Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA.
J Control Release. 2012 Aug 20;162(1):102-10. doi: 10.1016/j.jconrel.2012.06.008. Epub 2012 Jun 15.
Effective, low-cost, and safe treatments for sexually transmitted viral infections are urgently needed. Here, we show for the first time that intravaginal administration with nanoparticles of poly(lactic-co-glycolic acid) (PLGA) encapsulating short interfering RNA (siRNA) molecules is effective for prevention of genital HSV-2 infections in mice. PLGA nanoparticles (NPs) were designed to interfere with HSV-2 infection by siRNA-mediated knockdown of nectin, a host cell protein. NPs were characterized in vitro to determine the optimal formulation based on siRNA loading, controlled release profile, and mRNA knockdown. Mice inoculated intravaginally with a lethal dose of HSV-2, and treated with PLGA NPs, showed increased survival from ~9 days (in untreated mice) to >28 days (in PLGA NP treated mice) - the longest survival ever observed with siRNA treatment in this mouse model. This work provides proof-of-concept that topical administration of NPs containing siRNA against a pathologically relevant host cell target can knockdown the gene in tissue and improve survival after HSV-2 infection. Furthermore, this system provides a safe delivery platform that employs materials that are already approved by the FDA and can be modified to enhance delivery of other microbicides.
目前迫切需要有效、廉价且安全的治疗性传播病毒感染的方法。在此，我们首次表明，经阴道给予包裹小干扰 RNA（siRNA）分子的聚乳酸-共-羟基乙酸（PLGA）纳米颗粒可有效预防小鼠的生殖器单纯疱疹病毒 2 型（HSV-2）感染。PLGA 纳米颗粒（NPs）旨在通过 siRNA 介导的下调疱疹病毒进入介体（一种宿主细胞蛋白）来干扰 HSV-2 感染。我们对 NPs 进行了体外表征，以确定最佳配方，包括 siRNA 载量、控制释放曲线和 mRNA 敲低。用致死剂量的 HSV-2 经阴道接种的小鼠，并经 PLGA NPs 治疗，其存活率从约 9 天（未治疗的小鼠）增加到>28 天（PLGA NP 治疗的小鼠）-这是在该小鼠模型中用 siRNA 治疗观察到的最长存活时间。这项工作提供了一个概念验证，证明了针对病理相关宿主细胞靶标的含有 siRNA 的 NPs 的局部给药可以在组织中敲低基因，并改善 HSV-2 感染后的存活。此外，该系统提供了一个安全的递送平台，它采用的材料已经获得 FDA 的批准，并且可以进行修饰以增强其他杀微生物剂的递送。
