甲基丙烯酸酯
阳离子聚合
基因敲除
聚合物
生物物理学
单体
原子转移自由基聚合
小干扰RNA
聚合
内化
化学
RNA干扰
纳米颗粒
材料科学
组合化学
高分子化学
核糖核酸
纳米技术
生物化学
细胞
有机化学
生物
细胞凋亡
基因
作者
Yunfeng Yan,Guangliang Zhang,Chengfan Wu,Qidi Ren,Xiaomin Liu,Fangqian Huang,Yi Cao,Wenbo Ye
出处
期刊:ACS Biomaterials Science & Engineering
[American Chemical Society]
日期:2022-04-05
卷期号:8 (5): 1964-1974
被引量:3
标识
DOI:10.1021/acsbiomaterials.2c00196
摘要
RNA interference (RNAi) is a promising approach to the treatment of genetic diseases by the specific knockdown of target genes. Functional polymers are potential vehicles for the effective delivery of vulnerable small interfering RNA (siRNA), which is required for the broad application of RNAi-based therapeutics. The development of methods for the facile modulation of chemical structures of polymeric carriers and an elucidation of detailed delivery mechanisms remain important areas of research. In this paper, we synthesized a series of methacrylate-based polymers with controllable structures and narrow distributions by atom transfer radical polymerization using various combinations of cationic monomers (2-dimethylaminoethyl methacrylate, 2-diethylaminoethyl methacrylate, and 2-dibutylaminoethyl methacrylate) and hydrophobic monomers (2-butyl methacrylate (BMA), cyclohexyl methacrylate, and 2-ethylhexyl methacrylate). These polymers exhibited varying hydrophobicities, charge densities, and pKa values, enabling the discovery of effective carriers for siRNA by in vitro delivery assays. For the polymers with BMA segments, 50% of cationic segments were beneficial to the formation of siRNA nanoparticles (NPs) and the in vitro delivery of siRNA. The optimal ratio varied for different combinations of cationic and hydrophobic segments. In particular, 20k PMB 0.5, PME 0.5, and PEB 1.0 showed >75% luciferase knockdown. Efficacious delivery was dependent on high siRNA binding, the small size of NPs, and balanced hydrophobicity and charge density. Cellular uptake and endosomal escape experiments indicated that carboxybetaine modification of 20k PMB 0.5 did not remarkably affect the internalization of corresponding NPs after incubation for 6 h but significantly reduced the endosomal escape of NPs, which leads to the notable decrease in delivery efficacy of polymers. These results provide insights into the mechanism of polymer-based siRNA delivery and may inspire the development of novel polymeric carriers.
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