Multifunctional Forms of Polyoxazoline Copolymers and Drug Compositions Comprising the Same

Abstract

The present disclosure provides copolymers of 2-substituted-2-oxazolines possessing two or three reactive functional groups which are also chemically orthogonal. The copolymers described may be random copolymers, block copolymers or a mixture of random and block copolymer configurations. Furthermore, the present disclosure provides novel methods for synthesizing the above polymers find for conjugating to molecules such as targeting, diagnostic and therapeutic agents.

What is claimed: 
     
         1 . A heterofunctional polyoxazoline derivative of the general structure:
 R 1 —{[N(COX)CH 2 CH 2 ] o -[N(COR 2 )CH 2 —CH 2 )] n -[N(COY)CH 2 —CH 2 )] m } a -Z   wherein:   R 1  is an initiating group;   R 2  is independently selected for each repeating unit from an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted aralkyl or an unsubstituted or substituted heterocyclylalkyl group;   X is a pendent moiety containing a first functional group;   Y is a pendent moiety containing a second functional group;   Z is a terminating nucleophile, wherein Z is inert or wherein Z contains a third functional group;   a is ran which indicates a random copolymer or block which indicates a block copolymer;   o and m are each an integer independently selected from 1-50;   n is an integer selected from 0-1000; and   wherein the first and second functional groups are chemically orthogonal to one another.   
     
     
         2 . The heterofunctional polyoxazoline derivative of  claim 1  wherein R 1  is a hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl group. 
     
     
         3 . The heterofunctional polyoxazoline derivative of  claim 1  wherein X and Y contain an alkylene portion. 
     
     
         4 . The heterofunctional polyoxazoline derivative of  claim 1  wherein the first and second functional groups are each independently an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide or orthopyridyl disulfide and the third functional group, when present, is an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide or orthopyridyl disulfide. 
     
     
         5 . The heterofunctional polyoxazoline derivative of  claim 5  wherein the activated carboxylic acid is an N-hydroxysuccinimidyl (NHS) or 1-benzotriazineylyl 1-benzotriazine active ester. 
     
     
         6 . The heterofunctional polyoxazoline derivative of  claim 1  wherein Z contains the third functional group. 
     
     
         7 . The heterofunctional polyoxazoline derivative of  claim 6  wherein Z is —S—U—W, wherein U is a linking group and W is the third functional group. 
     
     
         8 . The heterofunctional polyoxazoline derivative of  claim 7  wherein W is a carboxylic acid, a protected carboxylic acid, an active ester, an amine or a protected amine. 
     
     
         9 . The heterofunctional polyoxazoline derivative of  claim 7  wherein U is an alkylene linking group. 
     
     
         10 . The heterofunctional polyoxazoline derivative of  claim 7  wherein the first and second functional groups are each chemically orthogonal to the third functional group. 
     
     
         11 . The heterofunctional polyoxazoline derivative of  claim 7  wherein at least one of the first and second functional groups is chemically orthogonal to the third functional group. 
     
     
         12 . The heterofunctional polyoxazoline derivative of  claim 1  wherein Z is inert. 
     
     
         13 . The heterofunctional polyoxazoline derivative of  claim 12  wherein Z is —S-T-V, T is a linking group and V is an inert group. 
     
     
         14 . The heterofunctional polyoxazoline derivative of  claim 13  wherein T is an alkylene linking group. 
     
     
         15 . The heterofunctional polyoxazoline derivative of  claim 13  wherein V is —CO 2 CH 3 or —C 6 H 5 . 
     
     
         16 . The heterofunctional polyoxazoline derivative of  claim 7  having the structure:
 R 1 —{[N(COX)CH 2 CH 2 ] o —N(COR 2 )CH 2 —CH 2 ) n -[N(COY)CH 2 —CH 2 )] m } a -S—(CH 2 ) p -W. 
 
     
     
         17 . The heterofunctional polyoxazoline derivative of  claim 7  having the structure:
 R 1 —{[N(COX)CH 2 CH 2 ] o -[N(COR 2 )CH 2 —CH 2 )] n -[N(COY)CH 2 —CH 2 )] m } a -S—(CH 2 ) p -NH 2 , wherein the first and second functional groups are each independently an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide or orthopyridyl disulfide. 
 
     
     
         18 . The heterofunctional polyoxazoline derivative of  claim 7  having the structure:
 R 1 —{[N(COX)CH 2 CH 2 ] o -[N(COR 2 )CH 2 —CH 2 )] n -[N(COY)CH 2 —CH 2 )] m } a -S—(CH 2 ) p -CO 2 H, wherein the first and second functional groups are each independently an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide or orthopyridyl disulfide. 
 
     
     
         19 . The heterofunctional polyoxazoline derivative of  claim 13  having the structure:
 R 1 —{[N(COX)CH 2 CH 2 ] o -[N(COR 2 )CH 2 —CH 2 )] n -[N(COY)CH 2 —CH 2 )] m } a -S—(CH 2 ) p -V. 
 
     
     
         20 . The heterofunctional polyoxazoline derivative of  claim 13  having the structure:
 R 1 —{[N(COX)CH 2 CH 2 ] o -[N(COR 2 )CH 2 —CH 2 )] n -[N(COY)CH 2 —CH 2 )] n } a -S—(CH 2 ) p -C 6 H 5 , wherein the first and second functional groups are each independently an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide or orthopyridyl disulfide. 
 
     
     
         21 . The heterofunctional polyoxazoline derivative of  claim 13  having the structure:
 R 1 —{[N(COX)CH 2 CH 2 ] o -[N(COR 2 )CH 2 —CH 2 )] n -[N(COY)CH 2 —CH 2 )] n } a -S—(CH 2 ) p -CO 2 CH 3 , wherein the first and second functional groups are each independently an alkyne, an amine, an oxyamine, an aldehyde, a ketone, an acetal, a ketal, an ester, a carboxylic acid, an activated carboxylic acid, an active carbonate, a chloroformate, an alcohol, an azide, a vinyl sulfone, a maleimide or orthopyridyl disulfide. 
 
     
     
         22 . The heterofunctional polyoxazoline derivative of  claim 1  linked to a target molecule. 
     
     
         23 . A target molecule-POZ conjugate comprising a heterofunctional polyoxazoline derivative of  claim 1  linked to at least one target molecule, wherein the at least one target molecule is linked to the POZ conjugate through at least one of the first, second or third functional groups. 
     
     
         24 . The target molecule-POZ conjugate of  claim 23  wherein the target molecule is a therapeutic moiety, a diagnostic moiety, a targeting moiety or a combination of the foregoing. 
     
     
         25 . The target molecule-POZ conjugate of  claim 24  wherein the conjugate contains a therapeutic moiety and a targeting moiety, a diagnostic moiety and a targeting moiety or a diagnostic moiety, a therapeutic moiety and a targeting moiety. 
     
     
         26 . The target molecule-POZ conjugate of  claim 23  wherein the target molecule is an organic molecule, a peptide, a protein, an antibody, an antibody fragment, a carbohydrate or an oligonucleotide. 
     
     
         27 . The target molecule-POZ conjugate of  claim 23  wherein the linkage between the POZ derivative and the target molecule is hydrolytically stable or hydrolytically unstable.