aspargine); -CH₂-CH₂-C(O)-NH₂ (glutamine); -CH₂-CO₂H (aspartic acid); -CH₂-CH₂-CO₂H (glutamic acid); -CH₂-CH₂-CH₂-CH₂-NH₂ (lysine); -CH₂-CH₂-CH₂-NH₂ (ornithine);

-CH₂-CH₂-CH₂-NH-C(NH)-NH₂ (arginine);

(tryptophan).

Amino acid side chains can be in the neutral form (as depicted above) or in a salt form. When R¹⁴ represents the side chain from the amino acid proline, the following compounds result:

*V

O \ CO₂R ₇ ⁷ When R⁹ is an amino acid derivative or a peptide, coupling of the amino acid or the peptide is accomplished through an amide linkage. The amide linkage may be formed between the terminal carboxylic acid group of the linker attached to the xanthophyll carotene and the amine of the amino acid or peptide.

When R⁶ is a carbohydrate, R⁶ includes, but is not limited to the following side chains: -CH₂-(CHOH)_n-CO₂H; -CH₂-(CHOH)_n-CHO; -CH₂-(CHOH)_n-CH₂OH; -CH₂-(CHOH)_n-C(O)- CH₂OH;

where R¹³ is hydrogen or -OH.

When R⁶ is a nucleoside, R⁶ may have the structure:

where R¹² is a purine or pyrimidine base, and R¹³ is hydrogen or -OH.

When R⁶ is -C(O)-[Ce-C₂₄ saturated hydrocarbon], the substituent, R⁶, is derived from coupling of a saturated fatty acid with the carotenoid parent structure. Examples of saturated fatty acids include, but are not limited to: hexanoic acid (caproic acid); octanoic acid (caprylic acid); decanoic acid (capric acid); dodecanoic acid (lauric acid); tridecanoic acid; tetradecanoic acid (myristic acid); pentadecanoic acid; hexadecanoic acid (palmitic acid); heptadecanoic acid (margaric acid); octadecanoic acid (stearic acid); eicosanoic acid (arachidic acid); docosanoic acid (behenic acid); tricosanoic acid; and tetracosanoic acid (lignoceric acid).

When R⁶ is -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon], the substituent, R⁶, is derived from coupling of a monounsaturated fatty acid with the carotenoid parent structure. Examples of monounsaturated fatty acids include, but are not limited to: 9-tetradecenoic acid (myristoleic acid); 9- hexadecenoic acid (palmitoleic acid); 11-octadecenoic acid (vaccenic acid); 9-octadenoic acid (oleic acid); 11-eicosenoic acid; 13-docosenoic acid (erucic acid); 15-tetracosanoic acid (nervonic acid); 9-trans- hexadecenoic acid (palmitelaidic acid); 9-trans-octadecenoic acid (elaidic acid); 8-eicosaenoic acid; and 5- eicosaenoic acid.

When R⁶ is -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon], the substituent, R⁶, is derived from coupling of a polyunsaturated fatty acid with the carotenoid parent structure. Examples of polyunsaturated fatty acids include, but are not limited to omega-3 polyunsaturated fatty acids, omega-6 polyunsaturated fatty acids; and conjugated polyunsaturated fatty acids. Examples of omega-3 polyunsaturated fatty acids include, but are not limited to: 9,12,15-octadecatrienoic acid (alpha-linolenic acid); 6,9,12,15- octadecatetraenoic acid (stearidonic acid); 11,14,17-eicosatrienoic acid (eicosatrienoic acid (ETA)); 8,11,14,17-eicsoatetraenoic acid (eicsoatetraenoic acid); 5,8,11, 14, 17-eicosapentaenoic acid (eicosapentaenoic acid (EPA)); 7,10,13,16,19-docosapentaenoic acid (docosapentaenoic acid (DPA)); 4,7, 10,13, 16, 19-docosahexaenoic acid (docosahexaenoic acid (DHA)); 6,9,12,15,18,21- tetracosahexaenoic acid (nisinic acid); 9E,l lZ,15E-octadeca-9,l l,15-trienoic acid (rumelenic acid); 9E,l lZ,13Z,15E-octadeca-9,l l,13,15-trienoic acid (α-parinaric acid); and all trans-octadeca-9,11,13,15- trienoic acid (β-parinaric acid). Examples of omega-6 polyunsaturated fatty acids include, but are not limited to: 9,12-octadecadienoic acid (linoleic acid); 6,9,12-octadecatrienoic acid (gamma-linolenic acid); 11,14-eicosadienoic acid (eicosadienoic acid); 8,11,14-eicosatrienoic acid (homo-gamma-linolenic acid); 5,8,11,14-eicosatetraenoic acid (arachidonic acid); 13,16-docosadienoic acid (docosadienoic acid); 7,10,13,16-docosatetraenoic acid (adrenic acid); 4,7, 10,13, 16-docosapentaenoic acid (docosapentaenoic acid); 8E,10E, 12Z-octadecatrienoic acid (calendic acid); 10E,12Z-octadeca-9,l l-dienoic acid; 8E,10E,12Z-octadecatrienoic acid (α-calendic acid); 8E,10E,12E-octadecatrienoic acid (β-calendic acid); 8E,10Z,12E-octadecatrienoic acid (jacaric acid); and 5Z,8Z,10E,12E,14Z-eicosanoic acid (bosseopentaenoic acid). Examples of conjugated polyunsaturated fatty acids include, but are not limited to: 9Z,l lE-octadeca-9,l l-dienoic acid (rumenic acid); 10E,12Z-octadeca-9,l l-dienoic acid; 8E,10E,12Z- octadecatrienoic acid (α-calendic acid); 8E,10E,12E-octadecatrienoic acid (β-calendic acid); 8E,10Z,12E- octadecatrienoic acid (jacaric acid); 9E,l lE,13Z-octadeca-9,l l,13-trienoic acid (α-eleostearic acid); 9E,l lE,13E-octadeca-9,l l,13-trienoic acid (β-eleostearic acid); 9Z,l lZ,13E-octadeca-9,l l,13-trienoic acid (catalpic acid); 9E,l lZ,13E-octadeca-9,l l,13-trienoic acid (punicic acid); 9E,l lZ,15E-octadeca- 9,11,15-trienoic acid (rumelenic acid); 9E,l lZ,13Z,15E-octadeca-9,l l,13,15-trienoic acid (α-parinaric acid); all trans-octadeca-9,11, 13, 15-trienoic acid (β-parinaric acid); and 5Z,8Z,10E,12E,14Z-eicosanoic acid (bosseopentaenoic acid).

