Self-assembled particles from zwitterionic polymers and related methods

Abstract

Zwitterionic block copolymers and zwitterionic conjugates that advantageously self-assemble into particles, particles assembled from the zwitterionic block copolymers and zwitterionic conjugates, pharmaceutical compositions that include the self-assembled particles, and methods for delivering therapeutic and diagnostic agents using the particles.

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows: 
     
         1 . A block copolymer, comprising:
 (a) a zwitterionic polymer block comprising a poly(carboxybetaine); and   (b) a hydrophobic block,   wherein the zwitterionic polymer block comprises a plurality of repeating units, each repeating unit having the formula:   
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of hydrogen, fluorine, trifluoromethyl, C1-C6 alkyl, and C6-C12 aryl groups; 
         R 2  and R 3  are independently selected from the group consisting of alkyl and aryl, or taken together with the nitrogen to which they are attached form a cationic center; 
         L 1  is a linker that covalently couples the cationic center [N + (R 5 )(R 6 )] to the polymer backbone [—(CH 2 —CR 4 ) n —]; 
         L 2  is a linker that covalently couples the anionic center [A(═O)—O − ] to the cationic center; 
         A is C; 
         M +  is a counter ion associated with the (A=O)O −  anionic center; 
         X −  is a counter ion associated with the cationic center; and 
         n is an integer from 1 to about 10,000. 
       
     
     
         2 . The copolymer of  claim 1 , wherein R 1 -R 8  are independently selected from the group consisting of C1-C3 alkyl. 
     
     
         3 . The copolymer of  claim 1 , wherein L 3  is selected from the group consisting of —C(═O)O—(CH 2 ) n — and —C(═O)NH—(CH 2 ) n —, wherein n is 1-20. 
     
     
         4 . The copolymer of  claim 1 , wherein L 4  is —(CH 2 ) n —, where n is an integer from 1-20. 
     
     
         5 . The copolymer of  claim 1 , wherein n is an integer from 10 to about 1,000. 
     
     
         6 . The copolymer of  claim 1 , wherein p is an integer from 10 to about 1,000. 
     
     
         7 . A block copolymer, comprising:
 (a) a mixed charge copolymer block comprising a mixed charge copolymer; and   (b) a hydrophobic block,   wherein the mixed charge copolymer comprises a plurality of repeating units, each repeating unit having the formula:   
       
         
           
           
               
               
           
         
         wherein 
         R 4  and R 5  are independently selected from hydrogen, fluorine, trifluoromethyl, C1-C6 alkyl, and C6-C12 aryl groups; 
         R 6 , R 7 , and R 8  are independently selected from alkyl and aryl, or taken together with the nitrogen to which they are attached form a cationic center; 
         A(═O)—OM) is an anionic center, wherein A is C, S, SO, P, or PO, and M +  is a metal or organic counterion; 
         L 3  is a linker that covalently couples the cationic center [N + (R 6 )(R 7 )(R 8 )] to the polymer backbone; 
         L 4  is a linker that covalently couples the anionic center [A(═O)—OM] to the polymer backbone; 
         X −  is the counter ion associated with the cationic center; 
         n is an integer from 1 to about 10,000; and 
         p is an integer from 1 to about 10,000. 
       
     
     
         8 . The copolymer of  claim 7 , wherein R 1 -R 8  are independently selected from the group consisting of C1-C3 alkyl. 
     
     
         9 . The copolymer of  claim 7 , wherein L 3  is selected from the group consisting of —C(═O)O—(CH 2 ) n — and —C(═O)NH—(CH 2 ) n —, wherein n is 1-20. 
     
     
         10 . The copolymer of  claim 7 , wherein L 4  is —(CH 2 ) n —, where n is an integer from 1-20. 
     
     
         11 . The copolymer of  claim 7 , wherein n is an integer from 10 to about 1,000. 
     
     
         12 . The copolymer of  claim 7 , wherein p is an integer from 10 to about 1,000. 
     
     
         13 . An assembly, comprising a plurality of block copolymers of  claim 1 . 
     
     
         14 . The assembly of  claim 13  in the form of a core-shell polymeric particle.