Targeting anabolic drugs for accelerated fracture repair

Abstract

The targeted delivery of growth factors, vasoactive peptides and other representative anabolic peptide drugs from different signaling cascades to bone fracture for accelerated healing is disclosed herein.

1 - 21 . (canceled) 
     
     
         22 . A compound having a structure of:
   X-Y-Z   wherein:   X is a growth factor, a growth factor fragment, an agent that activates a growth factor receptor, or an agent that activates a mitogen-activated protein kinase (MAPK) pathway;   Y is absent or a linker; and   Z is a bone-targeting molecule,   or a pharmaceutically acceptable salt thereof.   
     
     
         23 . The compound of  claim 22 , wherein Z comprises a polypeptide. 
     
     
         24 . The compound of  claim 22 , wherein Z comprises not less than 4 and not more than 40 amino acid residues. 
     
     
         25 . The compound of  claim 24 , wherein at least one amino acid is aspartic acid or glutamic acid. 
     
     
         26 . The compound of  claim 22 , wherein Z comprises not less than 6 and not more than 20 glutamic acid residues or not less than 6 and not more than 20 aspartic acid residues. 
     
     
         27 . The compound of  claim 22 , wherein Z is 10 D-glutamic acid residues or 10 D-aspartic acid residues. 
     
     
         28 . The compound of  claim 22 , 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, an ether, and an amide. 
     
     
         31 . The compound of  claim 28 , wherein Y comprises one or more ethylene glycol unit. 
     
     
         32 . The compound of  claim 31 , wherein Y comprises 2-8 oxyethylene units. 
     
     
         33 . The compound of  claim 22 , wherein the growth factor is a bone morphogenic protein (BMP), an insulin like growth factor (IGF), or a fibroblast growth factor. 
     
     
         34 . The compound of  claim 33 , wherein the BMP is selected from the group consisting of P4 (BMP2), BFP (BMP7), pBMP9 (BMP9), and B2A (BMP2/TGF beta). 
     
     
         35 . The compound of  claim 33 , wherein the IGF is selected from the group consisting of preptin (IGF-II) and mechano growth factor (MGF) (IGF-1). 
     
     
         36 . The compound of  claim 33 , wherein the fibroblast growth factor is selected from the group consisting of fibroblast growth factor 2 (F119) and F2A. 
     
     
         37 . The compound of  claim 22 , wherein the growth factor fragment is lactoferrin or ghrelin. 
     
     
         38 . The compound of  claim 37 , wherein the agent that activates the MAPK pathway is a c-Jun N-terminal kinase 3 (JNK3) agonist. 
     
     
         39 . The compound of  claim 38 , wherein the JNK3 agonist is selected from the group consisting of JNK3 and Annexin 1. 
     
     
         40 . A compound having a structure of:
   X-Y-Z   wherein:   X is a vasoactive compound or an angiogenic compound;   Y is absent or a linker; and   Z is a bone-targeting molecule,   or a pharmaceutically acceptable salt thereof.   
     
     
         41 . The compound of  claim 40 , wherein the vasoactive compound or the angiogenic compound is selected from the group consisting of C-type natriuretic peptide (CNP), thrombin peptide (TP508), vascular endothelial growth factor (VEGF) mimetic QK, and platelet derived growth factor 2A (P2A).