Branched polymers and their conjugates

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 water soluble and non-peptide polymer, wherein the molecular weight of each POLY is selected such that the total molecular weight or the branched reactive polymer is independently selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), polysaccharides, poly(α-hydroxy acid), poly(vinyl alcohol), plyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof is at least about 5,000 Da;

X′ is a heteroatom linkage;

X is a linker;

p is 0 or 1;

q is 2 to about 10; and

Y is a functional group reactive with an electrophilic or nucleophilic group.

2. The branched polymer of claim 1 , wherein X′ is —NH—, —O— or —S—.

3. The branched polymer of claim 1 , wherein q is 2 to about 5.

4. The branched polymer of claim 1 , wherein each POLY is symmetrically located on the aliphatic hydrocarbon.

5. The branched polymer of claim 1 , wherein R comprises from 3 to about 7 carbon atoms.

6. The branched polymer of claim 1 , wherein R comprises three carbon atoms.

7. The branched polymer of claim 1 , wherein each POLY and the Y functional group are attached to different carbon atoms of R.

8. The branched polymer of claim 1 , wherein each POLY is covalently attached to -Z wherein Z is a capping group or a functional group.

9. The branched polymer of claim 8 , wherein each Z is a capping group independently selected from the group consisting of alkoxy, alkyl, benzyl, aryl, and aryloxy.

10. The branched polymer of claim 8 , wherein each Z is methoxy.

11. The branched polymer of claim 8 , wherein each Z is a functional group independently selected from the group consisting of hydroxyl, active ester, active carbonate, acetal, aldehyde, aldehyde hydrate, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, hydrazide, thiol, alkanoic acid, acid halide, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxal, dione, mesylate, tosylate, and tresylate.

12. The branched polymer of claim 1 , wherein Y selected from the group consisting of hydroxyl, active ester, active carbonate, acetal, aldehyde, aldehyde hydrate, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, hydrazide, thiol, alkanoic acid, acid halide, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, indoacetamide, epoxide, glyoxal, dione, mesylate, tosylate, and tresylate.

13. The branched polymer claim 1 , wherein each POLY is poly(ethylene glycol).

14. The branched polymer of claim 1 , wherein each POLY is linear or branched.

15. The branched 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.

16. The branched polymer of claim 1 , wherein p is 0 and Y is hydroxyl.

17. The branched polymer of claim 1 , wherein Y has the structure —O-Gp, wherein Gp is a protecting group.

18. The branched polymer of claim 17 , wherein Gp is selected from the group consisting of benzyl, acetal and dihydropyranyl.

19. The branched polymer of claim 1 , having the structure:

20. A biologically active conjugate, comprising a biologically active molecule covalently attached to a branched reactive polymer of claim 1 , wherein X′ is —NH—, —O—, or —S—.

21. A method of preparing a branched poly(alkylene glycol) polymer, comprising:

providing an aliphatic hydrocarbon substituted with at least two nucleophilic groups and at least one protected functional group;

polymerizing alkylene oxide monomer units onto the aliphatic hydrocarbon at the site of the nucleophilic groups to form at least two poly(alkylene glycol) polymers attached to the aliphatic hydrocarbon via heteroatom linkages;

end-capping the poly(alkylene glycol) polymers with an alkyl group to form alkoxy-terminated polymers; and

deprotecting the protected hydroxyl group.

22. The method of claim 21 , wherein the aliphatic hydrocarbon has the structure:

wherein:

X is a linker;

p is 0 or 1; and

Gp is a protecting group.

23. The method of claim 21 , wherein the alkylene oxide monomer units are units of ethylene oxide.

24. The method of claim 21 , wherein said deprotecing step comprises hydrolysis or hydrogenolysis of the protected hydroxyl group.

25. The method of claim 21 , wherein said end-capping step comprises end-capping the polymers with methoxy.

26. The method of claim 21 , wherein the aliphatic hydrocarbon is selected from the group consisting of 2-benzyloxy-1,3-propanediol, 2-benzyloxyethoxy-1,3-propanediol, and 2-benzyloxyethoxyethyl-1,3-propanediol.

27. The method of claim 21 , further comprising converting the deprotected hydroxyl group to a second functional group.

28. The method of claim 27 , wherein the second functional group is selected from the group consisting of active ester, active carbonate, acetal, aldehyde, aldehyde hydrate, alkenyl, acrylate, methacrylate, acrylamide, active sulfone, amine, hydrazide, thiol, alkanoic acid, acid halide, isocyanate, isothiocyanate, maleimide, vinylsulfone, dithiopyridine, vinylpyridine, iodoacetamide, epoxide, glyoxal, dione, mesylate, tosylate, and tresylate.

29. 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 water soluble and non-peptide polymer is independently selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), polysaccharides, poly(α-hydroxy acid), poly(vinyl alcohol), plyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof covalently attached to a methoxy capping group;

X′ is —NH—, —O—, or —S—;

X is a linker;

p is 0 or 1;

q is 2 to about 10; and

Y is a functional group.

30. A branched reactive polymer having the structure:

—HO—R(—X′-POLY) q

wherein:

R is an aliphatic hydrocarbon having a length of at least three carbon atoms;

each POLY is a water soluble and non-peptide polymer is independently selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), polysaccharides, poly(α-hydroxy acid), poly(vinyl alcohol), plyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof;

X′ is —NH—, —O—, or —S—; and

q is 2 to about 10.

31. A biologically active conjugate, comprising a biologically active molecule covalently attached to 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 water soluble and non-peptidic polymer is independently selected from the group consisting of poly(alkylene glycol), poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), polysaccharides, poly(α-hydroxy acid), poly(vinyl alcohol), plyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, and mixtures thereof;

X′ is —NH—, —O—, or —S—;

X is linker ;

p is 0 or 1;

q is 2 to about 10; and

Y is a functional group.

32. The branched polymer of claim 1 , wherein the molecular weight of each POLY is selected such that the total molecular weight of the branched reactive polymer is at least about 5,000 to about 100,000 Da.

33. The branched polymer of claim 1 , wherein the molecular weight of each POLY is selected such that the total molecular weight of the branched reactive polymer is at least about 5,000 to about 60,000 Da.

34. The branched polymer of claim 1 , wherein the molecular weight of each POLY is selected such that the total molecular weight or the branched reactive polymer is at least about 8,000 to about 40,000 Da.

35. The branched polymer of claim 1 , wherein each POLY has a molecular weight of about 2,500 to about 30,000 Da.