Role of Polymer Architecture on the Activity of Polymer鈥揚rotein Conjugates for the Treatment of Accelerated Bone Loss Disorders
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- 作者：Bryan S. Tucker ; Jon D. Stewart ; J. Ignacio Aguirre ; L. Shannon Holliday ; C. Adrian Figg ; Jonathan G. Messer ; Brent S. Sumerlin
- 刊名：Biomacromolecules
- 出版年：2015
- 出版时间：August 10, 2015
- 年：2015
- 卷：16
- 期：8
- 页码：2374-2381
- 全文大小：461K
- ISSN：1526-4602
文摘
Polymers of similar molecular weights and chemical constitution but varying in their macromolecular architectures were conjugated to osteoprotegerin (OPG) to determine the effect of polymer topology on protein activity in vitro and in vivo. OPG is a protein that inhibits bone resorption by preventing the formation of mature osteoclasts from the osteoclast precursor cell. Accelerated bone loss disorders, such as osteoporosis, rheumatoid arthritis, and metastatic bone disease, occur as a result of increased osteoclastogenesis, leading to the severe weakening of the bone. OPG has shown promise as a treatment in bone disorders; however, it is rapidly cleared from circulation through rapid liver uptake, and frequent, high doses of the protein are necessary to achieve a therapeutic benefit. We aimed to improve the effectiveness of OPG by creating OPG鈥損olymer bioconjugates, employing reversible addition鈥揻ragmentation chain transfer polymerization to create well-defined polymers with branching densities varying from linear, loosely branched to densely branched. Polymers with each of these architectures were conjugated to OPG using a 鈥済rafting-to鈥?approach, and the bioconjugates were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The OPG鈥損olymer bioconjugates showed retention of activity in vitro against osteoclasts, and each bioconjugate was shown to be nontoxic. Preliminary in vivo studies further supported the nontoxic characteristics of the bioconjugates, and measurement of the bone mineral density in rats 7 days post-treatment via peripheral quantitative computed tomography suggested a slight increase in bone mineral density after administration of the loosely branched OPG鈥損olymer bioconjugate.