期刊
NANO LETTERS
卷 21, 期 8, 页码 3680-3689出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.nanolett.0c04468
关键词
siRNA delivery; endosomal escape; pH-response; block polymer; cancer immunotherapy
类别
资金
- National Natural Science Foundation of China [31871003, 31901053, 31671021, 31971306]
- Beijing Nova Program from Beijing Municipal Science & Technology Commission [Z201100006820005]
- Beijing-Tianjin-Hebei Basic Research Cooperation Project [19JCZDJC64100]
- Young Elite Scientist Sponsorship Program of Beijing Association for Science and Technology
- Fundamental Research Funds for the Central Universities from Beijing Institute of Technology [2018CX01023]
- Hunan Provincial Natural Science Foundation of China [2018JJ1019, 2019JJ50196]
- Hu-Xiang Young Talent Program [2018RS3094]
- Natural Science Foundation of Guangdong Province [2019A1515010776]
- Postdoctoral Science Foundation of China [2020M670169]
The study synthesized a series of quaternary ammonium-based amphiphilic triblock polymers with a pH-sensitive hydrophobic core that can rapidly release internalized siRNA in endosomal pH environment, leading to enhanced gene silencing activity and significant therapeutic effects in tumor models.
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), mPEG(45)-P(DPA(50)-co-DMAEMA(56))-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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