Degradable heterobifunctional poly (ethylene glycol) acrylates and gels and conjugates derived therefrom

Abstract

A heterobifunctional poly(ethylene glycol) is provided having a hydrolytically degradable linkage, a first terminus comprising an acrylate group, and a second terminus comprising a target such as a protein or pharmaceutical agent or a reactive moiety capable of coupling to a target. Hydrogels can be prepared. The hydrogels can be used as a carrier for a protein or a pharmaceutical agent that can be readily released in a controlled fashion.

That which is claimed is:  
     
         1 . A heterobifunctional polymer comprising: 
 a poly(alkylene oxide) backbone;    a first terminus comprising an acrylate group;    a second terminus comprising a target or a reactive moiety capable of coupling to a target; and    a hydrolytically degradable linkage for releasing said target upon hydrolysis.    
     
     
         2 . A compound represented by the formula:  
       CH 2 ═CZ—CO 2 —POLY—W—POLY′—Q  
       where 
 Z represents H or alkyl;  
 POLY and POLY′ are poly(alkylene oxide) groups that can be the same or different and are represented by the formula  
 —(CH 2 CHRO) n —CH 2 CHR—  
 in which R is H or alkyl, and n ranges from about 10 to about 4000;  
 Q represents a functional group; and  
 W represents a hydrolytically unstable linkage.  
 
     
     
         3 . A compound represented by the formula:  
       CH 2 ═CZ—CO 2 —POLY—W—Q  
       where 
 Z represents H or alkyl;  
 POLY is poly(alkylene oxide), represented by the formula  
 —(CH 2 CHRO) n —CH 2 CHR—  
 in which R is H or alkyl, and n ranges from about 10 to about 4000;  
 Q represents a functional group; and  
 W represents a hydrolytically unstable linkage.  
 
     
     
         4 . The compound of either of    claim 2    or    3   , wherein POLY and POLY′ are poly(ethylene glycol).  
     
     
         5 . The compound of either of    claim 2    or    3   , wherein W comprises a hydrolyzable covalent bond selected from the group consisting of esters, orthoesters, imines, acetals, peptide bonds, and disulfides.  
     
     
         6 . The compound of either of    claim 2    or    3   , wherein W has a structure of:  
       —O(CH 2 ) m —CO 2 R 1 —CO 2 — 
       where m ranges from 1 to 10, and R 1  is —CH 2 —, —CH 2 CH 2 — or —CH(CH 3 )CH 2 —, or W has the structure —O—(CH 2 ) m —CO 2 —.  
     
     
         7 . The compound of either of    claim 2    or    3   , wherein Q is selected from the group consisting of aldehydes, carboxylic acids, active esters, active carbonates, sulfonate esters, amines, hydrazides, orthopyridyl disulfides, and thiols.  
     
     
         8 . A conjugate having a formula of:  
       (CH 2 ═CZ—CO 2 —POLY—W—POLY′—L) x —T  
       where 
 Z is H or an alkyl group;  
 POLY and POLY′ are poly(alkylene oxides) comprising groups that can be the same or different and are represented by the formula  
 —(CH 2 CHRO) n —CH 2 CHR— 
 in which R is H or alkyl, and n ranges from about 10 to about 4000;  
 W represents a hydrolytically unstable linkage;  
 L is hydrolytically stable linkage;  
 x is an integer of 1-10; and  
 T is a target molecule.  
 
     
     
         9 . The conjugate of    claim 7   , wherein R is H.  
     
     
         10 . The conjugate of    claim 7   , wherein W has the structure of:  
       —O(CH 2 ) m —CO 2 R 1 —CO 2 — 
       where m ranges from 1 to 10, R 1  is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, and —CH(CH 3 )CH 2 — or W has the structure —O—(CH 2 ) m —CO 2 —.  
     
     
         11 . The conjugate of    claim 7   , wherein T is selected from the group consisting of proteins, polysaccharides, oligonucleotides, lipids, vitamins, hormones, or small molecule pharmaceuticals.  
     
     
         12 . A compound having the following structure:  
       CH 2 ═CZCO 2 —POLY—W—Q  
       where 
 Z represents H or alkyl;  
 POLY is a poly(alkylene oxide) represented by the formula  
 —(CH 2 CHRO) n —CH 2 CHR— 
 in which R is H or alkyl, and n ranges from about 10 to about 4000;  
 Q represents a functional group; and  
 W represents a hydrolytically unstable linkage.  
 
