巴非霉素
内体
化学
共域化
胞浆
生物物理学
细胞生物学
小干扰RNA
基因沉默
转染
基因敲除
生物化学
细胞
生物
酶
基因
细胞凋亡
自噬
作者
Chunhui Li,Jinyun Zhou,Yifan Wu,Yi Dong,Lin Du,Tongren Yang,Yongheng Wang,Shuai Guo,Mengjie Zhang,Abid Hussain,Haihua Xiao,Yuhua Weng,Yong Huang,Xiaoxia Wang,Zicai Liang,Cao H,Yongxiang Zhao,Xing‐Jie Liang,Anjie Dong,Yuanyu Huang
出处
期刊:Nano Letters
[American Chemical Society]
日期:2021-02-17
卷期号:21 (8): 3680-3689
被引量:62
标识
DOI:10.1021/acs.nanolett.0c04468
摘要
Efficient endosomal escape is the most essential but challenging issue for siRNA drug development. Herein, a series of quaternary ammonium-based amphiphilic triblock polymers harnessing an elaborately tailored pH-sensitive hydrophobic core were synthesized and screened. Upon incubating in an endosomal pH environment (pH 6.5–6.8), mPEG45-P(DPA50-co-DMAEMA56)-PT53 (PDDT, the optimized polymer) nanomicelles (PDDT-Ms) and PDDT-Ms/siRNA polyplexes rapidly disassembled, leading to promoted cytosolic release of internalized siRNA and enhanced silencing activity evident from comprehensive analysis of the colocalization and gene silencing using a lysosomotropic agent (chloroquine) and an endosomal trafficking inhibitor (bafilomycin A1). In addition, PDDT-Ms/siPLK1 dramatically repressed tumor growth in both HepG2-xenograft and highly malignant patient-derived xenograft models. PDDT-Ms-armed siPD-L1 efficiently blocked the interaction of PD-L1 and PD-1 and restored immunological surveillance in CT-26-xenograft murine model. PDDT-Ms/siRNA exhibited ideal safety profiles in these assays. This study provides guidelines for rational design and optimization of block polymers for efficient endosomal escape of internalized siRNA and cancer therapy.
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