Yan Yunfeng, Zhu Fangtao, Su Huahui, Liu Xiaomin, Ren Qidi, Huang Fangqian, Ye Wenbo, Zhao Mengdan, Zhao Yunchun, Zhao Junpeng, Shuai Qi
College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, P. R. China.
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou, Zhejiang, 310014, P. R. China.
Macromol Biosci. 2022 Dec;22(12):e2200232. doi: 10.1002/mabi.202200232. Epub 2022 Sep 17.
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.
开发有效且安全的递送载体是基于小干扰RNA（siRNA）的治疗药物临床转化的前提条件之一。在本研究中，利用开环聚合（ROP）和硫醇-烯点击反应构建了一个包含144种功能性三嵌段聚合物的文库。这些三嵌段聚合物由亲水性聚环氧乙烷（PEO）、疏水性聚己内酯（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，以将siRNA递送至HeLa-Luc细胞，发现了三种有效的载体。体外评估表明，用领先的聚合物载体制备的负载siLuc的纳米颗粒（NPs）对荧光素酶基因具有足够的敲低作用，且细胞毒性相对较低。聚合物的化学结构显著影响所得负载siRNA的NPs的物理化学性质，这导致NPs的不同细胞摄取以及负载的siRNA的内体逃逸，从而影响整体体外siRNA递送效率。将基于P2-4.5A8的siRNA NPs全身给药至患有异种移植肿瘤的小鼠后，其在肿瘤部位大量蓄积，这表明PEO和PCL嵌段有利于改善siRNA NPs的血液循环和生物分布。这种功能性三嵌段聚合物平台在开发用于治疗癌症的基于siRNA的疗法方面可能具有巨大潜力。
