Improved Bone Delivery of Osteoprotegerin by Bisphosphonate Conjugation in a Rat Model of Osteoarthritis
Improved Bone Delivery of Osteoprotegerin by Bisphosphonate Conjugation in a Rat Model of Osteoarthritis
复制标题
DOI：
10.1021/mp8002368
复制
发表时间：
2009-03-01
影响因子：
4.9
通讯作者：
Uludag, Hasan
中科院分区：
文献类型：
--
作者：
Doschak, Michael R.;Kucharski, Cezary M.;Uludag, Hasan
本研究调查了模型治疗蛋白质，即骨保护素（OPG），骨关节炎的动物模型中的骨部位的交付。OPG通过二硫键与"趋骨"巯基双膦酸盐（thiolBP）化学偶联。与未修饰的OPG相比，OPG的BP缀合物显示出体外更高的羟基磷灰石亲和力。静脉注射后，在正常骨转换条件下，OPG-thiolBP结合物的骨摄取比对照OPG增加2倍。此外，72 h后OPG-thiolBP结合物的保留率显著更高。当给予骨关节炎大鼠进行积极的骨重建时，24小时后，OPG-thiolBP结合物向骨的递送比对照OPG增加4倍以上。这些结果表明BP缀合作为骨质疏松性骨疾病中治疗性细胞因子的药物递送策略的显著优势。
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.