Specific examples of carotenoid derivatives include, but are not limited to, the following compounds and pharmaceutically acceptable salts of these compounds:

Further details regarding the use and synthesis of carotenoid derivatives and analogs suitable for use in the presently described embodiments may be found in the following U.S. patent documents: U.S. Patent No. 7,145,025 entitled "STRUCTURAL CAROTENOID ANALOGS FOR THE INHIBITION AND AMELIORATION OF DISEASE" issued December 5, 2006; U.S. Patent Application Publication No. 2005/0113372 entitled "CAROTENOID ANALOGS OR DERIVATIVES FOR THE INHIBITION AND AMELIORATION OF DISEASE"; U.S. Patent Application Publication No. 2005/0075337, entitled "PHARMACEUTICAL COMPOSITIONS INCLUDING CAROTENOID ANALOGS OR DERIVATIVES FOR THE INHIBITION AND AMELIORATION OF DISEASE"; U.S. Patent Application Publication No. 2005/0261254 entitled "CAROTENOID ANALOGS OR DERIVATIVES FOR THE INHIBITION AND AMELIORATION OF INFLAMMATION"; U.S. Patent Application Publication No. 2006/0058269 entitled "CAROTENOID ANALOGS OR DERIVATIVES FOR THE INHIBITION AND AMELIORATION OF INFLAMMATION"; U.S. Patent Application Publication No. 2006/0178538 entitled "METHODS FOR THE SYNTHESIS OF CHIRAL DIHYDROXY INTERMEDIATES USEFUL FOR THE CHIRAL SYNTHESIS OF CAROTENOIDS"; U.S. Patent Application Publication No. 2006/0183947 entitled "METHODS FOR THE SYNTHESIS OF

ASTAXANTHIN"; U.S. Patent Application Publication No. 2006/0155150 entitled "METHODS FOR THE SYNTHESIS OF LUTEIN"; U.S. Patent Application Publication No. 2006/0088905 entitled "METHODS FOR THE SYNTHESIS OF ZEAXANTHIN"; U.S. Patent Application Publication No. 2006/0167319 entitled "METHODS FOR THE SYNTHESIS OF UNSATURATED KETONE INTERMEDIATES USEFUL FOR THE SYNTHESIS OF CAROTENOIDS"; U.S. Patent Application Publication No. 2006/0183185 entitled "METHODS FOR THE SYNTHESIS OF ASTAXANTHIN"; U.S. Patent Application Publication No. 2006/0111580 entitled "METHODS FOR THE SYNTHESIS OF CHIRAL DIHYDROXY KETONE INTERMEDIATES USEFUL FOR THE CHIRAL SYNTHESIS OF CAROTENOIDS"; U.S. Patent Application Publication No. 2006/0088904 entitled "METHODS FOR THE SYNTHESIS OF ASTAXANTHIN"; U.S. Patent Application Publication No. 2006/0270590 entitled "REDUCTION IN COMPLEMENT ACTIVATION AND INFLAMMATION DURING TISSUE INJURY BY CAROTENOIDS, CAROTENOID ANALOGS, OR DERIVATIVES THEREOF"; U.S. Patent Application Publication No. 2006/0270589entitled "CAROTENOIDS, CAROTENOID ANALOGS, OR CAROTENOID DERIVATIVES FOR THE STABILIZATION OR IMPROVEMENT OF VISUAL ACUITY"; U.S. Patent Application Publication No. 2007/0015735 entitled "WATER- DISPERSIBLE CAROTENOIDS, INCLUDING ANALOGS AND DERIVATIVES"; U.S. Patent Application Publication No. 2006/0276372 entitled "CAROTENOIDS, CAROTENOID ANALOGS, OR CAROTENOID DERIVATIVES FOR THE TREATMENT OF PROLIFERATIVE DISORDERS"; U.S. Application Serial No. 11/417,307 entitled "USE OF CAROTENOIDS AND/ORCAROTENOID DERIVATIVES/ANALOGS FOR REDUCTION/INHIBITION OF CERTAIN NEGATIVE EFFECTS OF COX INHIBITORS"; U.S. Serial No. 60/691,518 entitled "METHODS FOR SYNTHESIS OF CAROTENOIDS, INCLUDING ANALOGS, DERIVATIVES, AND SYNTHETIC AND BIOLOGICAL INTERMEDIATES"; U.S. Patent Application Publication No. 2006/0293545 entitled "METHODS FOR SYNTHESIS OF CAROTENOIDS, INCLUDING ANALOGS, DERIVATIVES, AND SYNTHETIC AND BIOLOGICAL INTERMEDIATES"; U.S. Application Serial No. 11/636,401 entitled

"STRUCTURAL CAROTENOID ANALOGS OR DERIVATIVES FOR THE MODULATION OF SYSTEMIC AND/OR TARGET ORGAN REDOX STATUS"; and U.S. Serial No. 11/699,924 entitled "SYNTHESIS OF CAROTENOID ANALOGS OR DERIVATIVES WITH IMPROVED ANTIOXIDANT CHARACTERISTICS", all of which are commonly owned with the present application and which are hereby expressly incorporated by reference in their entirety as though fully set forth herein. Water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 1 mg/mL in some embodiments. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 5 mg/mL. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 10 mg/mL. In certain embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 20 mg/mL. In some embodiments, water-soluble carotenoid analogs or derivatives may have a water solubility of greater than about 50 mg/mL.

Naturally occurring carotenoids such as xanthophyll carotenoids of the C40 series, which includes commercially important compounds such as lutein, zeaxanthin, and astaxanthin, have poor aqueous solubility in the native state. Varying the chemical structure(s) of the esterified moieties may vastly increase the aqueous solubility and/or dispersibility of derivatized carotenoids. In some embodiments, highly water-dispersible C₄₀ carotenoid derivatives may include natural source i?i?i?-lutein (β,ε-carotene-3,3'-diol) derivatives. Derivatives may be synthesized by esterification with inorganic phosphate and succinic acid, respectively, and subsequently converted to the sodium salts. Deep orange, evenly colored aqueous suspensions were obtained after addition of these derivatives to USP-purified water. Aqueous dispersibility of the disuccinate sodium salt of natural lutein was 2.85 mg/mL; the diphosphate salt demonstrated a > 10-fold increase in dispersibility at 29.27 mg/mL. Aqueous suspensions may be obtained without the addition of heat, detergents, co-solvents, or other additives.

The direct aqueous superoxide scavenging abilities of these derivatives were subsequently evaluated by electron paramagnetic resonance (EPR) spectroscopy in a well-characterized in vitro isolated human neutrophil assay. The derivatives may be potent (millimolar concentration) and nearly identical aqueous-phase scavengers, demonstrating dose-dependent suppression of the superoxide anion signal (as detected by spin-trap adducts of DEPMPO) in the millimolar range. Evidence of card-pack aggregation was obtained for the diphosphate derivative with UV-Vis spectroscopy (discussed herein), whereas limited card-pack and/or head-to-tail aggregation was noted for the disuccinate derivative. These lutein-based soft drugs may find utility in those commercial and clinical applications for which aqueous-phase singlet oxygen quenching and direct radical scavenging may be required.

The absolute size of a carotenoid derivative (in 3 dimensions) is important when considering its use in biological and/or medicinal applications. Some of the largest naturally occurring carotenoids are no greater than about C₅₀. This is probably due to size limits imposed on molecules requiring incorporation into and/or interaction with cellular membranes. Cellular membranes may be particularly co-evolved with molecules of a length of approximately 30 nm. In some embodiments, carotenoid derivatives may be greater than or less than about 30 nm in size. In certain embodiments, carotenoid derivatives may be able to change conformation and/or otherwise assume an appropriate shape, which effectively enables the carotenoid derivative to efficiently interact with a cellular membrane.

Although the above structure, and subsequent structures, depict alkenes in the E configuration this should not be seen as limiting. Compounds discussed herein may include embodiments where alkenes are in the Z configuration or include alkenes in a combination of Z and E configurations within the same molecule. The compounds depicted herein may naturally convert between the Z and E configuration and/or exist in equilibrium between the two configurations.

Compounds described herein embrace isomers mixtures, racemic, optically active, and optically inactive stereoisomers and compounds. Carotenoid analogs or derivatives may have increased water solubility and/or water dispersibility relative to some or all known naturally occurring carotenoids. In some embodiments, one or more co-antioxidants may be coupled to a carotenoid or carotenoid derivative or analog.

