Compositions and methods for controlled localized delivery of bone forming therapeutic agents
The present invention provides compositions and methods for providing controllable local delivery of a therapeutic agent to promote bone formation. In certain embodiments, the invention is used as a treatment for a subject with osteoporosis, bone cancer or bone fracture. The invention provides a therapeutic agent that is tethered to a polymer to form a therapeutic-tethered macromer, where the therapeutic agent is controllably released from the conjugate by degradation of the tether. In certain embodiments, the therapeutic agent is an inhibitor of GSK3β. In certain embodiments, the composition of the invention is specifically targeted to a site in need of bone formation.
1. A composition for controlled local delivery of a therapeutic agent to bone, the composition comprising a therapeutic-tethered macromer comprising a polymer functionalized with a targeting ligand and a therapeutic agent tethered to said polymer, wherein the therapeutic agent promotes bone formation, and wherein the targeting ligand comprises a targeting peptide comprising the amino acid sequence of SEQ ID NO: 1 that specifically binds to tartrate-resistant acid phosphatase (TRAP).
2. The composition of claim 1 , wherein the therapeutic agent is an inhibitor of GSK3β.
3. The composition of claim 1 , wherein the therapeutic agent is selected from the group consisting of a nucleic acid, protein, peptide, small molecule, aptamer, antagonist, and peptidomimetic.
4. The composition of claim 2 , wherein the therapeutic agent is 6-bromoindirubin-3′-oxime (BIO).
5. The composition of claim 1 , wherein the therapeutic agent is tethered to the polymer via at least one degradable tether.
6. The composition of claim 5 , wherein the degradable tether is selected from the group consisting of an ester, a thioester, an orthoester, an amide, an anhydride, a disulfide bond, and a peptide sequence.
7. The composition of claim 1 , wherein the polymer comprises poly(ethylene glycol) (PEG) methacrylate.
8. The composition of claim 1 , wherein the therapeutic agent is controllably released from the therapeutic-tethered macromer at a site in need of bone formation.
9. The composition of claim 1 , wherein the therapeutic-tethered macromer is contained within a hydrogel.
10. The composition of claim 1 , wherein the composition comprises a bone-homed particle comprising the therapeutic-tethered macromer.
11. The composition of claim 10 , wherein the bone-homed particle comprises at least one targeting domain that specifically binds to a target associated with a site in need of bone formation.
12. The composition of claim 11 , wherein the at least one targeting domain is selected from the group consisting of a nucleic acid, peptide, antibody, antibody fragment, inorganic molecule, organic molecule, and combination thereof.
13. The composition of claim 10 , wherein the bone-homed particle comprises at least one monomer that targets the particle to bone.
14. The composition of claim 10 , wherein the bone-homed particle comprises at least one monomer that targets the particle to a resorptive pit.
15. The composition of claim 13 , wherein the monomer is a phosphate-containing monomer.
16. The composition of claim 13 , wherein the monomer is 6-methacryloylxyhexyl dihydrogen phosphate.
17. The composition of claim 14 , wherein the monomer is an acidic amino acid mimetic monomer.
18. The composition of claim 17 , wherein the monomer is selected from the group consisting of methacryalted glutamic acid and methacrylated aspartic acid.
19. The composition of claim 10 , wherein the particle comprises multivalent targeting.
20. The composition of claim 10 , wherein the bone-homed particle is a micelle.
21. The composition of claim 10 , wherein the bone-homed particle is a polymer.
22. The composition of claim 21 , wherein the polymer is a brush polymer.
23. The composition of claim 21 , wherein the polymer is a copolymer.
24. The composition of claim 21 , wherein the polymer comprises one or more monomers that target the polymer to bone.
25. The composition of claim 21 , wherein the polymer comprises one or more monomers that target the polymer to a resorptive pit.