Pharmacokinetic and pharmacodynamic profiles of recombinant human erythropoietin-loaded poly(lactic-co-glycolic acid) microspheres in rats
Pharmacokinetic and pharmacodynamic profiles of recombinant human erythropoietin-loaded poly(lactic-co-glycolic acid) microspheres in rats
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DOI：
10.1038/aps.2011.157
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发表时间：
2012-01-01
影响因子：
8.2
通讯作者：
Jiang, Yang
中科院分区：
文献类型：
--
作者：
Zhou, Xiang-lian;He, Jin-tian;Jiang, Yang
目的：目的：研究重组人促红细胞生成素（rhEPO）聚乳酸-羟基乙酸共聚物（PLGA）微球在大鼠体内的药动学和药效学特征。在雄性Sprague-Dawley大鼠中评价了载rhEPO微球的药代动力学和药效学。ELISA法测定血清rhEPO水平。结果：rhEPO在PLGA微球中的体外释放符合零级释放动力学，释放时间约为30 d。肌肉注射rhEPO（10 000或30 000 IU/kg）后，大鼠血清rhEPO浓度在第1天达到最高水平，随后逐渐下降，并维持在接近稳定的水平约4周。此外，rhEPO从PLGA微球中的释放被发现主要由溶解/扩散机制控制。体外和体内释放数据之间具有良好的线性相关性（R-2=0.98）。单次肌肉注射rhEPO PLGA微球（10 000或30 000 IU/kg）可使大鼠血红蛋白和红细胞浓度升高28 d以上。结论：以PLGA为载体的rhEPO微球具有良好的免疫原性，可持续释放rhEPO约1个月。
Aim: To characterize the pharmacokinetic and pharmacodynamic profiles of the recombinant human erythropoietin (rhEPO)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres in rats.Methods: The rhEPO-loaded microspheres were prepared using a solid-in-oil-in-water emulsion method. Pharmacokinetics and pharmacodynamics of the rhEPO-loaded microspheres were evaluated in male Sprague-Dawley rats. The serum rhEPO level was determined with ELISA. The level of anti-rhEPO antibody in the serum was measured to assess the immunogenicity of rhEPO released from the microspheres.Results: rhEPO was almost completely released from the PLGA microspheres in vitro, following zero-order release kinetics over approximately 30 d. After intramuscular injection (10 000 or 30 000 IU rhEPO/kg) in the rats, the serum rhEPO concentration reached maximum levels on d 1, then decreased gradually and was maintained at nearly steady levels for approximately 4 weeks. Furthermore, the release of rhEPO from the PLGA microspheres was found to be controlled mainly by a dissolution/diffusion mechanism. A good linear correlation (R-2=0.98) was obtained between the in vitro and in vivo release data. A single intramuscular injection of the rhEPO-loaded PLGA microspheres (10 000 or 30 000 IU rhEPO/kg) in the rats resulted in elevated hemoglobin and red blood cell concentrations for more than 28 d. Moreover, the immunogenicity of rhEPO released from the PLGA microspheres was comparable with that of the unencapsulated rhEPO.Conclusion: The results prove the feasibility of using the PLGA-based microspheres to deliver rhEPO for approximately 1 month.