Some specific embodiments may include phosphate, succinate, co-antioxidant (e.g., Vitamin C, Vitamin C analogs, Vitamin C derivatives, Vitamin E, Vitamin E analogs, Vitamin E derivatives, or flavonoids), or combinations thereof derivatives or analogs of carotenoids. Flavonoids may include, for example, quercetin, xanthohumol, isoxanthohumol, or genistein. Derivatives or analogs may be derived from any known carotenoid (naturally or synthetically derived). Specific examples of naturally occurring carotenoids which compounds described herein may be derived from include for example zeaxanthin, lutein, lycophyll, astaxanthin, and lycopene. The synthesis of water-soluble and/or water-dispersible carotenoids (e.g., C₄₀) analogs or derivatives — as potential parenteral agents for clinical applications may improve the injectability of these compounds as therapeutic agents, a result perhaps not achievable through other formulation methods. The methodology may be extended to carotenoids with fewer than 40 carbon atoms in the molecular skeleton and differing ionic character. The methodology may be extended to carotenoids with greater than 40 carbon atoms in the molecular skeleton. The methodology may be extended to non-symmetric carotenoids. The aqueous dispersibility of these compounds allows proof-of-concept studies in model systems (e.g. cell culture), where the high lipophilicity of these compounds previously limited their bioavailability and hence proper evaluation of efficacy. Esterification or etherification may be useful to increase oral bioavailability, a fortuitous side effect of the esterification process, which can increase solubility in gastric mixed micelles. These compounds, upon introduction to the mammalian GI tract, are rapidly and effectively cleaved to the parent, non-esterified compounds, and enter the systemic circulation in that manner and form (see, e.g., FIG. 2). The effect of the intact ester and/or ether compound on the therapeutic endpoint of interest can be obtained with parenteral administration of the compound(s). The net overall effect is an improvement in potential clinical utility for the lipophilic carotenoid compounds as therapeutic agents.

In one embodiment, a subject may be administered a pharmaceutical composition comprising a carotenoid analog or derivative. The analog or derivative may be broken down according to the following reaction:

C₅₂H₆₄Na₂O₂(^ OO

In some embodiments, the principles of retrometabolic drug design may be utilized to produce novel soft drugs from the asymmetric parent carotenoid scaffold (e.g., i?i?i?-lutein (β,ε-carotene-3,3'- diol)). For example, lutein scaffold for derivatization was obtained commercially as purified natural plant source material, and was primarily the i?i?i?-stereoisomer (one of 8 potential stereoisomers). Lutein (Scheme 1) possesses key characteristics — similar to starting material astaxanthin — which make it an ideal starting platform for retrometabolic syntheses: (1) synthetic handles (hydroxyl groups) for conjugation, and (2) an excellent safety profile for the parent compound. As stated above, lutein is available commercially from multiple sources in bulk as primarily the RRR-stereoisomer, the primary isomer in the human diet and human retinal tissue.

In some embodiments, carotenoid analogs or derivatives may have increased water solubility and/or water dispersibility relative to some or all known naturally occurring carotenoids. In some embodiments, the carotenoid derivatives may include compounds having a structure including a polyene chain (i.e., backbone of the molecule). The polyene chain may include between about 5 and about 15 unsaturated bonds. In certain embodiments, the polyene chain may include between about 7 and about 12 unsaturated bonds. In some embodiments a carotenoid derivative may include 7 or more conjugated double bonds to achieve acceptable antioxidant properties. In some embodiments, decreased antioxidant properties associated with shorter polyene chains may be overcome by increasing the dosage administered to a subject or patient.

Some embodiments may include solutions or pharmaceutical preparations of carotenoids and/or carotenoid derivatives combined with co-antioxidants, in particular vitamin C and/or vitamin C analogs or derivatives. Pharmaceutical preparations may include about a 2: 1 ratio of vitamin C to carotenoid respectively.

In some embodiments, co-antioxidants (e.g., vitamin C) may increase solubility of the chemical compound. In certain embodiments, co-antioxidants (e.g., vitamin C) may decrease toxicity associated with at least some carotenoid analogs or derivatives. In certain embodiments, co-antioxidants (e.g., vitamin C) may increase the potency of the chemical compound synergistically. Co-antioxidants may be coupled (e.g., a covalent bond) to the carotenoid derivative. Co-antioxidants may be included as a part of a pharmaceutically acceptable formulation.

As used herein terms such as "structural carotenoid analogs or derivatives" may be generally defined as carotenoids and the biologically active structural analogs or derivatives thereof. "Derivative" in the context of this application is generally defined as a chemical substance derived from another substance either directly or by modification or partial substitution. "Analog" in the context of this application is generally defined as a compound that resembles another in structure but is not necessarily an isomer. Typical analogs or derivatives include molecules which demonstrate equivalent or improved biologically useful and relevant function, but which differ structurally from the parent compounds. Parent carotenoids are selected from the more than 700 naturally occurring carotenoids described in the literature, and their stereo- and geometric isomers. Such analogs or derivatives may include, but are not limited to, esters, ethers, carbonates, amides, carbamates, phosphate esters and ethers, sulfates, glycoside ethers, with or without spacers (linkers). As used herein the terms "the synergistic combination of more than one carotenoid or structural analog or derivative or synthetic intermediate of carotenoids" may be generally defined as any composition including one xanthophyll carotenoid or a structural carotenoid analog or derivative or synthetic intermediate combined with one or more different xanthophyll carotenoids or structural carotenoid analogs or derivatives or synthetic intermediates or co-antioxidants, either as derivatives or in solutions and/or formulations.

Certain embodiments may include administering a carotenoid or a structural carotenoid analogs or derivatives or synthetic intermediates alone or in combination to a subject such that disease severity and/or complications associated with a neurodegenerative disorders or conditions associated with oxidative stress are thereby at least partially reduced, inhibited and/or ameliorated. The xanthophyll carotenoid or a structural carotenoid analogs or derivatives or synthetic intermediates may be water-soluble and/or water dispersible derivatives. The carotenoid derivatives may include any substituent that substantially increases the water solubility of the naturally occurring carotenoid. The carotenoid derivatives may retain and/or improve the antioxidant properties of the parent carotenoid. The carotenoid derivatives may retain the non-toxic properties of the parent carotenoid. The carotenoid derivatives may have increased bioavailability, relative to the parent carotenoid, upon administration to a subject. The parent carotenoid may be naturally occurring. Other embodiments may include the administering a composition comprised of the synergistic combination of more than one xanthophyll carotenoid or structural carotenoid analog or derivative or synthetic intermediate to a subject such that disease severity and/or complications associated with a neurodegenerative disorders or conditions associated with oxidative stress are thereby at least partially reduced, inhibited and/or ameliorated. The composition may be a "racemic" (i.e. mixture of the potential stereoisomeric forms) mixture of carotenoid derivatives. Included as well are pharmaceutical compositions comprised of structural analogs or derivatives or synthetic intermediates of carotenoids in combination with a pharmaceutically acceptable carrier. In one embodiment, a pharmaceutically acceptable carrier may be serum albumin. In one embodiment, structural analogs or derivatives or synthetic intermediates of carotenoids may be complexed with human serum protein such as, for example, human serum albumin (i.e., HSA) in a solvent. In an embodiment, HSA may act as a pharmaceutically acceptable carrier.

