Targeting anabolic drugs for accelerated fracture repair

Abstract

Aspects of the disclosure include materials and methods for the targeted delivery of growth factors, and other compounds that stimulate bone growth and in some aspect bone healing. Some aspects of the disclosure include methods for synthesizing and testing these compounds. Some aspects of the invention include methods of using the compounds disclosed herein to treat bone fractures and bone defects.

1 - 19 . (canceled) 
     
     
         20 . A compound having a structure of:
   X-Y-Z   wherein:
 X is an extracellular matrix component, a fragment of an extracellular matrix component, or an agent that activates an extracellular matrix component; 
 Y is absent or a linker; and 
 Z is a bone-targeting molecule; 
   or a pharmaceutically acceptable salt thereof.   
     
     
         21 . The compound of  claim 20 , wherein Z comprises a polypeptide. 
     
     
         22 . The compound of  claim 20 , wherein Z comprises not less than 4 and not more than 40 amino acid residues. 
     
     
         23 . The compound of  claim 22 , wherein at least one amino acid is aspartic acid or glutamic acid. 
     
     
         24 . The compound of  claim 20 , wherein Z comprises not less than 6 and not more than 20 D-glutamic acid residues. 
     
     
         25 . The compound of  claim 24 , wherein Z is 10 D-glutamic acid residues. 
     
     
         26 . The compound of  claim 20 , wherein Z comprises not less than 6 and not more than 20 D-aspartic acid residues. 
     
     
         27 . The compound of  claim 26 , wherein Z is 10 D-aspartic acid residues. 
     
     
         28 . The compound of  claim 20 , wherein Y is a releasable linker or a non-releasable linker. 
     
     
         29 . The compound of  claim 28 , wherein the releasable linker comprises at least one releasable linker group, each releasable linker group being independently selected from the group consisting of a disulfide (S-S), an ester, and a protease-specific amide bond. 
     
     
         30 . The compound of  claim 28 , wherein the non-releasable linker comprises at least one non-releasable linker group, each non-releasable linker group being independently selected from the group consisting of a carbon-carbon bond and an amide. 
     
     
         31 . The compound of  claim 28 , wherein Y comprises one or more ethylene glycol units. 
     
     
         32 . The compound of  claim 31 , wherein Y comprises 2-8 oxyethylene units. 
     
     
         33 . The compound of  claim 20 , wherein the extracellular matrix component is selected from the group consisting of a laminin, a fibronectin, and an osteopontin fragment. 
     
     
         34 . The compound of  claim 33 , wherein the laminin is selected from the group consisting of a laminin fragment (IKVAV) and Ln2-P3. 
     
     
         35 . The compound of  claim 33 , wherein the fibronectin is selected from the group consisting of PHSRN and ITGA. 
     
     
         36 . The compound of  claim 33 , wherein the osteopontin fragment is selected from the group consisting of a collagen binding motif, a osteopontin derived peptide, and a collagen binding domain. 
     
     
         37 . The compound of  claim 20 , wherein the agent that activates the extracellular matrix component is an integrin ligand. 
     
     
         38 . The compound of  claim 37 , wherein the integrin ligand is selected from the group consisting of ITGaS cys, ITGA stb-KD, ITGA stb-KE, ITGA stb-DAPE, and ITGA stb-DAPD. 
     
     
         39 . The compound of  claim 20 , wherein the extracellular matrix component is selected from the group consisting of chemotatic collagen (CTC), P15, and DGEA.