Hydroxyapatite-targeting multiarm polymers and conjugates made therefrom
The present invention provides, among other things, polymeric reagents suitable for reaction with biologically active agents to form conjugates, the polymeric reagents comprising one or more polymer chains and a plurality of hydroxyapatite-targeting moieties, and optionally the reagents include one or more degradable linkages that serve to divide the polymer chains into polymer segments having a molecular weight suitable for renal clearance.
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.