Journal
MOLECULAR PHARMACEUTICS
Volume 6, Issue 2, Pages 634-640Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp8002368
Keywords
Osteoprotegerin; bisphosphonate; bone remodeling; osteoarthritis; anterior cruciate ligament; bone targeting
Funding
- Canadian Institutes of Health Research (CIHR)
- Canadian Arthritis Society (TAS)
- Natural Sciences and En-inecrino Research Council (NSERC)
- NSERC Industrial Research
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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.
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