In some embodiments, a single stereoisomer of a structural analog or derivative or synthetic intermediate of carotenoids may be administered to a human subject in order to ameliorate a pathological condition. Administering a single stereoisomer of a particular compound (e.g., as part of a pharmaceutical composition) to a human subject may be advantageous (e.g., increasing the potency of the pharmaceutical composition). Administering a single stereoisomer may be advantageous due to the fact that only one isomer of potentially many may be biologically active enough to have the desired effect.

In some embodiments, compounds described herein may be administered in the form of nutraceuticals. "Nutraceuticals" as used herein, generally refers to dietary supplements, foods, or medical foods that: 1. possess health benefits generally defined as reducing the risk of a disease or health condition, including the management of a disease or health condition or the improvement of health; and 2. are safe for human consumption in such quantity, and with such frequency, as required to realize such properties. Generally a nutraceutical is any substance that is a food or a part of a food and provides medical or health benefits, including the prevention and treatment of disease. Such products may range from isolated nutrients, dietary supplements and specific diets to genetically engineered designer foods, herbal products, and processed foods such as cereals, soups and beverages. It is important to note that this definition applies to all categories of food and parts of food, ranging from dietary supplements such as folic acid, used for the prevention of spina bifida, to chicken soup, taken to lessen the discomfort of the common cold. This definition also includes a bio-engineered designer vegetable food, rich in antioxidant ingredients, and a stimulant functional food or pharmafood. Within the context of the description herein where the composition, use and/or delivery of pharmaceuticals are described nutraceuticals may also be composed, used, and/or delivered in a similar manner where appropriate. DOSAGE AND ADMINISTRATION The carotenoids, carotenoid derivative or analog may be administered at a dosage level up to conventional dosage levels for such derivatives or analogs, but will typically be less than about 2 gm per day. Suitable dosage levels may depend upon the overall systemic effect of the chosen xanthophyll carotenoids, carotenoid derivatives or analogs, but typically suitable levels will be about 0.001 to 50 mg/kg body weight of the patient per day, from about 0.005 to 30 mg/kg per day, or from about 0.05 to 10 mg/kg per day. The compound may be administered on a regimen of up to 6 times per day, between about 1 to 4 times per day, or once per day. In the case where an oral composition is employed, a suitable dosage range is, e.g. from about

0.01 mg to about 100 mg of a xanthophyll carotenoid, carotenoid derivative or analog per kg of body weight per day, preferably from about 0.1 mg to about 10 mg per kg and for cytoprotective use from 0.1 mg to about 100 mg of a xanthophyll carotenoid, carotenoid derivative or analog per kg of body weight per day. It will be understood that the dosage of the therapeutic agents will vary with the nature and the severity of the condition to be treated, and with the particular therapeutic agents chosen. The dosage will also vary according to the age, weight, physical condition and response of the individual patient. The selection of the appropriate dosage for the individual patient is within the skills of a clinician.

In some embodiments, compositions may include all compositions of 1.0 gram or less of a particular structural carotenoid analog, in combination with 1.0 gram or less of one or more other structural carotenoid analogs or derivatives or synthetic intermediates and/or co-antioxidants, in an amount which is effective to achieve its intended purpose. While individual subject needs vary, determination of optimal ranges of effective amounts of each component is with the skill of the art. Typically, a structural carotenoid analog or derivative or synthetic intermediates may be administered to mammals, in particular humans, orally at a dose of 5 to 100 mg per day referenced to the body weight of the mammal or human being treated for a particular disease. Typically, a structural carotenoid analog or derivative or synthetic intermediate may be administered to mammals, in particular humans, parenterally at a dose of between 5 to 1000 mg per day referenced to the body weight of the mammal or human being treated for a particular disease. In other embodiments, about 100 mg of a structural carotenoid analog or derivative or synthetic intermediate is either orally or parenterally administered to treat or prevent disease.

The unit oral dose may comprise from about 0.25 mg to about 1.0 gram, or about 5 to 25 mg, of a structural carotenoid analog. The unit parenteral dose may include from about 25 mg to 1.0 gram, or between 25 mg and 500 mg, of a structural carotenoid analog. The unit intracoronary dose may include from about 25 mg to 1.0 gram, or between 25 mg and 100 mg, of a structural carotenoid analog. The unit doses may be administered one or more times daily, on alternate days, in loading dose or bolus form, or titrated in a parenteral solution to commonly accepted or novel biochemical surrogate marker(s) or clinical endpoints as is with the skill of the art.

In addition to administering a structural carotenoid analog or derivative or synthetic intermediate as a raw chemical, the compounds may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers, preservatives, excipients and auxiliaries which facilitate processing of the structural carotenoid analog or derivative or synthetic intermediates which may be used pharmaceutically. The preparations, particularly those preparations which may be administered orally and which may be used for the preferred type of administration, such as tablets, softgels, lozenges, dragees, and capsules, and also preparations which may be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally or by inhalation of aerosolized preparations, may be prepared in dose ranges that provide similar bioavailability as described above, together with the excipient. While individual needs may vary, determination of the optimal ranges of effective amounts of each component is within the skill of the art.

In some embodiments in which one or more additional medicaments or compositions suitable for the treatment of a neurodegenerative disorders or conditions associated with oxidative stress in a subject are administered in conjunction with a carotenoid, a carotenoid derivative or a carotenoid analog, the carotenoid, carotenoid derivative or analog may be administered separately in separate dosage forms or together in a single unit dosage form. Where separate dosage formulations are used, the xanthophylls carotenoid, carotenoid derivative or analog and one or more additional medicaments or compositions may be administered at substantially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially, and in any order. In certain embodiments the xanthophyll carotenoid, carotenoid derivative or analog the one or more additional medicaments or compositions may be co-administered concurrently on a once-a-day (QD) dosing schedule; however, varying dosing schedules, such as the xanthophyll carotenoid, carotenoid derivative or analog once per day and the one or more additional medicaments or compositions once, twice or more times per day, or the one or more additional medicaments or compositions once per day and the carotenoid derivative or analog once, twice or more times per day, is also encompassed herein. According to certain application(s) of the present embodiments, a single oral dosage formulation comprising the carotenoid derivative or analog and the one or more additional medicaments or compositions may be preferred. In other embodiments, it may be desirable to administer the carotenoid derivative or analog separately from the one or more additional medicaments or compositions. A single dosage formulation will provide convenience for the patient. The one or more additional medicaments or compositions suitable for the treatment of a neurodegenerative disorders or conditions associated with oxidative stress in a subject may be administered at a dosage level up to conventional dosage levels for such compounds. Suitable dosage levels will depend upon the effect and the pharmacological porterties of the chosen additional medicaments or compositions, but typically suitable levels will be between about 0.001 to 50 mg/kg body weight of the patient per day, between about 0.005 to 30 mg/kg per day, or between about 0.05 to 10 mg/kg per day. In some embodiments, the compound may be administered on a regimen of up to 6 times per day, from 1 to 4 times per day, or once per day.

