Multi-arm polymer prodrugs

Abstract

Provided herein are water-soluble prodrugs. The prodrugs of the invention comprise a water-soluble polymer having three or more arms, at least three of which are covalently attached to an active agent, e.g., a small molecule. The conjugates of the invention provide an optimal balance of polymer size and structure for achieving improved drug loading, since the conjugates of the invention possess three or more active agents releasably attached to a multi-armed water soluble polymer. The prodrugs of the invention are therapeutically effective, and exhibit improved properties in-vivo when compared to unmodified parent drug.

1 . A polymer conjugate comprising a linear water-soluble and non-peptidic polymer scaffold comprising from 3 to about 50 pendent active agent moieties, each active agent moiety being covalently attached to the scaffold via a spacer comprising a hydrolyzable linkage, wherein: (i) the spacer comprises an amino acid, (ii) said scaffold has a molecular weight ranging from about 1,000 daltons to about 100,000 daltons, and (iii) said active agent moiety is a camptothecin compound. 
     
     
         2 . The conjugate of  claim 1 , wherein said amino acid is glycine. 
     
     
         3 . The conjugate of  claim 1 , wherein said spacer has an atom length of from between about 5 and 25 atoms. 
     
     
         4 . The conjugate of  claim 1 , wherein said hydrolyzable linkage is a carboxylate ester. 
     
     
         5 . The conjugate of  claim 4 , wherein said camptothecin compound is released from said conjugate following administration via hydrolysis of the ester linkage. 
     
     
         6 . The conjugate of  claim 1 , wherein said scaffold comprises molecules of a polyol. 
     
     
         7 . The conjugate of  claim 6 , wherein said polyol is a cyclodextrin. 
     
     
         8 . The conjugate of  claim 1 , wherein said scaffold is a linear water-soluble and non-peptidic copolymer. 
     
     
         9 . The conjugate of  claim 8 , wherein said copolymer is a copolymer of a polyethylene glycol and a poly(saccharide). 
     
     
         10 . The conjugate of  claim 9 , wherein said poly(saccharide) is a cyclodextrin. 
     
     
         11 . The conjugate of  claim 1 , wherein said scaffold has a molecular weight ranging from about greater than about 60,000 daltons to about 100,000 daltons. 
     
     
         12 . The conjugate of  claim 1 , which when evaluated in a suitable animal model for solid tumor-type cancers and administered in a therapeutically effective amount, is effective to suppress tumor growth to an extent that is at least twice that observed for camptothecin when evaluated over a time course of 30 days. 
     
     
         13 . A conjugate having the following structure:
   POLY 1 (X-D) q      
       wherein:
 POLY 1  is a linear water-soluble and non-peptidic copolymer; 
 D is a camptothecin compound; 
 X is a spacer comprising an amino acid and a hydrolyzable linkage, said camptothecin compound is released, 
 and 
 (q) is from 3 to about 50. 
 
     
     
         14 . The conjugate of  claim 13 , wherein said amino acid is glycine. 
     
     
         15 . The conjugate of  claim 13 , wherein said hydrolyzable linkage is a carboxylate ester. 
     
     
         16 . The conjugate of  claim 15 , wherein said camptothecin compound is released from said conjugate following administration via hydrolysis of the ester linkage. 
     
     
         17 . The conjugate of  claim 13 , wherein said copolymer is a copolymer of a polyethylene glycol and a poly(saccharide). 
     
     
         18 . The conjugate of  claim 17 , wherein said poly(saccharide) is a cyclodextrin. 
     
     
         19 . The conjugate of  claim 13 , wherein said spacer X has a structure Y-Z where Y is a spacer fragment covalently attached to Z, a hydrolyzable linkage. 
     
     
         20 . The conjugate of  claim 19 , wherein Z is a carboxylate ester. 
     
     
         21 . The conjugate of  claim 20 , wherein Y has the structure —(CR x R y ) a —K—(CR x R y ) b —(CH 2 CH 2 O) c —, wherein each R x  and R y , in each occurrence, is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, and substituted aryl, a ranges from 0 to 12, b ranges from 0 to 12, c ranges from 0 to 25, K is selected from —C(O)—, —C(O)NH—, —NH—C(O)—, —O—, —S—, O—C(O)—, C(O)—O—, O—C(O)—O—, O—C(O)—NH—, NH—C(O)—O—. 
     
     
         22 . The conjugate of  claim 13 , which when evaluated in a suitable animal model for solid tumor-type cancers and administered in a therapeutically effective amount, is effective to suppress tumor growth to an extent that is at least twice that observed for camptothecin when evaluated over a time course of 30 days.