     
     
         13 . The compound of    claim 11   , wherein POLY is poly(ethylene glycol).  
     
     
         14 . The compound of    claim 11   , wherein W comprises a hydrolyzable covalent bond selected from the group consisting of esters, orthoesters, imines, acetals, peptide bonds, and disulfides.  
     
     
         15 . The compound of    claim 11   , wherein W has the structure of:  
       —O(CH 2 ) m —CO 2 R 1 —CO 2 — 
       where m ranges from 1 to 10 and R 1  is —CH 2 —, —CH 2 CH 2 —, or —CH(CH 3 )CH 2 — or W has the structure —O—(CH 2 ) m —CO 2 —.  
     
     
         16 . The compound of    claim 11   , wherein Q is selected from the group consisting of aldehydes, carboxylic acids, active esters, active carbonates, sulfonate esters, amines, hydrazides, orthopyridyl disulfides, N-succinimidyl, and thiols.  
     
     
         17 . A conjugate having the following structure:  
       (CH 2 ═CZCO 2 —POLY—W—L) x —T  
       where 
 Z represents H or alkyl;  
 POLY is a poly(alkylene oxide) comprising a group represented by the formula  
 —(CH 2 CHRO) n —CH 2 CHR— 
 in which R is H or alkyl, and n ranges from about 10 to about 4000;  
 W represents a hydrolytically unstable linkage;  
 L is a hydrolytically stable linkage;  
 x is an integer from 1 to 10; and  
 T is a target molecule.  
 
     
     
         18 . A polymer selected from the group consisting of compounds represented by the formula:  
       CH 2 ═CZ—CO 2 —POLY—W—POLY′—Q 1 , (CH 2 ═CZ—CO 2 —POLY—W—POLY′—L) x —T, CH 2 ═CZCO 2 —POLY—W—Q, and (CH 2 ═CZCO 2 —POLY—W—L) x —T,  
       where 
 Z is H or an alkyl group;  
 POLY and POLY′ are poly(alkylene oxides) that can be the same or different and are represented by the formula  
 —(CH 2 CHRO) n —CH 2 CHR— 
 in which R is H or alkyl, and n ranges from about 10 to about 4000;  
 W represents a hydrolytically unstable linkage;  
 Q represents a functional group;  
 L is hydrolytically stable linkage;  
 x is an integer of 1-10; and  
 T is a target molecule.  
 
     
     
         19 . The polymer composition of    claim 17   , wherein W has the structure of:  
       —O(CH 2 ) m —CO 2 R 1 —CO 2 — 
       where m ranges from 1 to 10, R 1  is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, and —CH(CH 3 )CH 2 — or W has the structure of —O—(CH 2 ) m —CO 2 —.  
     
     
         20 . The polymer composition of    claim 17   , wherein T is a protein.  
     
     
         21 . The polymer composition of    claim 17   , wherein R is H.  
     
     
         22 . A hydrogel comprising a co-polymerization product of a multiacrylate and at least one compound selected from the group consisting of compounds represented by the formula:  
       CH 2 ═CZ—CO 2 —POLY—W—POLY′—Q 1 , (CH 2 ═CZ—CO 2 —POLY—W−POLY′—L) x —T, CH 2 ═CZCO 2 —POLY—W—Q, and (CH 2 ═CZCO 2 —POLY—W—L) x T,  
       where 
 Z is H or an alkyl group;  
 POLY and POLY′ are poly(alkylene oxides) that may be the same or different and are represented by the formula  
 —(CH 2 CHRO) n —CH 2 CHR— 
 in which R is H or alkyl, and n ranges from about 10 to about 4000;  
 W represents a hydrolytically unstable linkage;  
 Q represents a functional group;  
 L is hydrolytically stable linkage;  
 x is an integer of 1-10; and  
 T is a target molecule.  
 
     
     
         23 . The hydrogel of    claim 21   , wherein said multiacrylate is selected from the group consisting of PEG diacrylates and N-vinylpyrrolidone.  
     
     
         24 . The hydrogel of    claim 22   , wherein said PEG diacrylate is CH 2 ═CHCO 2 —PEG—O—CH 2 CO 2 CH(CH 3 )CH 2 CONH—PEGO 2 CCH═CH 2  or CH 2 ═CHCO 2 —PEG—O—CH 2 CO 2 PEG—O 2 CCH═CH 2+L.    
     
     
         25 . The hydrogel of    claim 21   , wherein T is a protein.