In the case where an oral composition is employed, an exemplary dosage range is, e.g. from about 0.01 mg to about 100 mg of each additional medicament or composition per kg of body weight per day, or from about 0.1 mg to about 10 mg per kg of each additional medicament or composition per kg of body weight per day. Dosage levels of additional compositions or medicaments suitable for the treatment of neurodegenerative disorders or conditions associated with oxidative stress may be on the order of about 0.1 mg to about 10,000 mg of the active ingredient compound are useful in the treatment of the above conditions, with preferred levels of about 1.0 mg to about 1 ,000 mg. The amount of active ingredient that may be combined with other anticancer agents to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks. The following dosages, which are provided by way of illustrative example, may serve as general guidance in the determination of suitable dosage ranges for certain of the additional medicaments for treating neurodegenerative disorders or conditions contemplated for use herein. It will of course be readily appreciated by the skilled practitioner that alternative dosages may be employed without departing from the spirit and scope of the presently described embodiments.

PHARMACEUTICAL COMPOSITIONS Any suitable route of administration may be employed for providing a patient with an effective dosage of drugs of the present invention. For example, oral, rectal, topical, parenteral, ocular, intracranial, pulmonary, nasal, and the like may be employed. Dosage forms may include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. In certain embodiments, it may be advantageous that the compositions described herein be administered orally. In other embodiments, it may be advantageous that the compositions described herein be administered parenterally. In yet other embodiments, it may be advantageous that the compositions described herein be administered locally, at the site of tissue injury.

The compositions may include those compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

For administration by inhalation, the drugs used in the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.

Suitable topical formulations for use in the present embodiments may include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like. In practical use, drugs used can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.

The pharmaceutical preparations may be manufactured in a manner which is itself known to one skilled in the art, for example, by means of conventional mixing, granulating, dragee-making, softgel encapsulation, dissolving, extracting, or lyophilizing processes. Thus, pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid and semi-solid excipients and suitable preservatives, and/or co-antioxidants. Optionally, the resulting mixture may be ground and processed. The resulting mixture of granules may be used, after adding suitable auxiliaries, if desired or necessary, to obtain tablets, softgels, lozenges, capsules, or dragee cores.

Suitable excipients may be fillers such as saccharides (e.g., lactose, sucrose, or mannose), sugar alcohols (e.g., mannitol or sorbitol), cellulose preparations and/or calcium phosphates (e.g., tricalcium phosphate or calcium hydrogen phosphate). In addition binders may be used such as starch paste (e.g., maize or corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone). Disintegrating agents may be added (e.g., the above-mentioned starches) as well as carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate). Auxiliaries are, above all, flow-regulating agents and lubricants (e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or PEG). Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. Softgelatin capsules ("softgels") are provided with suitable coatings, which, typically, contain gelatin and/or suitable edible dye(s). Animal component-free and kosher gelatin capsules may be particularly suitable for the embodiments described herein for wide availability of usage and consumption. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol (PEG) and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures, including dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetone, ethanol, or other suitable solvents and co-solvents. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl- cellulose phthalate, may be used. Dye stuffs or pigments may be added to the tablets or dragee coatings or softgelatin capsules, for example, for identification or in order to characterize combinations of active compound doses, or to disguise the capsule contents for usage in clinical or other studies.

Other pharmaceutical preparations that may be used orally include push-fit capsules made of gelatin, as well as soft, thermally sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules may contain the active compounds in the form of granules that may be mixed with fillers such as, for example, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers and/or preservatives. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils such as rice bran oil or peanut oil or palm oil, or liquid paraffin. In some embodiments, stabilizers and preservatives may be added.

In some embodiments, pulmonary administration of a pharmaceutical preparation may be desirable. Pulmonary administration may include, for example, inhalation of aerosolized or nebulized liquid or solid particles of the pharmaceutically active component dispersed in and surrounded by a gas. Possible pharmaceutical preparations, which may be used rectally, include, for example, suppositories, which consist of a combination of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules that consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons. Suitable formulations for parenteral administration include, but are not limited to, aqueous solutions of the active compounds in water-soluble and/or water dispersible form, for example, water- soluble salts, esters, carbonates, phosphate esters or ethers, sulfates, glycoside ethers, together with spacers and/or linkers. Suspensions of the active compounds as appropriate oily injection suspensions may be administered, particularly suitable for intramuscular injection. Suitable lipophilic solvents, co-solvents (such as DMSO or ethanol), and/or vehicles including fatty oils, for example, rice bran oil or peanut oil and/or palm oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides, may be used. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol, dextran, and/or cyclodextrins. Cyclodextrins (e.g., β-cyclodextrin) may be used specifically to increase the water solubility for parenteral injection of the structural carotenoid analog. Liposomal formulations, in which mixtures of the structural carotenoid analog or derivative with, for example, egg yolk phosphotidylcholine (E-PC), may be made for injection. Optionally, the suspension may contain stabilizers, for example, antioxidants such as BHT, and/or preservatives, such as benzyl alcohol.

The compounds of this invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. A physician or veterinarian may determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress or the development prostate cancer in a subject.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, between about 0.01 to 100 mg/kg of body weight per day, or between about 1.0 to 20 mg/kg/day. Intravenously administered doses may range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four or more times daily.

The pharmaceutical compositions described herein may further be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as "pharmacologically inert carriers") suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the pharmacologically active component may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. The compounds of the present invention may also 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 phosphatidylcholines .

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams or more of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

In an embodiment, the pharmaceutical compositions can be administered locally to the site of neural injury such as by local injection, a minimally invasive drug delivery system, or during a surgical procedure. Alternatively, in some embodiments it may be preferable to administer the composition(s) systemically (such as e.g., by oral or parenteral delivery) such that the concentration of the pharmacologically active agents is sufficient to increase the bioavailability of the carotenoid analog in neural tissues of the subject.

In an embodiment, the active compounds may be administered to the patient systemically. The term systemic as used herein includes subcutaneous injection; intravenous, intramuscular, intraestemal injection; infusion; inhalation, transdermal administration, oral administration; and intra-operative instillation.

One systemic method involves an aerosol suspension of respirable particles comprising the active compound, which the subject inhales. The active compound would be absorbed into the bloodstream via the lungs, and subsequently contact the lacrimal glands in a pharmaceutically effective amount. The respirable particles may be liquid or solid, with a particle size sufficiently small to pass through the mouth and larynx upon inhalation; in general, particles ranging from about 1 to 10 microns, but more preferably 1-5 microns, in size are considered respirable.

Another method of systemically administering the active compounds involves administering a liquid/liquid suspension in the form of eye drops or eye wash or nasal drops of a liquid formulation, or a nasal spray of respirable particles that the subject inhales. Liquid pharmaceutical compositions of the active compound for producing a nasal spray or nasal or eye drops may be prepared by combining the active compound with a suitable vehicle, such as sterile pyrogen free water or sterile saline by techniques known to those skilled in the art.

The active compounds may also be systemically administered through absorption by the skin using transdermal patches or pads. The active compounds are absorbed into the bloodstream through the skin. Plasma concentration of the active compounds can be controlled by using patches containing different concentrations of active compounds. Other methods of systemic administration of the active compound involves oral administration, in which pharmaceutical compositions containing active compounds are in the form of tablets, lozenges, aqueous or oily suspensions, viscous gels, chewable gums, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Additional means of systemic administration of the active compound to the subject may involve a suppository form of the active compound, such that a therapeutically effective amount of the compound reaches the eyes via systemic absorption and circulation.

