Polyarginine-Mediated siRNA Delivery: A Mechanistic Study of Intracellular Trafficking of PCL-R15/siRNA Nanoplexes.,Molecular Pharmaceutics

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Polyarginine-Mediated siRNA Delivery: A Mechanistic Study of Intracellular Trafficking of PCL-R15/siRNA Nanoplexes.
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-03-19 , DOI: 10.1021/acs.molpharmaceut.0c00120
Hai-Tao Zhang _{1,

2,

3} , Minzhi Yu ₂ , Yu-Jie Niu ₂ , Wei-Zhong Liu ₂ , Wen-Hao Pang ₂ , Jinsong Ding ₁ , Jian-Cheng Wang ₂

Affiliation

As a cell-penetrating peptide, polyarginine is widely used in drug delivery systems based on its membrane permeation ability. Previously, we developed the mPEG-PLA-b-polyarginine(R15) triblock copolymer, which exhibited a high siRNA delivery efficiency both in vitro and in vivo. As a continued effort, here the amphiphilic diblock polymer PCL-R15 was synthesized as a simplified model to further elucidate the structure-activity relationship of arginine-based amphiphilic polymers as siRNA delivery systems, and the cellular trafficking mechanisms of the PCL-R15/siRNA nanoplexes were investigated to understand the interaction patterns between the nanoplexes and cells. Compared to the R15/siRNA complexes, the introduction of PCL moiety was found to result in the stronger interactions with cells and the enhanced transfection efficiency after the formation of condensed nanoplexes. Caveolae-mediated endocytosis and clathrin-mediated endocytosis were major routes for the internalization of PCL-R15/siRNA nanoplexes. The intracellular release of siRNA from nanoplexes was confirmed by fluorescence resonance energy transfer assay. It was also noticed that the internalized PCL-R15/siRNA nanoplexes were transported through digestive routes and trapped in lysosomes, which may be the bottleneck for efficient siRNA delivery of PCL-R15/siRNA nanoplexes. This study investigated the relationship between the polymer structure of PCL-R15 and the cellular interaction patterns, which may render implications on the rational design of polyarginine-based siRNA delivery systems.

中文翻译：

聚精氨酸介导的siRNA传递：PCL-R15 / siRNA纳米复合物细胞内运输的机制研究。

聚精氨酸作为一种可穿透细胞的肽，基于其膜的渗透能力而广泛用于药物输送系统。以前，我们开发了mPEG-PLA-b-聚精氨酸（R15）三嵌段共聚物，该共聚物在体外和体内均显示出高siRNA递送效率。作为一项持续的工作，此处合成了两亲性二嵌段聚合物PCL-R15作为简化模型，以进一步阐明基于精氨酸的两亲性聚合物作为siRNA传递系统的结构-活性关系，以及PCL-R15 / siRNA的细胞运输机制研究纳米复合物以了解纳米复合物与细胞之间的相互作用模式。与R15 / siRNA复合物相比，在形成浓缩的纳米复合物后，发现引入PCL部分可导致与细胞的相互作用更强，转染效率更高。小窝介导的内吞作用和网格蛋白介导的内吞作用是PCL-R15 / siRNA纳米复合物内在化的主要途径。通过荧光共振能量转移测定法证实了siRNA从纳米复合物中的细胞内释放。还注意到，内化的PCL-R15 / siRNA纳米复合物通过消化途径运输并被困在溶酶体中，这可能是有效siRNA传递PCL-R15 / siRNA纳米复合物的瓶颈。这项研究调查了PCL-R15的聚合物结构与细胞相互作用模式之间的关系，

更新日期：2020-03-19

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