Multi-arm polymer prodrugs

Abstract

Provided herein are water-soluble prodrugs, compositions comprising such prodrugs, and related methods of making and administering the same. The prodrugs of the invention comprise a water-soluble polymer having three or more arms, at least three of which are typically 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.

What is claimed is: 
     
         1 . A multi-arm polymer prodrug having the structure:
   R(-Q-POLY 1 -X-D) q    I
   wherein   R is an organic radical possessing from about 3 to about 150 carbon atoms,   Q is a linker,   POLY 1  is a water-soluble and non-peptidic polymer,   X is a spacer comprising a hydrolyzable linkage, such that upon hydrolysis of said hydrolyzable linkage, D is released,   D is a small molecule, and   q is greater than or equal to 3.   
     
     
         2 . The multi-arm polymer prodrug of  claim 1 , wherein R possesses a number of carbon atoms selected from (a) about 3 to about 50 carbon atoms, (b) about 3 to about 25 carbon atoms, and (c) the group consisting of 3, 4, 5, 6, 7, 8, 9, and 10. 
     
     
         3 . The multi-arm polymer prodrug of  claim 2 , wherein R, taken together with Q, is a residue of a polyol, a polythiol, or a polyamine. 
     
     
         4 . The multi-armed polymer prodrug of  claim 1 , wherein Q is hydrolytically stable. 
     
     
         5 . The multi-armed polymer prodrug of  claim 4 , wherein Q contains from about 1 to about 10 atoms. 
     
     
         6 . The multi-armed polymer prodrug of  claim 1 , wherein POLY 1  is a polyethylene glycol. 
     
     
         7 . The multi-armed polymer prodrug of  claim 1 , wherein X has the structure Y—Z, wherein Y is a spacer fragment covalently attached to Z, a hydrolytically degradable linkage. 
     
     
         8 . The multi-armed polymer prodrug of  claim 7 , wherein X is either —CH 2 —C(O)—NH—CH 2 —C(O)O— or —CH 2 —C(O)—NH—(CH 2 CH 2 O) 2 —C(O)—O—. 
     
     
         9 . The multi-armed polymer prodrug of  claim 1 , wherein the value of q is selected from the group consisting of 3, 4, 5, 6, 7, 8, 9, and 10. 
     
     
         10 . The multi-armed polymer prodrug of  claim 9 , wherein each of said “q” polymer arms (-Q-POLY 1 -X-D) is the same. 
     
     
         11 . The multi-armed polymer prodrug of  claim 1 , wherein D is a small molecule having a molecular weight of less than about 800. 
     
     
         12 . The multi-armed polymer prodrug of  claim 1 , wherein D is an anticancer agent. 
     
     
         13 . The polymer-taxane prodrug of  claim 12 , wherein q is 3 or 4. 
     
     
         14 . A composition comprising a multi-arm polymer prodrug of  claim 1 , said composition further comprising the prodrug having one or more of ‘q’ polymer arms absent D. 
     
     
         15 . A composition comprising a multi-arm polymer prodrug having the structure:
   R(-Q-POLY 1 -X′-D 0,1 ) q    I
   wherein   R is an organic radical possessing from about 3 to about 150 carbon atoms,   Q is a linker,   POLY 1  is a water-soluble and non-peptidic polymer,   X′ is either (i) a spacer, X, comprising a hydrolyzable linkage, such that upon hydrolysis of said hydrolyzable linkage, D, is released, or is (ii) X″, a terminal moiety,   D is a small molecule, where D 1  indicates the presence of D and D 0  indicates its absence,   q is greater than or equal to 3,   wherein if X′ is X, then D is D 1 , and if X′ is X″, then D is D 0 , and said composition comprises at least one multi-arm polymer prodrug species wherein X′ is X.   
     
     
         16 . The composition of  claim 15 , comprising one or more prodrug species having the structure:
   R-(Q-POLY 1 -X-D 1 ) m (Q-POLY 1 -X″) s  
   wherein m+s=q, and
 m and s each independently range from 0 to q. 
   
     
     
         17 . The composition of  claim 15 , having an average number of D per multi-arm polymer ranging from 2.1-3.75. 
     
     
         18 . The composition of  claim 16 , comprising a mixture of “q” prodrug species. 
     
     
         19 . The composition of  claim 16 , wherein X″ is —CH 2 COOH. 
     
     
         20 . A pharmaceutical composition comprising a prodrug recited in  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         21 . A method of delivering a prodrug to a mammalian subject, said method comprising administering to said mammalian subject a therapeutically effective amount of the prodrug of  claim 1 . 
     
     
         22 . A method of treating cancer in a mammalian subject, said method comprising:
 administering a therapeutically effective amount of a prodrug of  claim 12  to a subject diagnosed as having one or more cancerous solid tumors, over a duration of time effective to produce an inhibition of solid tumor growth in said subject.   
     
