Targeting systemically administered proteins to bone by bisphosphonate conjugation.
To develop a methodology for bone-specific delivery of proteins, a bone-seeking aminobisphosphonate (aminoBP) was previously conjugated to a model protein, bovine serum albumin (BSA). The conjugates were shown to exhibit a high affinity to bone in vitro and in vivo. This study was conducted to determine whether the systemic delivery of proteins to bone can be increased by aminoBP conjugation. Two model proteins used for this study were BSA and lysozyme (LYZ). For each protein, an unmodified (i.e., control) and aminoBP-conjugated protein were (125)I-labeled and injected into rats, and the organ delivery of the proteins were determined. Intravenous (IV) injection of aminoBP-BSA resulted in a 2.0- to 3.7-fold increased delivery to bones as compared to the control protein in young rats. In osteopenic, ovariectomized rats, aminoBP conjugation enhanced the bone delivery of BSA by 2.2- to 7.5-fold. A 3.7- to 5.6-fold increased delivery was also observed for LYZ after IV injection in normal rats. In addition to IV route of administration, subcutaneous injection was also effective in delivering a higher amount of aminoBP-conjugated proteins to bone. We conclude that conjugating bone-seeking aminoBPs to proteins improved their delivery to mineralized tissues. The proposed targeting approach has the potential to improve the efficacy of recombinant proteins capable of stimulating bone formation by enhancing their localization to bones.
Uludag
Hasan
H
Department of Chemical and Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, Alberta T6G 2G6, Canada. hasan.uludag@ualberta.ca
Yang
Jennifer
J
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D004164:Diphosphonates / Q000737:chemistry*; D005260:Female; D007275:Injections, Intravenous; D009113:Muramidase / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
D004164:Diphosphonates; D012710:Serum Albumin, Bovine; D009113:Muramidase