Branched polymers
The present invention is directed to branched reactive water-soluble polymers comprising at least two polymer arms, such as poly(ethylene glycol), attached to a central aliphatic hydrocarbon core molecule through heteroatom linkages. The branched polymers bear at least one functional group for reacting with a biologically active agent to form a biologically active conjugate. The functional group of the branched polymer can be directly attached to the aliphatic hydrocarbon core or via an intervening linkage, such as a heteroatom, -alkylene-, —O-alkylene-O—, -alkylene-O-alkylene-, -aryl-O—, —O-aryl-, (—O-alkylene-) m , or (-alkylene-O—) m linkage, wherein m is 1-10.
1. A branched reactive polymer having the structure:
Y—(X) p -R(—X′-POLY) q
wherein:
R is an aliphatic hydrocarbon having a length of at least three carbon atoms;
each POLY is a poly(ethylene glycol) that terminates with a hydroxyl or methoxy group;
X′ is a heteroatom linkage selected from —NH—, —O— or —S—;
X is a linker of 1 to ten atoms;
p is 0 or 1;
q is 2 to about 10; and
Y is a maleimide,
and further wherein the branched reactive polymer has a molecular weight of about 500 Da to about 100,000 Da.
2. The branched reactive polymer of claim 1 , wherein X′ is —O—.
3. The branched reactive polymer of claim 1 , wherein q is 2 to about 5.
4. The branched reactive polymer of claim 1 , wherein each POLY is symmetrically located on the aliphatic hydrocarbon.
5. The branched reactive polymer of claim 1 , wherein R comprises from 3 to about 7 carbon atoms.
6. The branched reactive polymer of claim 1 , wherein R comprises three carbon atoms.
7. The branched reactive polymer of claim 1 , wherein each POLY is linear or branched.
8. The branched reactive polymer of claim 1 , wherein p is 1 and X is selected from the group consisting of a heteroatom, -alkylene-, —O-alkylene-O—, -alkylene-O-alkylene-, -aryl-O—, —O-aryl-, (—O-alkylene-) m , and (-alkylene-O—) m , wherein m is 1-10.
9. The branched reactive polymer of claim 1 , wherein p is 0.
10. A biologically active conjugate, comprising a biologically active molecule covalently attached to a branched reactive polymer of claim 1 , wherein the biologically active molecule is a biologically active protein.
11. The branched reactive polymer of claim 1 , wherein the branched reactive polymer has a molecular weight of about 5,000 Da to about 60,000 Da.
12. The biologically active conjugate of claim 10 , wherein the biologically active protein is a biologically active fragment of Factor VIII.