Further means of systemic administration of the active compound involve direct intra-operative instillation of a gel, cream, or liquid suspension form of a therapeutically effective amount of the active compound. For topical application, the solution containing the active compound may contain a physiologically compatible vehicle, as those skilled in the art can select, using conventional criteria. The vehicles may be selected from the known pharmaceutical vehicles which include, but are not limited to, saline solution, water polyethers such as polyethylene glycol, polyvinyls such as polyvinyl alcohol and povidone, cellulose derivatives such as methylcellulose and hydroxypropyl methylcellulose, petroleum derivatives such as mineral oil and white petrolatum, animal fats such as lanolin, polymers of acrylic acid such as carboxypolymethylene gel, vegetable fats such as peanut oil and polysaccharides such as dextrans, and glycosaminoglycans such as sodium hyaluronate and salts such as sodium chloride and potassium chloride.

For systemic administration such as injection and infusion, the pharmaceutical formulation is prepared in a sterile medium. The active ingredient, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Adjuvants such as local anaesthetics, preservatives and buffering agents can also be dissolved in the vehicle. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic acceptable diluent or solvent. Among the acceptable vehicles and solvents that may be employed are sterile water, saline solution, or Ringer's solution. For oral use, an aqueous suspension is prepared by addition of water to dispersible powders and granules with a dispersing or wetting agent, suspending agent one or more preservatives, and other excipients. Suspending agents include, for example, sodium carboxymethylcellulose, methylcellulose and sodium alginate. Dispersing or wetting agents include naturally-occurring phosphatides, condensation products of an allylene oxide with fatty acids, condensation products of ethylene oxide with long chain aliphatic alcohols, condensation products of ethylene oxide with partial esters from fatty acids and a hexitol, and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anydrides. Preservatives include, for example, ethyl, and n-propyl p-hydroxybenzoate. Other excipients include sweetening agents (e.g., sucrose, saccharin), flavoring agents and coloring agents. Those skilled in the art will recognize the many specific excipients and wetting agents encompassed by the general description above.

For oral application, tablets are prepared by mixing the active compound with nontoxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. Formulation for oral use may also be presented as chewable gums by embedding the active ingredient in gums so that the active ingredient is slowly released upon chewing.

For rectal administration, the compositions in the form of suppositories can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the compound. Such excipients include cocoa butter and polyethylene glycols.

The pharmaceutical activity of carotenoid analogs and derivatives as well as additional medicaments in accordance with the objects of this invention may be assessed using, for example, any of the methods shown below. Other methods for assessing the pharmacological activity of the present formulations are well within the skill level of the ordinary practitioner of the pharmaceutical arts.

The present invention provides that neuronal degeneration, in particular neuronal degeneration associated with oxidative stress, be inhibited or reduced in vivo by administration of various pharmacologically active agents, or combinations thereof. The present invention describes the utility of various carotenoid analogs and derivatives, various additional medicaments suitable for the treatment of such disorders, and various combinations of carotenoid analogs and derivative with additional medicaments, by addressing a plurality of diseases under which a therapeutic modality is clinically beneficial.

DOSAGE AND ADMINISTRATION

The carotenoid, carotenoid derivative or analog may be administered at a dosage level up to conventional dosage levels for xanthophyll carotenoids, carotenoid derivatives or analogs, but will typically be less than about 2 gm per day. Suitable dosage levels may depend upon the overall systemic effect of the chosen xanthophyll carotenoids, carotenoid derivatives or analogs, but typically suitable levels will be about 0.001 to 50 mg/kg body weight of the patient per day, from about 0.005 to 30 mg/kg per day, or from about 0.05 to 10 mg/kg per day. The compound may be administered on a regimen of up to 6 times per day, between about 1 to 4 times per day, or once per day.

In the case where an oral composition is employed, a suitable dosage range is, e.g. from about 0.01 mg to about 100 mg of a xanthophyll carotenoid, carotenoid derivative or analog per kg of body weight per day, preferably from about 0.1 mg to about 10 mg per kg and for cytoprotective use from 0.1 mg to about 100 mg of a xanthophyll carotenoid, carotenoid derivative or analog per kg of body weight per day.

It will be understood that the dosage of the therapeutic agents will vary with the nature and the severity of the condition to be treated, and with the particular therapeutic agents chosen. The dosage will also vary according to the age, weight, physical condition and response of the individual patient. The selection of the appropriate dosage for the individual patient is within the skills of a clinician.

In some embodiments, compositions may include all compositions of 1.0 gram or less of a particular structural carotenoid analog, in combination with 1.0 gram or less of one or more other structural carotenoid analogs or derivatives or synthetic intermediates and/or co-antioxidants, in an amount which is effective to achieve its intended purpose. While individual subject needs vary, determination of optimal ranges of effective amounts of each component is with the skill of the art. Typically, a structural carotenoid analog or derivative or synthetic intermediates may be administered to mammals, in particular humans, orally at a dose of 5 to 100 mg per day referenced to the body weight of the mammal or human being treated for a particular disease. Typically, a structural carotenoid analog or derivative or synthetic intermediate may be administered to mammals, in particular humans, parenterally at a dose of between 5 to 1000 mg per day referenced to the body weight of the mammal or human being treated for a particular disease. In other embodiments, about 100 mg of a structural carotenoid analog or derivative or synthetic intermediate is either orally or parenterally administered to treat or prevent disease. The unit oral dose may comprise from about 0.25 mg to about 1.0 gram, or about 5 to 25 mg, of a structural carotenoid analog. The unit parenteral dose may include from about 25 mg to 1.0 gram, or between 25 mg and 500 mg, of a structural carotenoid analog. The unit intracoronary dose may include from about 25 mg to 1.0 gram, or between 25 mg and 100 mg, of a structural carotenoid analog. The unit doses may be administered one or more times daily, on alternate days, in loading dose or bolus form, or titrated in a parenteral solution to commonly accepted or novel biochemical surrogate marker(s) or clinical endpoints as is with the skill of the art.

In addition to administering a structural carotenoid analog or derivative or synthetic intermediate as a raw chemical, the compounds may be administered as part of a pharmaceutical preparation containing suitable pharmaceutically acceptable carriers, preservatives, excipients and auxiliaries which facilitate processing of the structural carotenoid analog or derivative or synthetic intermediates which may be used pharmaceutically. The preparations, particularly those preparations which may be administered orally and which may be used for the preferred type of administration, such as tablets, softgels, lozenges, dragees, and capsules, and also preparations which may be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally or by inhalation of aerosolized preparations, may be prepared in dose ranges that provide similar bioavailability as described above, together with the excipient. While individual needs may vary, determination of the optimal ranges of effective amounts of each component is within the skill of the art. In some embodiments in which one or more additional medicaments or compositions suitable for the treatment of prostate cancer in a subject are administered in conjunction with a xanthophyll carotenoid, a carotenoid derivative or a carotenoid analog, the xanthophyll carotenoid, carotenoid derivative or analog may be administered separately in separate dosage forms or together in a single unit dosage form. Where separate dosage formulations are used, the xanthophylls carotenoid, carotenoid derivative or analog and one or more additional medicaments or compositions may be administered at substantially the same time, i.e., concurrently, or at separately staggered times, i.e., sequentially, and in any order. In certain embodiments the xanthophyll carotenoid, carotenoid derivative or analog the one or more additional medicaments or compositions may be co-administered concurrently on a once-a-day (QD) dosing schedule; however, varying dosing schedules, such as the xanthophyll carotenoid, carotenoid derivative or analog once per day and the one or more additional medicaments or compositions once, twice or more times per day, or the one or more additional medicaments or compositions once per day and the xanthophyll carotenoid, carotenoid derivative or analog once, twice or more times per day, is also encompassed herein. According to certain application(s) of the present embodiments, a single oral dosage formulation comprising the xanthophyll carotenoid, carotenoid derivative or analog and the one or more additional medicaments or compositions may be preferred. In other embodiments, it may be desirable to administer the xanthophyll carotenoid, carotenoid derivative or analog separately from the one or more additional medicaments or compositions. A single dosage formulation will provide convenience for the patient. The one or more additional medicaments or compositions suitable for the treatment of prostate cancer in a subject may be administered at a dosage level up to conventional dosage levels for such compounds. Suitable dosage levels will depend upon the effect and the pharmacological porterties of the chosen additional medicaments or compositions, but typically suitable levels will be between about 0.001 to 50 mg/kg body weight of the patient per day, between about 0.005 to 30 mg/kg per day, or between about 0.05 to 10 mg/kg per day. In some embodiments, the compound may be administered on a regimen of up to 6 times per day, from 1 to 4 times per day, or once per day.

