Metap-2 inhibitor polymersomes for therapeutic administration

Patent metadata

Field	Value
Publication number	US-2016136292-A1
Application number	US-201615005184-A
Country	US
Kind code	A1
Filing date	Jan 25, 2016
Priority date	Jun 26, 2007
Publication date	May 19, 2016
Grant date	—

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.

First claim

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 diblo

Assignees

• Childrens Medical Center

Inventors

• Benny-Ratsaby Ofra
• D Amato Robert
• Folkman Judah

Classifications

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title