title: Improved bone delivery of osteoprotegerin by bisphosphonate conjugation in a rat model of osteoarthritis.
abstract: This study investigated the delivery of a model therapeutic protein, namely, osteoprotegerin (OPG), to bone sites in an animal model of osteoarthritis. The OPG was chemically conjugated to a "bone seeking" thiol-bisphosphonate (thiolBP) via a disulfide linkage. The BP conjugates of OPG were shown to display a higher hydroxyapatite affinity in vitro as compared to unmodified OPG. After intravenous injection, the bone uptake of OPG-thiolBP conjugate was increased 2-fold over that of control OPG under conditions of normal bone turnover. Furthermore, the retention of the OPG-thiolBP conjugate was significantly higher after 72 h. When administered to osteoarthritic rats undergoing active bone remodeling, the delivery of OPG-thiolBP conjugate to bone was increased more than 4-fold over that of control OPG after 24 h. These results suggest a significant advantage of BP conjugation as a drug delivery strategy for therapeutic cytokines in osteopenic bone diseases.
authors.affiliation: Faculty of Pharmacy & Pharmaceutical Sciences and Department of Chemical & Materials Engineering, University of Alberta, Edmonton, Alberta, Canada. mdoschak@ualberta.ca
authors.forename: Michael R
authors.initials: MR
authors.lastname: Doschak
authors.forename: Cezary M
authors.initials: CM
authors.lastname: Kucharski
authors.forename: Jennifer E I
authors.initials: JE
authors.lastname: Wright
authors.forename: Ronald F
authors.initials: RF
authors.lastname: Zernicke
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludağ
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004164:Diphosphonates / Q000378:metabolism*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D010003:Osteoarthritis / Q000188:drug therapy*; D053244:Osteoprotegerin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D004164:Diphosphonates; D053244:Osteoprotegerin