In the case where an oral composition is employed, an exemplary dosage range is, e.g. from about 0.01 mg to about 100 mg of each additional medicament or composition per kg of body weight per day, or from about 0.1 mg to about 10 mg per kg of each additional medicament or composition per kg of body weight per day.

General guidance in determining effective dose ranges for pharmacologically active compounds and compositions for use in the presently described embodiments may be found, for example, in the publications of the International Conference on Harmonisation and in REMINGTON'S PHARMACEUTICAL SCIENCES, 8^th Edition Ed. Bertram G. Katzung, chapters 27 and 28, pp. 484-528 (Mack Publishing Company 1990) and yet further in BASIC & CLINICAL PHARMACOLOGY, chapters 5 and 66, (Lange Medical Books/McGraw-Hill, New York, 2001). PHARMACEUTICAL COMPOSITIONS

Any suitable route of administration may be employed for providing a patient with an effective dosage of drugs of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. In certain embodiments, it may be advantageous that the compositions described herein be administered orally.

Suitable topical formulations for use in the present embodiments may include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like.

In practical use, drugs used can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.

The pharmaceutical preparations may be manufactured in a manner which is itself known to one skilled in the art, for example, by means of conventional mixing, granulating, dragee-making, softgel encapsulation, dissolving, extracting, or lyophilizing processes. Thus, pharmaceutical preparations for oral use may be obtained by combining the active compounds with solid and semi-solid excipients and suitable preservatives, and/or co-antioxidants. Optionally, the resulting mixture may be ground and processed. The resulting mixture of granules may be used, after adding suitable auxiliaries, if desired or necessary, to obtain tablets, softgels, lozenges, capsules, or dragee cores. Suitable excipients may be fillers such as saccharides (e.g., lactose, sucrose, or mannose), sugar alcohols (e.g., mannitol or sorbitol), cellulose preparations and/or calcium phosphates (e.g., tricalcium phosphate or calcium hydrogen phosphate). In addition binders may be used such as starch paste (e.g., maize or corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone).

Disintegrating agents may be added (e.g., the above-mentioned starches) as well as carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof (e.g., sodium alginate). Auxiliaries are, above all, flow-regulating agents and lubricants (e.g., silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or PEG). Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. Softgelatin capsules ("softgels") are provided with suitable coatings, which, typically, contain gelatin and/or suitable edible dye(s). Animal component-free and kosher gelatin capsules may be particularly suitable for the embodiments described herein for wide availability of usage and consumption. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol (PEG) and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures, including dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetone, ethanol, or other suitable solvents and co-solvents. In order to produce coatings resistant to gastric juices, solutions of suitable cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl- cellulose phthalate, may be used. Dye stuffs or pigments may be added to the tablets or dragee coatings or softgelatin capsules, for example, for identification or in order to characterize combinations of active compound doses, or to disguise the capsule contents for usage in clinical or other studies.

Other pharmaceutical preparations that may be used orally include push-fit capsules made of gelatin, as well as soft, thermally sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol. The push-fit capsules may contain the active compounds in the form of granules that may be mixed with fillers such as, for example, lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers and/or preservatives. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils such as rice bran oil or peanut oil or palm oil, or liquid paraffin. In some embodiments, stabilizers and preservatives may be added. In some embodiments, pulmonary administration of a pharmaceutical preparation may be desirable. Pulmonary administration may include, for example, inhalation of aerosolized or nebulized liquid or solid particles of the pharmaceutically active component dispersed in and surrounded by a gas.

Possible pharmaceutical preparations, which may be used rectally, include, for example, suppositories, which consist of a combination of the active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules that consist of a combination of the active compounds with a base. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

Suitable formulations for parenteral administration include, but are not limited to, aqueous solutions of the active compounds in water-soluble and/or water dispersible form, for example, water- soluble salts, esters, carbonates, phosphate esters or ethers, sulfates, glycoside ethers, together with spacers and/or linkers. Suspensions of the active compounds as appropriate oily injection suspensions may be administered, particularly suitable for intramuscular injection. Suitable lipophilic solvents, co-solvents (such as DMSO or ethanol), and/or vehicles including fatty oils, for example, rice bran oil or peanut oil and/or palm oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides, may be used. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethyl cellulose, sorbitol, dextran, and/or cyclodextrins. Cyclodextrins (e.g., β-cyclodextrin) may be used specifically to increase the water solubility for parenteral injection of the structural carotenoid analog. Liposomal formulations, in which mixtures of the structural carotenoid analog or derivative with, for example, egg yolk phosphotidylcholine (E-PC), may be made for injection. Optionally, the suspension may contain stabilizers, for example, antioxidants such as BHT, and/or preservatives, such as benzyl alcohol.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, between about 0.01 to 100 mg/kg of body weight per day, or between about 1.0 to 20 mg/kg/day. Intravenously administered doses may range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four or more times daily. The pharmaceutical compositions described herein may further be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal skin patches. When administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as "pharmacologically inert carriers") suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the pharmacologically active component may be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds of the present invention may also 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 phosphatidylcholines . Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams or more of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water-soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack

Publishing Company, a standard reference text in this field.

In this patent, certain U.S. patents, U.S. patent applications, and other materials (e.g., articles) have been incorporated by reference. The text of such U.S. patents, U.S. patent applications, and other materials is, however, only incorporated by reference to the extent that no conflict exists between such text and the other statements and drawings set forth herein. In the event of such conflict, then any such conflicting text in such incorporated by reference U.S. patents, U.S. patent applications, and other materials is specifically not incorporated by reference in this patent.

Further modifications and alternative embodiments of various aspects of the invention may be apparent to those skilled in the art in view of this description. Accordingly, this description is to be construed as illustrative only and is for the purpose of teaching those skilled in the art the general manner of carrying out the invention. It is to be understood that the forms of the invention shown and described herein are to be taken as the presently preferred embodiments. Elements and materials may be substituted for those illustrated and described herein, parts and processes may be reversed, and certain features of the invention may be utilized independently, all as would be apparent to one skilled in the art after having the benefit of this description to the invention. Changes may be made in the elements described herein without departing from the spirit and scope of the invention as described in the following claims. In addition, it is to be understood that features described herein independently may, in certain embodiments, be combined.

Claims

WHAT IS CLAIMED IS:

A pharmaceutical composition suitable for in the treatment of prostate cancer, BPH or prostatitis in a subject, said pharmaceutical composition comprising a therapeutically effective amount of one or more carotenoid analogs or derivatives, said amount being sufficient to at least partially inhibit the activity of NF-κB at least in a portion prostate cancer cells in the subject.

