Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom

1. A polymer conjugate having the structure:

wherein:

B is —(X 3 ) d -(L 3 ) e -(X 4 ) f -POLY 2 -L 4 -Drug or —(X 3 ) d -(L 3 ) e -(X 4 ) f -L 4 -Drug;

each POLY 1 and POLY 2 , which may be the same or different, is a water-soluble, non-peptidic polymer;

each X 1 , X 2 , X 3 , and X 4 , which may be the same or different, is a spacer moiety;

each L 1 , L 2 , L 3 , and L 4 which may be the same or different, are linkages;

Drug is a residue of a biologically active moiety;

Z 3 is L 5 -Drug wherein L 5 is a linkage or Z 3 is selected from a multiarm structure selected from the group consisting of

wherein each m is 1-350, Me is methyl, and each Z is a hydroxyapatite-targeting moiety with the proviso that at least one Z 3 is a multiarm structure;

each a, b, c, d, e, and f, which may be the same or different, is either zero or one;

R is a monomeric or oligomeric multiarm core molecule derived from a molecule comprising at least p+1 sites available for attachment; and

p is an integer in the range of 2-32.

2. The polymer conjugate of claim 1 , wherein each POLY 1 and POLY 2 , when present, has a number average molecular weight of less than about 22,000 Da.

3. The polymer conjugate of claim 2 , wherein each POLY 1 and POLY 2 , when present, has a number average molecular weight of less than about 15,000 Da.

4. The polymer conjugate of claim 3 , wherein each POLY 1 and POLY 2 , when present, has a number average molecular weight of less than about 8,000 Da.

5. The polymer conjugate of claim 1 , wherein each hydroxyapatite-targeting moiety is independently selected from the group consisting of tetracycline, calcein, bisphosphonates, polyaspartic acid, polyglutamic acid, and aminophosphosugars.

6. The polymer conjugate of claim 1 , wherein at least one of L 1 , L 2 , and L 3 is hydrolytically or enzymatically cleavable.

7. The polymer conjugate of claim 1 , wherein one or both of POLY 1 and POLY 2 , when present, have a segmented structure comprising two to about five water-soluble, non-peptidic polymer segments attached through linkages.

8. The polymer of claim 7 , wherein one or both of POLY 1 and POLY 2 , when present, have a structure according to the formula -POLY-L-POLY-, wherein each POLY is a water-soluble, non-peptidic polymer and L is a linkage.

9. The polymer conjugate of claim 1 , wherein each POLY 1 and POLY 2 , when present, are polymers independently selected from the group consisting of poly(alkylene glycols), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(acrylic acid), poly(vinyl alcohol), polyphosphazene, polyoxazoline, poly(N-acryloylmorpholine), and copolymers, terpolymers, or mixtures thereof.

10. The polymer conjugate of claim 1 , wherein each POLY 1 and POLY 2 , when present, is poly(ethylene glycol).

11. The polymer of claim 1 , wherein each POLY 1 and POLY 2 , when present, has the structure —CH 2 CH 2 O(CH 2 CH 2 O) n —CH 2 CH 2 —, where n is 1-350.

12. The polymer of claim 11 , wherein p is 3 to about 10.

13. The polymer of claim 1 , wherein R is derived from a polyol with the structure R 1 (OH) p , wherein R is a branched hydrocarbon, optionally including one or more ether linkages, and p is at least 3.

14. The polymer of claim 13 , wherein the polyol is selected from the group consisting of glycerol, pentaerythritol, and sugar-derived alcohols, and oligomers or polymers of each of the foregoing.

15. The polymer of claim 1 , wherein p is 2 to about 10, and R is derived from a molecule selected from the group consisting of polyols, disulfides, and peptides, and oligomers or polymers of each of the foregoing, and combinations thereof.

16. The polymer of claim 1 , wherein R is derived from a di-peptide or tri-peptide comprising at least one lysine residue.

17. The polymer conjugate of claim 1 , wherein Drug is selected from the group consisting of growth factors, antibiotics, chemotherapeutic agents, and analgesics.

18. The polymer conjugate of claim 17 , wherein Drug is a growth factor selected from the group consisting of fibroblast growth factors, platelet-derived growth factors, bone morphogenic proteins, osteogenic proteins, transforming growth factors, LIM mineralization proteins, osteoid-inducing factors, angiogenins, endothelins; growth differentiation factors, ADMP-1, endothelins, hepatocyte growth factor and keratinocyte growth factor, heparin-binding growth factors, hedgehog proteins, interleukins, colony-stimulating factors, epithelial growth factors, insulin-like growth factors, cytokines, osteopontin, and osteonectin.

19. A polymer conjugate comprising the reaction product of the polymer of the formula

wherein each n is 1-350, with a biologically active agent.

20. The polymer conjugate of claim 19 , wherein the biologically active agent is selected from the group consisting of growth factors, antibiotics, chemotherapeutic agents, and analgesics.

21. The polymer conjugate of claim 20 , wherein the biologically active agent is a growth factor selected from the group consisting of fibroblast growth factors, platelet-derived growth factors, bone morphogenic proteins, osteogenic proteins, transforming growth factors, LIM mineralization proteins, osteoid-inducing factors, angiogenins, endothelins; growth differentiation factors, ADMP-1, endothelins, hepatocyte growth factor and keratinocyte growth factor, heparin-binding growth factors, hedgehog proteins, interleukins, colony-stimulating factors, epithelial growth factors, insulin-like growth factors, cytokines, osteopontin, and osteonectin.