Fracture targeted bone regeneration through parathyroid hormone receptor stimulation

Abstract

Disclosed herein includes a drug delivery system comprising at least one peptide and a targeting ligand for bone fracture and/or for bone healing. Some embodiments include a peptide delivery system comprising at least an acidic, basic, hydrophilic, hydrophobic or neutral peptide linked to an acidic peptide or nonpeptidic polyanion for use in targeting the aforementioned attached peptide to a bone fracture surface. In some embodiments, a conjugated peptide expresses an anabolic function that acts through PTH receptor 1, and various formats of targeting ligands guide the drug to raw hydroxyapatite. This system offsets some side effects caused by free anabolic drug, such as high blood calcium concentration

1 . A compound having a structure of:
   X—Y—Z
   wherein:   Z is a peptide consisting essentially of glutamic acid residues, aspartic acid residues, or a combination thereof, the peptide having not less than 6 and not more than 40 amino acid residues;
 Y is a linker; and 
 X is a bone anabolic agent, 
   or a pharmaceutically acceptable salt thereof.   
     
     
         2 . The compound of  claim 1 , wherein Z is charged. 
     
     
         3 . The compound of  claim 1 , wherein Z comprises not less than 6 and not more than 35 glutamic acid residues. 
     
     
         4 . The compound of  claim 1 , wherein Z comprises not less than 6 and not more than 35 aspartic acid residues. 
     
     
         5 . The compound of  claim 1 , wherein Y is a non-releasable linker. 
     
     
         6 . The compound of  claim 1 , wherein Y is a releasable linker. 
     
     
         7 . The compound of  claim 1 , wherein Y comprises a polypeptide. 
     
     
         8 . The compound of  claim 1 , wherein X is an agonist of parathyroid hormone receptor 1 (PTHR1). 
     
     
         9 . The compound of  claim 1 , wherein X is a bone anabolic peptide or fragment thereof. 
     
     
         10 . The compound of  claim 1 , wherein X is a hydrophilic peptide, a hydrophobic peptide, a neutral peptide, a cationic peptide, an anionic peptide, or any combination thereof. 
     
     
         11 . The compound of  claim 1 , wherein X comprises 10 to 70 amino acid residues. 
     
     
         12 . The compound of  claim 1 , wherein X is selected from the group consisting of: at least one polypeptide having at least 80% sequence identity to a full length parathyroid hormone related peptide (SEQ ID NO: 12), at least one polypeptide having at least 80% sequence identity to a full length parathyroid hormone (SEQ ID NO: 13), and at least one polypeptide having at least 80% identity to a full length abaloparatide (SEQ ID NO: 3). 
     
     
         13 . A method of treating a bone fracture, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound having a structure of:
   X—Y—Z
   wherein:
 Z is a peptide consisting essentially of glutamic acid residues, aspartic acid residues, or a combination thereof, the peptide having not less than 6 and not more than 40 amino acid residues; 
 Y is a linker; and 
 X is a bone anabolic agent, 
   or a pharmaceutically acceptable salt thereof.   
     
     
         14 . The method of  claim 13 , wherein Y is a releasable linker or a non-releasable linker. 
     
     
         15 . The method of  claim 13 , wherein X is an agonist of parathyroid hormone receptor 1 (PTHR1). 
     
     
         16 . The method of  claim 13 , wherein the compound, or a pharmaceutically acceptable salt thereof, is administered to the patient in need thereof orally, parenterally, rectally, or transdermally. 
     
     
         17 . The method of  claim 16 , wherein the compound, or a pharmaceutically acceptable salt thereof, is subcutaneously administered to the patient in need thereof. 
     
     
         18 . The method of  claim 13 , wherein the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, provides a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, to the bone fracture of the patient in need thereof. 
     
     
         19 . The method of  claim 13 , wherein the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, provides a therapeutically effective amount of the bone anabolic agent to the bone fracture of the patient in need thereof. 
     
     
         20 . The method of  claim 13 , wherein the therapeutically effective amount of the compound, or a pharmaceutically acceptable salt thereof, is from about 0.01 nmol/kg/day to about 100 nmol/kg/day.