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 having the general structure:
R 1 —{[N(COX)CH 2 CH 2 ] O -[n(COR 2 )CH 2 —CH 2 )] a }—S—U—W
wherein:
R 1 is an initiating group;
R 2 is an unsubstituted or substituted alkyl, an unsubstituted or substituted alkenyl, an unsubstituted or substituted aralkyl or an unsubstituted or substituted heterocyclylalkyl group;
U is a linking group;
X is a pendent moiety containing a first functional group;
W comprises a moiety bearing a second functional group;
a is random which indicates a random copolymer or block which indicates a block copolymer;
o is an integer 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 the first and second functional group 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.
3. The heterofunctional polyoxazoline derivative of claim 2 wherein the carboxylic acid is a negatively charged species and the amine is a positively charged species.
4. The heterofunctional polyoxazoline derivative of claim 1 wherein R 1 is a hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl group.
5. The heterofunctional polyoxazoline derivative of claim 1 wherein U is an alkylene linking group.
6. The heterofunctional polyoxazoline derivative of claim 5 wherein W is —CO 2 H or —NH 2 .
7. The heterofunctional polyoxazoline derivative of claim 1 linked to at least one a target molecule to form a target molecule-POZ conjugate.
8. The heterofunctional polyoxazoline derivative of claim 7 wherein the at least one target molecule is linked to the polyoxazoline derivative through at least one of the first or second functional groups.
9. The heterofunctional polyoxazoline derivative of claim 8 wherein the at least one target molecule is a therapeutic moiety, a diagnostic moiety or a targeting moiety and the target molecule-POZ 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.