A first pharmaceutical composition for use with a second pharmaceutical composition, the first pharmaceutical composition comprising at least one carotenoid analog or derivative, and the second pharmaceutical composition comprising at least one additional medicament or composition suitable for the treatment of prostate cancer, BPH or prostatitis.

A pharmaceutical composition comprising at least one naturally occurring carotenoid or a carotenoid analog or derivative in combination with at least one additional medicament or composition suitable for the treatment of prostate cancer, BPH or prostatitis.

The pharmaceutical composition according to any of claim 1-3, wherein the carotenoid analog or derivative has the structure

where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; H; alkyl; aryl; - alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; -aryl- CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl- CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)-aryl-CO₂ ^"; - C(O)-(NR⁷)-alkyl-N(R⁷)₂; -C(O)-(NR⁷)- aryl-N(R⁷)₂; -C(O)-(NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)-(NR⁷)-aryl-N⁺(R⁷)₃; -C(NR⁷)-alkyl-CO₂R⁹; -C(O)-(NR⁷)- aryl-CO₂R⁹; -C(O)-(NR⁷)-alkyl-CO₂ ^"; -C(O)-(NR⁷)-aryl-CO₂ ^"; -C(O)-(NR⁷)-alkyl-N(R⁷)-alkyl-N(R⁷)₂; - C(O)-(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-[C₆-C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, lysine, glycine, sarcosine, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant, or any pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to any of claim 1-3, wherein the carotenoid analog or derivative has the structure

where each R¹ and R² are independently:

where R⁴ is hydrogen, methyl, or -CH₂OH; and where each R⁵is independently hydrogen or -OH.

6. The pharmaceutical composition according to any of claim 1-3, wherein the carotenoid analog or derivative has the structure

where each R¹ and R² are independently:

where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; H; alkyl; aryl; - alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; -aryl- CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl- CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(O)-(NR⁷)-alkyl-N(R⁷)₂; -C(O)-(NR⁷)- aryl-N(R⁷)₂; -C(O)-(NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)-(NR⁷)-aryl-N⁺(R⁷)₃; -C(O)-(NR⁷)-alkyl-CO₂R⁹; -C(O)- (NR⁷)-aryl-CO₂R⁹; -C(O)-(NR⁷)-alkyl-CO₂ ^"; -C(O)- (NR⁷)-aryl-CO₂ ^~; -C(O)-(NR⁷)-alkyl-N(R⁷)-alkyl- N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-amino acid; -C(O)-(NR⁷)-amino acid; -C(O)-[C₆- C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, lysine, glycine, sarcosine, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant.

7. The pharmaceutical composition according to any of claims 1-3, wherein the carotenoid analog or derivative has the structure

where each R⁵ is independently hydrogen, -CH₃, -OH, -CH₂OH or -OR⁶ wherein at least one R⁵ group in the carotenoid analog or derivative is -OR⁶; wherein each R6 is independently: H; alkyl; aryl; -alkyl- N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl-N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^~; -aryl-CO₂ ^"; - C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; -C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; - C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)-aryl-CO₂ ^"; -C(O)-(NR⁷)-alkyl-N(R⁷)₂; -C(O)-(NR⁷)-aryl- N(R⁷)₂; -C(O)-(NR⁷)-alkyl-N⁺(R⁷)₃; -C(O)-(NR⁷)-aryl-N⁺(R⁷)₃; -C(O)-(NR⁷)-alkyl-CO₂R⁹; -C(O)-(NR⁷)- aryl-CO₂R⁹; -C(O)-(NR⁷)-alkyl-CO₂ ^"; -C(O)-(NR⁷)-aryl-CO₂ ^"; -C(O)-(NR⁷)-alkyl-N(R⁷)-alkyl-N(R⁷)₂; - C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-amino acid; -C(NR⁷)-amino acid; -C(O)-[C₆-C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, lysine, glycine, sacrosine, a peptide, a carbohydrate, a nucleoside, or a co-antioxidant, or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to any of claims 4-7, where each -OR⁶ is independentl) T

acceptable salts of any of these compounds, where each R is independently H, alkyl, aryl, benzyl, Group IA metal, or co-antioxidant, or a pharmaceutically acceptable salt thereof.

9. The pharmaceutical composition according to any of claims 4-7, wherein the carotenoid analog or derivative has the structure

wherein each R6 is independently: H; alkyl; aryl; -alkyl-N(R⁷)₂; -aryl-N(R⁷)₂; -alkyl-N⁺(R⁷)₃; -aryl- N⁺(R⁷)₃; -alkyl-CO₂R⁹; -aryl-CO₂R⁹; -alkyl-CO₂ ^"; -aryl-CO₂ ^"; -C(O)-alkyl-N(R⁷)₂; -C(O)-aryl-N(R⁷)₂; - C(O)-alkyl-N⁺(R⁷)₃; -C(O)-aryl-N⁺(R⁷)₃; -C(O)-alkyl-CO₂R⁹; -C(O)-aryl-CO₂R⁹; -C(O)-alkyl-CO₂ ^"; -C(O)- aryl-CO₂ ^"; -C(NR⁷)-alkyl-N(R⁷)₂; -C(NR⁷)-aryl-N(R⁷)₂; -C(NR⁷)-alkyl-N⁺(R⁷)₃; -C(NR⁷)-aryl-N⁺(R⁷)₃; - C(NR⁷)-alkyl-CO₂R⁹; -C(NR⁷)-aryl-CO₂R⁹; -C(NR⁷)-alkyl-CO₂ ^"; -C(NR⁷)-aryl-CO₂ ^"; -C(NR⁷)-alkyl-N(R⁷)- alkyl-N(R⁷)₂; -C(O)-OR⁸; -P(O)(OR⁸)₂; -S(O)(OR⁸)₂; -C(O)-amino acid; -C(NR⁷)-amino acid; -C(O)-[C₆- C₂₄ saturated hydrocarbon]; -C(O)-[C₆-C₂₄ monounsaturated hydrocarbon]; -C(O)-[C₆-C₂₄ polyunsaturated hydrocarbon]; a peptide; a carbohydrate; a nucleoside reside; or a co-antioxidant; where R⁷ is hydrogen, alkyl, or aryl; where R⁸ is hydrogen, alkyl, aryl, benzyl or a co-antioxidant; and where R⁹ is hydrogen, alkyl, aryl, -P(O)(OR⁸)₂, -S(O)(OR⁸)₂, an amino acid, a peptide, a carbohydrate, a nucleoside, or a co- antioxidant, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to any one of claim 1-9, further comprising an effective amount of at least one anti-cancer agent.

11. A method of treating prostate cancer, BPH or prostatitis in a subject comprising administering to a subject who would benefit from such treatment a pharmaceutically acceptable composition comprising a therapeutically effective amount of a carotenoid analog or derivative sufficient to at least partially inhibit one or more components of NF-κB signaling in at least a portion of the prostate cancer cells in the subject.

12. A method of treating prostate cancer, BPH or prostatitis in a subject comprising administering to a subject who would benefit from such treatment a therapeutically effective amount of a pharmaceutically acceptable composition comprising a carotenoid analog or derivative.

13. A pharmaceutical composition comprising a carotenoid .

14. A method of treating prostrate cancer comprising administering to a subject a carotenoid.