Metap-2 inhibitor polymersomes for therapeutic administration

Abstract

Described herein are MetAP-2 inhibitors and compositions and formulations thereof, and more particularly compositions and formulations of MetAP-2 inhibitors wherein the MetAP-2 inhibitor is associated with a block copolymer comprising a hydrophilic polymer moiety and a hydrophobic polymer moiety. The present invention also relates to compositions and formulations comprising MetAP-2 inhibitors for oral administration or administration via routes such as topical or ocular administration. The present invention also provides methods to treat conditions associated with or related to the over-expression or over-activity of MetAP-2 by administering the compositions and formulations comprising MetAP-2 inhibitors as disclosed herein.

1 . A composition comprising a methionine aminopeptidase-2 (MetAP-2) inhibitor formulation having anti-proliferative activity, wherein said formulation comprises a MetAP-2 inhibitor covalently linked to a block copolymer comprising a hydrophilic polymer moiety and a hydrophobic polymer moiety. 
     
     
         2 . The composition of  claim 1 , wherein said MetAP-2 inhibitor is a fumagillol derivative. 
     
     
         3 . The composition of  claim 1 , wherein said MetAP-2 inhibitor is covalently linked with the hydrophobic moiety of said block copolymer. 
     
     
         4 . The composition of  claim 1 , wherein said hydrophobic polymer moiety of said block copolymer is selected from the group consisting of poly(d,L-lactic acid), poly(caprolactone) (PCL), and poly(propylene oxide). 
     
     
         5 . The composition of  claim 1 , wherein said hydrophilic moiety is a poly(ethylene glycol) (PEG) polymer. 
     
     
         6 . The composition of  claim 1 , wherein said block copolymer is a diblock copolymer comprising a PEG-PLA diblock copolymer having hydrophilic PEG and hydrophobic PLA moieties. 
     
     
         7 . The composition of  claim 1  wherein said formulation is formulated for oral administration, topical administration, IV administration, peritoneal administration, injection, ocular administration, suppository administration, pulmonary administration or inhalation, and nasal administration. 
     
     
         8 . The composition of  claim 1 , wherein said anti-proliferative activity is an anti-tumor activity. 
     
     
         9 . The composition of  claim 2 , wherein said fumagillol derivative comprises a derivative selected from the group consisting of 6-O—(N-chloroacetylcarbamoyl)fumagillol (TNP-470), 6-O-(4-methoxyaniline)acetyl fumagillol, 6-O-(3,4,5-trimethexyaniline)acetyl fumagillol, 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol, 6-O-(cyclopropylamino)acetyl fumagillol, 6-O-(cyclobutylamino)acetyl fumagillol, 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5 20 dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1 cyclohexanol and 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5 dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol. 
     
     
         10 . The composition of  claim 1 , wherein said MetAP-2 inhibitor is selected from the group consisting of a bengamide, a sulphonamide, a bestatin, a 3-amino-2-hydroxyamide, a hydroxyamide, an acylhydrazine, ovacillin, a reversible MetAP-2 inhibitor and an irreversible MetAP-2 inhibitor. 
     
     
         11 . A method of treating a condition involving or relying upon MetAP-2 activity for its pathology, the method comprising administering a MetAP-2 inhibitor formulation comprising a MetAP-2 inhibitor having anti-proliferative activity, covalently linked to a block copolymer comprising a hydrophilic polymer moiety and a hydrophobic polymer moiety. 
     
     
         12 . The method of  claim 11 , wherein said MetAP-2 inhibitor is a fumagillol derivative. 
     
     
         13 . The method of  claim 11 , wherein said MetAP-2 inhibitor is associated with the hydrophobic moiety of said block copolymer. 
     
     
         14 . The method of  claim 11 , wherein said hydrophobic polymer moiety of said block copolymer is selected from the group consisting of poly(d,L-lactic acid), poly(caprolactone) (PCL) and poly(propylene oxide). 
     
     
         15 . The method of  claim 11 , wherein said hydrophilic moiety is a poly(ethylene glycol) (PEG) polymer. 
     
     
         16 . The method of  claim 11 , wherein said block copolymer is a diblock copolymer comprising a PEG-PLA diblock copolymer having hydrophilic PEG and hydrophobic PLA moieties. 
     
     
         17 . The method of  claim 11 , wherein said anti-proliferative composition has anti-tumor activity. 
     
