Polysaccharide nanogel delivery of a TNF-α and RANKL antagonist peptide allows systemic prevention of bone loss
Polysaccharide nanogel delivery of a TNF-α and RANKL antagonist peptide allows systemic prevention of bone loss
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DOI：
10.1016/j.ejps.2009.01.002
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发表时间：
2009-05-12
影响因子：
4.6
通讯作者：
Ohya, Keiichi
中科院分区：
文献类型：
--
作者：
Alles, Neil;Soysa, Niroshani S.;Ohya, Keiichi
我们在这里报告了纳米凝胶介导的肽药物传递系统。低稳定性是肽类药物临床应用的主要障碍。W 9-肽是一种TNF-α和RANKL拮抗剂，被用作测试含胆固醇的普鲁兰多糖（CHP）纳米凝胶作为药物递送系统的可行性的模型。我们发现CHP-纳米凝胶可以与W 9-肽形成复合物，并阻止其在体外聚集。采用低钙饮食的小鼠骨吸收模型研究体内作用。每天两次注射24 mg/kg W 9-肽，有或没有CHP-纳米凝胶，持续7天。此后，进行放射学和组织学评估。注射W 9-肽（24 mg/kg）与CHP-纳米凝胶防止了骨矿物质密度的降低，而没有CHP-纳米凝胶的相同剂量不能显示任何抑制作用。骨组织形态计量学分析显示，CHP-W 9复合物治疗组破骨细胞数量和表面积显著减少，尿脱氧吡啶啉水平反映了骨吸收参数的减少。总之，这些数据表明CHP-纳米凝胶作为W 9-肽的合适载体起作用，并且它防止聚集并增加W 9-肽的稳定性。本研究揭示了CHP-纳米凝胶介导的肽递送在体内预防骨吸收的可行性。(C)2009年由Elsevier B. V.出版
We report here a nanogel-mediated peptide drug delivery system. Low stability is a major drawback towards clinical application of peptide drugs. The W9-peptide, a TNF-alpha and RANKL antagonist, was used as a model for testing the feasibility of cholesterol-bearing pullulan (CHP)-nanogel as the drug delivery system. We found CHP-nanogel could form complex with the W9-peptide and prevents its aggregation in vitro. Murine bone resorption model using low dietary calcium was used to investigate the in vivo effect. Two-time-injection of 24 mg/kg W9-peptide per day with or without CHP-nanogel was given for 7 days. Thereafter, radiological, and histological assessments were performed. The injections of the W9-peptide (24 mg/kg) with CHP-nanogel prevented the reduction in bone mineral density whereas the same dose without CHP-nanogel could not show any inhibitory effect. Histomorphometric analysis of tibiae showed significant decrease of osteoclast number and surface in CHP-W9 complex treated group and the levels of urinary deoxypyridinoline reflected these decrease of bone resorption parameters. Taken together these data shows that CHP-nanogel worked as a suitable carrier for the W9-peptide and it prevented aggregation and increased the stability of the W9-peptide. This study reveals the feasibility of CHP-nanogel-mediated peptide delivery in preventing bone resorption in vivo. (C) 2009 Published by Elsevier B.V.