Multifunctional forms of polyoxazoline copolymers and drug compositions comprising the same
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 and for conjugating to molecules such as targeting, diagnostic and therapeutic agents.
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 is S—U—W, wherein U is a linking group and W is a third functional group selected from the group consisting of: 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;
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 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.
4. The heterofunctional polyoxazoline derivative of claim 3 wherein the carboxylic acid is a negatively charged species and the amine is a positively charged species.
5. The heterofunctional polyoxazoline derivative of claim 1 wherein the first and second functional groups are each chemically orthogonal to the third functional group.
6. The heterofunctional polyoxazoline derivative of claim 1 wherein W is an alkyne, an amine, a carboxylic acid, or an activated carboxylic acid.
7. The heterofunctional polyoxazoline derivative of claim 1 wherein W is —CO 2 H or —NH 2 .
8. The heterofunctional polyoxazoline derivative of claim 1 wherein at least one of the first and second functional groups is chemically orthogonal to the third functional group.
9. The heterofunctional polyoxazoline derivative of claim 1 linked to at least one target molecule to form a target molecule-POZ conjugate.
10. The heterofunctional polyoxazoline derivative of claim 9 , where the at least one target molecule is a therapeutic agent, a targeting agent or a therapeutic agent and a targeting agent.