     
         23 . A method of improving the retention of SN-38 in a cancerous solid tumor following administration of irinotecan, said method comprising covalently attaching a multi-arm polymer to irinotecan to form a composition comprising a mixture of one or more prodrug species having the structure, 
       
         
           
           
               
               
           
         
         wherein 0-Irinotecan is 
       
       
         
           
           
               
               
           
         
         m+s=4, and 
         n ranges from 40 to 500. 
       
       whereby said resulting composition, when administered to a mammalian subject diagnosed as having one or more cancerous solid tumors, over a suitable duration of time, is effective to result in an accumulation of SN-38 in said one or more tumors that is enhanced over that observed following administration of unmodified irinotecan. 
     
     
         25 . A method of treating a mammalian subject for a condition responsive to treatment with a taxane, said method comprising administering to said subject a therapeutically effective amount of a prodrug of  claim 12 , wherein D is a taxane anticancer agent. 
     
     
         26 . A method of treating a mammalian subject for a condition responsive to treatment with a camptothecin, said method comprising administering to said subject a therapeutically effective amount of a prodrug of  claim 12 , wherein the anticancer agent is a camptothecin. 
     
     
         27 . A method for preparing a multi-arm polymer prodrug of the invention, said method comprising:
 (i) providing a small molecule, D, comprising a functional group, F, suitable for forming a hydrolyzable linkage, Z   (ii) reacting the small molecule with a bifunctional spacer, Y′, comprising each a first and a second functional group, F1 and F2, wherein F2 is suitable for reaction with F and F1 is optionally in protected form (F1-Y′-F2), under conditions effective to form a partially modified active agent comprising a hydrolyzable linkage, Z, resulting from reaction of F and F2 (D-Z—Y′-F1),   (iii) optionally, if in protected form, deprotecting F1 contained in the partially modified active agent from (ii), and   (iv) reacting the partially modified active agent, D-Z—Y′-F1, with a multi-armed water-soluble polymer comprising the structure:
   R(-Q-POLY 1 -F3) q    
   where
 R is an organic radical possessing from about 3 to about 150 carbon atoms, 
 Q is a linker, 
 POLY 1  is a water-soluble and non-peptidic polymer, 
 q is greater than or equal to 3, and 
 F3 is a functional group that is reactive with F1, 
   under reaction conditions effective to promote reaction between F3 and F1 to convert Y′ to Y to thereby form a polymer prodrug having the structure
   R(-Q-POLY 1 -Y—Z-D) q ,
 
 where Y is a spacer fragment, and Z is a hydrolyzable linkage, which, upon hydrolysis, releases D. 
   
     
     
         28 . The method of  claim 27 , wherein in step (iv), a stoichiometric excess in an amount greater than “q” moles of the partially modified active agent, D-Z—Y′-F1, is reacted with the multi-armed water-soluble polymer, R(-Q-POLY 1 -F3) q . 
     
     
         29 . The method of  claim 27 , wherein said small molecule D comprises additional functional groups reactive with F2, and said method further comprises protecting said additional functional groups with suitable protecting groups prior to reaction with said bifunctional spacer. 
     
     
         30 . The method of  claim 27 , further comprising (v) removing said protecting groups from the small molecules of said prodrug, R(-Q-POLY 1 -Y—Z-D) q . 
     
     
         31 . A method for preparing a multi-arm polymer prodrug of the invention, said method comprising:
 (i) providing a reactive multi-arm polymer having the structure, R(-Q-POLY 1 -F3) q , where
 R is an organic radical possessing from about 3 to about 150 carbon atoms, 
 Q is a linker, 
 POLY 1  is a water-soluble and non-peptidic polymer, 
 q is greater than or equal to 3, and 
 F3 is a reactive functional group 
   (ii) reacting the multi-arm polymer with a bifunctional spacer, Y′, comprising each a first and a second functional group, F1 and F2, wherein F1 is suitable for reaction with F3, and F1 is optionally in protected form (F1-Y′-F2), under conditions effective to form an intermediate multi-arm polymer resulting from reaction of F3 and F1, R(-Q-POLY 1 -Y—F2) q , and   (iii) optionally, if in protected form, deprotecting F2 in the intermediate multi-arm polymer, R(-Q-POLY 1 -Y—F2) q , and   (iv) reacting the intermediate multi-arm polymer, R(-Q-POLY 1 -Y—F2) q  with a small molecule, D, comprising a functional group, F, suitable for forming a hydrolyzable linkage, Z, upon reaction of F with F2, under conditions effective to thereby form a prodrug having the structure:
   R(-Q-POLY 1 -Y—Z-D) q ,
 
   where Z is a hydrolyzable linkage, which, upon hydrolysis, releases D.