Acid-Sensitive Sheddable PEGylated PLGA Nanoparticles Increase the Delivery of TNF-α siRNA in Chronic Inflammation Sites.
Acid-Sensitive Sheddable PEGylated PLGA Nanoparticles Increase the Delivery of TNF-α siRNA in Chronic Inflammation Sites.
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DOI：
10.1038/mtna.2016.39
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发表时间：
2016-07-19
期刊：
影响因子：
--
通讯作者：
Cui Z
中科院分区：
文献类型：
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作者：
Aldayel AM;Naguib YW;O'Mary HL;Li X;Niu M;Ruwona TB;Cui Z
利用特异性针对促炎细胞因子如肿瘤坏死因子-α（TNF-α）的小干扰RNA（siRNA）治疗慢性炎症的研究越来越受到关注。然而，需要能够在静脉内施用后增加siRNA在慢性炎症部位中的分布的递送系统。在本文中，我们报告了siRNA掺入的聚（乳酸-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。通过标准复乳法制备TNF-α siRNA掺入的PLGA纳米粒，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，其使得（i）纳米粒PEG化和（ii）PEG化在低pH环境（例如在慢性炎症部位）中可脱落。在脂多糖诱导的慢性炎症的小鼠模型中，酸敏感的可脱落的PEG化PLGA纳米颗粒显示出比用酸不敏感的乳化剂制备的PLGA纳米颗粒显著更高的慢性炎症部位中的积累或分布（即，硬脂酰-酰胺-聚乙二醇2000），并显著增加了掺入纳米颗粒中的TNF-α siRNA在发炎小鼠足中的分布。
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.