Aldayel Abdulaziz M, Naguib Youssef W, O'Mary Hannah L, Li Xu, Niu Mengmeng, Ruwona Tinashe B, Cui Zhengrong
Pharmaceutics Division, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA.
Mol Ther Nucleic Acids. 2016 Jul 19;5(7):e340. doi: 10.1038/mtna.2016.39.
There has been growing interest in utilizing small interfering RNA (siRNA) specific to pro-inflammatory cytokines, such as tumor necrosis factor-α ( TNF-α), in chronic inflammation therapy. However, delivery systems that can increase the distribution of the siRNA in chronic inflammation sites after intravenous administration are needed. Herein we report that innovative functionalization of the surface of siRNA-incorporated poly (lactic-co-glycolic) acid (PLGA) nanoparticles significantly increases the delivery of the siRNA in the chronic inflammation sites in a mouse model. The TNF-α siRNA incorporated PLGA nanoparticles were prepared by the standard double emulsion method, but using stearoyl-hydrazone-polyethylene glycol 2000, a unique acid-sensitive surface active agent, as the emulsifying agent, which renders (i) the nanoparticles PEGylated and (ii) the PEGylation sheddable in low pH environment such as that in chronic inflammation sites. In a mouse model of lipopolysaccharide-induced chronic inflammation, the acid-sensitive sheddable PEGylated PLGA nanoparticles showed significantly higher accumulation or distribution in chronic inflammation sites than PLGA nanoparticles prepared with an acid-insensitive emulsifying agent (i.e., stearoyl-amide-polyethylene glycol 2000) and significantly increased the distribution of the TNF-α siRNA incorporated into the nanoparticles in inflamed mouse foot.
在慢性炎症治疗中，利用针对促炎细胞因子（如肿瘤坏死因子-α，TNF-α）的小干扰RNA（siRNA）的兴趣日益浓厚。然而，需要一种能够在静脉给药后增加siRNA在慢性炎症部位分布的递送系统。在此，我们报告，掺入siRNA的聚（乳酸-共-乙醇酸）（PLGA）纳米颗粒表面的创新功能化显著增加了siRNA在小鼠模型慢性炎症部位的递送。掺入TNF-α siRNA的PLGA纳米颗粒通过标准双乳液法制备，但使用硬脂酰腙-聚乙二醇2000（一种独特的酸敏感表面活性剂）作为乳化剂，这使得（i）纳米颗粒聚乙二醇化，以及（ii）聚乙二醇化在低pH环境（如慢性炎症部位的环境）中可脱落。在脂多糖诱导的慢性炎症小鼠模型中，酸敏感可脱落聚乙二醇化PLGA纳米颗粒在慢性炎症部位的积累或分布显著高于用酸不敏感乳化剂（即硬脂酰酰胺-聚乙二醇2000）制备的PLGA纳米颗粒，并显著增加了掺入纳米颗粒的TNF-α siRNA在发炎小鼠足部的分布。
