Tnp-470 polymer conjugates and use thereof

Abstract

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, wherein the polymer is water soluble and has a molecular weight in the range of 100 Da to 800 kDa. 
   
   
       2 . The composition of  claim 1 , wherein the polymer has a molecular weight no greater than 60 kDa. 
   
   
       3 . The composition of  claim 1 , wherein the polymer has a molecular weight in the range of 15 to 40 kDa. 
   
   
       4 . The composition of  claim 1 , wherein the polymer is a hydroxypropyl(meth)acrylamide-methacrylic acid copolymer. 
   
   
       5 . The composition of  claim 1 , further comprising a peptide linker between the TNP-470 and the polymer. 
   
   
       6 . The composition of  claim 1 , further comprising a targeting ligand. 
   
   
       7 . The composition of  claim 4 , comprising the structure: 
     
       
         
         
             
             
         
       
     
     wherein y is in the range of 0.04-20 and x is in the range of 80-99.96. 
   
   
       8 . A method of treating an angiogenic disease comprising administering a composition of  claims 1 - 7  to a mammal in need thereof. 
   
   
       9 . The method of  claim 8 , wherein angiogenic disease is a solid tumor. 
   
   
       10 . 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 in the range of 100 Da to 800 kDa. 
   
   
       11 . The composition of  claim 1 , wherein the polymer has a molecular weight no greater than 60 kDa. 
   
   
       12 . The composition of  claim 1 , wherein the polymer has a molecular weight in the range of 15 to 40 kDa. 
   
   
       13 . The method of  claim 10 , wherein the polymer is a hydroxypropyl(meth)acrylamide-methacrylic acid copolymer. 
   
   
       14 . The method of  claim 10 , further comprising a peptide linker between the antiangiogenic agent and the polymer. 
   
   
       15 . The method of  claim 10 , comprising the structure: 
     
       
         
         
             
             
         
       
     
     wherein y is in the range of 0.04-20 and x is in the range of 80-99.96. 
   
   
       16 . The method of  claim 15 , wherein y is 5-10 and x is 90-95. 
   
   
       17 . An HPMA-TNP-470 conjugate comprising the structure: 
     
       
         
         
             
             
         
       
     
     Wherein x is 90-95 and y is 5-10.