Construction of Degradable and Amphiphilic Triblock Polymer Carriers for Effective Delivery of siRNA
Construction of Degradable and Amphiphilic Triblock Polymer Carriers for Effective Delivery of siRNA
复制标题
用于有效递送 siRNA 的可降解和两亲性三嵌段聚合物载体的构建
DOI：
10.1002/mabi.202200232
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发表时间：
2022
影响因子：
4.6
通讯作者：
Qi Shuai
中科院分区：
文献类型：
--
作者：
Yunfeng Yan;Fangtao Zhu;Huahui Su;Xiaomin Liu;Qidi Ren;Fangqian Huang;Wenbo Ye;Mengdan Zhao;Yunchun Zhao;Junpeng Zhao;Qi Shuai
有效和安全的递送载体的开发是基于siRNA的治疗剂临床转化的先决条件之一。在这项研究中，使用开环聚合（ROP）和硫醇-烯点击反应构建了144个功能性三嵌段聚合物的库。这些三嵌段聚合物由亲水性聚（环氧乙烷）（PEO）、疏水性聚（ε-己内酯）（PCL）和阳离子胺嵌段组成。通过对这些聚合物进行高通量筛选，发现了三种有效的载体，用于将siRNA递送至HeLa‐Luc细胞。体外评价显示，用领先的聚合物载体制造的SiLuc负载的纳米颗粒（NP）表现出足够的荧光素酶基因敲低和相对较低的细胞毒性。聚合物的化学结构显著影响所得siRNA负载的NP的物理化学性质，这导致NP的不同细胞摄取和负载的siRNA的内体逃逸，从而导致总体体外siRNA递送功效。在对具有异种移植肿瘤的小鼠进行全身给药后，基于P2 - 4.5A8的siRNA NP基本上在肿瘤部位积累，这表明PEO和PCL阻断剂有利于改善siRNA NP的血液循环和生物分布。这种功能性三嵌段聚合物平台可能在开发用于治疗癌症的基于siRNA的疗法方面具有巨大潜力。
The development of effective and safe delivery carriers is one of the prerequisites for the clinical translation of siRNA‐based therapeutics. In this study, a library of 144 functional triblock polymers using ring‐opening polymerization (ROP) and thiol‐ene click reaction is constructed. These triblock polymers are composed of hydrophilic poly (ethylene oxide) (PEO), hydrophobic poly (ε‐caprolactone) (PCL), and cationic amine blocks. Three effective carriers are discovered by high‐throughput screening of these polymers for siRNA delivery to HeLa‐Luc cells. In vitro evaluation shows that siLuc‐loaded nanoparticles (NPs) fabricated with leading polymer carriers exhibit sufficient knockdown of luciferase genes and relatively low cytotoxicity. The chemical structure of polymers significantly affects the physicochemical properties of the resulting siRNA‐loaded NPs, which leads to different cellular uptake of NPs and endosomal escape of loaded siRNA and thus the overall in vitro siRNA delivery efficacy. After systemic administration to mice with xenograft tumors, siRNA NPs based on P2‐4.5A8 are substantially accumulated at tumor sites, suggesting that PEO and PCL blocks are beneficial for improving blood circulation and biodistribution of siRNA NPs. This functional triblock polymer platform may have great potential in the development of siRNA‐based therapies for the treatment of cancers.