TNP-470 polymer conjugates and use thereof
The present invention relates to conjugates of water-soluble polymers and o(chloracetyl-carbamoyl) fumagillol (TNP-470) and use of those conjugates as specific intracellular carriers of the TNP-470 into tumor vessels. The present invention further relates to use of those conjugates to lower the neurotoxicity of TNP-470. Preferably, the polymer has a molecular weight in the range of 100 Da to 800 kDa. More preferably, the polymer has a molecular weight no greater than 60 kDa. Most preferably, the polymer has a molecular weight in the range of 15 kDa to 40 kDa.
1. A composition comprising a TNP-470 conjugated to a polymer, wherien the polymer is water soluble and has a molecular weight not greater than 60 kDa, wherein the polymer is a hydroxypropyl(meth)acrylamide-methacrylic acid copolymer.
2. The composition of claim 1 , wherein the polymer has a molecular weight in the range of 15 to 40 kDa.
3. The composition of claim 1 , futher comprising a peptide linker between the TNP-470 and the polymer.
4. The composition of claim 1 , further comprising a targeting ligand.
5. The composition of claim 1 , comprising the structure:
wherein y is in the range of 0.04-20 and x is in the range of 80-99.96.
6. A method of treating an angiogenic disease comprising administering a composition of claim 1 to a mammal in need thereof, wherein the angiogenic disease is a solid tumor, a lymphoma, a leukemia, diabetic retinopathy or macular degeneration.
7. A method for decreasing neurotoxicity of TNP-470, comprising conjugating the TNP-470 to a polymer, wherein the polymer is water soluble and has a molecular weight not greater than 60 kDa.
8. The nethod of claim 7 , wherein the polymer has a molecular weight in the range of 15 to 40 kDa.
9. The method of claim 7 , wherein the polymer is a hydroxypropyl(meth)acrylamide-methacrylic acid copolymer.
10. The method of claim 7 , further comprising a peptide linker between the antiangiogenic agent and the polymer.
11. The method of claim 7 , comprising the structure:
wherein y is in the range of 0.04-20 and x is in the range of 80-99.96.
12. The method of claim 11 , wherein y is 5-10 and x is 90-95.
13. An HPMA-TNP-470 conjugate comprising the structure:
wherein x is 90-95 and y is 5-10.