     
         18 . The method of  claim 12 , wherein said fumagillol derivative comprises a derivative selected from the group consisting of 6-O—(N-chloroacetylcarbamoyl)fumagillol (TNP-470), 6-O-(4-methoxyaniline)acetyl fumagillol, 6-O-(3,4,5-trimethexyaniline)acetyl fumagillol, 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol, 6-O-(cyclopropylamino)acetyl fumagillol, 6-O-(cyclobutylamino)acetyl fumagillol, 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5 20 dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1 cyclohexanol and 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5 dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol. 
     
     
         19 . The method of  claim 11 , wherein said MetAP-2 inhibitor is selected from the group consisting of a bengamide, a sulphonamide MetAP-2 inhibitor, a bestatin, a 3-amino-2-hydroxyamide MetAP-2 inhibitor, a hydroxyamide MetAP-2 inhibitor, an acylhydrazine MetAP-2 inhibitor, ovacillin, a reversible MetAP-2 inhibitor and an irreversible MetAP-2 inhibitor. 
     
     
         20 . The method of  claim 11 , wherein said condition comprises a tumor activity. 
     
     
         21 . The method of  claim 11 , wherein the condition is selected from the group consisting of cancer, metastatic tumors, psoriasis, age-related macular degeneration (AMD), thyroid hyperplasia, preeclampsia, rheumatoid arthritis and osteo-arthritis, Alzheimer's disease, obesity, pleural effusion, atherosclerosis, endometriosis, diabetic/other retinopathies, ocular neovascularizations, IL-2 therapy associated edema and other edemas, malaria, SARS, HIV, herpes, lupus, IPF, COPD, asthma, cystic fibrosis, transplant rejection, allergic reaction, multiple sclerosis, bacterial infection, viral infection, conditions involving or characterized by vascular hyperpermeability, inflammation, and spinal injury. 
     
     
         22 . A method of making a diblock copolymer composition comprising a MetAP-2 inhibitor that has anti-proliferative activity, the method comprising conjugating said MetAP-2 inhibitor to a diblock copolymer comprising a hydrophilic polymer moiety and a hydrophobic polymer moiety. 
     
     
         23 . The method of  claim 22 , wherein said MetAP-2 inhibitor is a fumagillol derivative that has anti-angiogenic activity. 
     
     
         24 . The method of  claim 22 , wherein said MetAP-2 inhibitor comprises 6-O—(N-chloroacetylcarbamoyl)fumagillol (TNP-470). 
     
     
         25 . A diblock copolymer composition comprising a MetAP-2 inhibitor, said composition produced by the method of  claim 22 . 
     
     
         26 . The diblock copolymer composition of  claim 25 , wherein said MetAP-2 inhibitor is a fumagillol derivative that has anti-proliferative activity. 
     
     
         27 . The diblock copolymer composition of  claim 26 , wherein said fumagillol derivative comprises 6-O—(N-chloroacetylcarbamoyl)fumagillol (TNP-470). 
     
     
         28 . A composition comprising a formulation of a fumagillol derivative that has anti-angiogenic activity, said formulation comprising said derivative covalently associated with a block copolymer comprising a hydrophilic polymer moiety and a hydrophobic polymer moiety. 
     
     
         29 . The composition of  claim 28 , wherein said formulation comprises a micelle comprising said block copolymer associated with said fumagillol derivative. 
     
     
         30 . The composition of  claim 28 , wherein said fumagillol derivative thereof is associated with the hydrophobic moiety of said block copolymer. 
     
     
         31 . The composition of  claim 28 , wherein said hydrophobic polymer moiety of said block copolymer is selected from the group consisting of poly(d,L-lactic acid), poly(L-lysine), poly(aspartic acid), poly(caprolactone) (PCL) and poly(propylene oxide). 
     
     
         32 . The composition of  claim 28 , wherein said hydrophilic polymer moiety of said block copolymer is a polyethylene glycol (PEG). 
     
     
         33 . The composition of  claim 28 , wherein said block copolymer is a diblock copolymer comprising a PEG-PLA diblock copolymer having hydrophilic PEG and hydrophobic PLA moieties. 
     
     
         34 . The composition of  claim 28 , wherein said formulation is formulated for oral administration. 
     
     
         35 . The composition of  claim 28 , wherein said anti-angiogenic activity is an anti-tumor activity. 
     
