Inserm, U 844, INM, Hôpital Saint Eloi, Montpellier, France.
Eur J Pharm Biopharm. 2012 Nov;82(3):457-64. doi: 10.1016/j.ejpb.2012.07.021. Epub 2012 Aug 16.
The aim of this study was to investigate potentialities of poly(dl-lactide-co-glycolide) (PLGA) microspheres for the delivery of small interfering RNAs (siRNAs) against tumor necrosis factor α (TNF-α) to achieve prolonged and efficient inhibition of TNF-α for the treatment of rheumatoid arthritis (RA). PLGA microspheres were prepared by a modified multiple emulsion-solvent evaporation method. The formulations were characterized in terms of morphology, mean diameter and siRNAs distribution, encapsulation efficiency, and in vitro release kinetics. The efficiency of this system was then evaluated both in vitro and in vivo using the murine monocytic cell line J774 and a pre-clinical model of RA, respectively. siRNA-encapsulating PLGA microspheres were characterized by a high encapsulation efficiency and a slow and prolonged anti-TNF-α siRNAs. Our results provide evidence that, upon intra-articular administration, PLGA microspheres slowly releasing siRNAs effectively inhibited the expression of TNF-α in arthritic joints. Our system might represent an alternative strategy for the design of novel anti-rheumatic therapies based on the use of RNA interference in RA.
本研究旨在探讨聚（DL-丙交酯-共-乙交酯）（PLGA）微球在递送针对肿瘤坏死因子-α（TNF-α）的小干扰 RNA（siRNA）方面的潜力，以实现对 TNF-α 的长效和高效抑制，从而治疗类风湿关节炎（RA）。PLGA 微球通过改良的复乳-溶剂蒸发法制备。通过形态、平均粒径和 siRNA 分布、包封效率以及体外释放动力学对制剂进行了表征。然后，分别使用小鼠单核细胞系 J774 和 RA 的临床前模型，在体外和体内评估了该系统的效果。包载 siRNA 的 PLGA 微球具有高包封效率和缓慢而持久的抗 TNF-α siRNA 释放特性。我们的结果表明，关节内给予 PLGA 微球后，可缓慢释放 siRNA，从而有效抑制关节炎关节中 TNF-α 的表达。我们的系统可能为基于 RNA 干扰在 RA 中的应用而设计新型抗风湿疗法提供了一种替代策略。