     
         36 . The composition of  claim 28 , wherein said fumagillol derivative comprises a derivative selected from the group consisting of 6-O—(N-chloroacetylcarbamoyl)fumagillol (TNP-470), 6-O-(4-methoxyaniline)acetyl fumagillol, 6-O-(3,4,5-trimethexyaniline)acetyl fumagillol, 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol, 6-O-(cyclopropylamino)acetyl fumagillol, 6-O-(cyclobutylamino)acetyl fumagillol, 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5 20 dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1 cyclohexanol and 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5 dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol. 
     
     
         37 . A method of treating an angiogenesis-mediated condition, the method comprising orally administering a composition comprising a formulation of a fumagillol derivative that retains anti-angiogenic activity, said formulation comprising said fumagillol derivative is covalently associated with a block copolymer comprising a hydrophilic polymer moiety and a hydrophobic polymer moiety. 
     
     
         38 . The method of  claim 37 , wherein said formulation comprises a micelle comprising said block copolymer associated with said fumagillol derivative. 
     
     
         39 . The method of  claim 37 , wherein said fumagillol derivative thereof is associated with the hydrophobic moiety of said block copolymer. 
     
     
         40 . The method of  claim 37 , wherein said hydrophobic polymer moiety of said block copolymer is selected from the group consisting of poly(d,L-lactic acid), poly(L-lysine), poly(aspartic acid), poly(caprolactone) (PCL) and poly(propylene oxide). 
     
     
         41 . The method of  claim 37 , wherein said hydrophilic polymer moiety of said block copolymer is polyethylene glycol (PEG). 
     
     
         42 . The method of  claim 37 , wherein said block copolymer is a diblock copolymer comprising a PEG-PLA diblock copolymer having hydrophilic PEG and hydrophobic PLA moieties. 
     
     
         43 . The method of  claim 37  wherein said anti-angiogenic activity is an anti-tumor activity. 
     
     
         44 . The method of  claim 37  wherein said fumagillol derivative comprises a derivative selected from the group consisting of 6-O—(N-chloroacetylcarbamoyl)fumagillol (TNP-470), 6-O-(4-methoxyaniline)acetyl fumagillol, 6-O-(3,4,5-trimethexyaniline)acetyl fumagillol, 6-O-(4-(N,N-dimethylethoxy)aniline)acetyl fumagillol, 6-O-(cyclopropylamino)acetyl fumagillol, 6-O-(cyclobutylamino)acetyl fumagillol, 4-((cyclopropylamino)acetyl)oxy-2-(1,2-epoxy-1,5 20 dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1 cyclohexanol and 4-((cyclobutylamino)acetyl)oxy-2-(1,2-epoxy-1,5 dimethyl-4-hexenyl)-3-methoxy-1-chloromethyl-1-cyclohexanol. 
     
     
         45 . The method of  claim 37  wherein said formulation comprises a diblock copolymer micelle formed with said diblock copolymer. 
     
     
         46 . The method of  claim 37  wherein said angiogenesis-mediated condition comprises a tumor activity. 
     
     
         47 . The method of  claim 37 , wherein the angiogenesis-mediated condition is selected from the group consisting of cancer, metastatic tumors, psoriasis, age-related macular degeneration (AMD), thyroid hyperplasia, preclampsia, rheumatoid arthritis and osteo-arthritis, Alzheimer's disease, obesity, pleural effusion, atherosclerosis, endometriosis, diabetic/other retinopathies, ocular neovascularizations, IL-2 therapy associated edema and other edemas. 
     
     
         48 . A method of making a diblock copolymer micelle comprising a fumagillol derivative that has anti-angiogenic activity, the method comprising conjugating said fumagillol derivative to a diblock copolymer comprising a hydrophilic polymer moiety and a hydrophobic polymer moiety and forming micelles of the resulting conjugate. 
     
     
         49 . The method of  claim 48 , wherein said fumagillol derivative comprises 6-O—(N-chloroacetylcarbamoyl)fumagillol (TNP-470). 
     
     
         50 . A diblock copolymer micelle comprising a fumagillol derivative, said micelle produced by the method of  claim 48 . 
     
     
         51 . The diblock copolymer micelle of  claim 48 , wherein said fumagillol derivative comprises 6-O—(N-chloroacetylcarbamoyl)fumagillol (TNP-470).