Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA

Chunhui Li; Junhui Zhou; Yidi Wu; Yanliang Dong; Lili Du; Tongren Yang; Yongheng Wang; Shuai Guo; Mengjie Zhang; Abid Hussain; Haihua Xiao; Yuhua Weng; Yong Huang; Xiaoxia Wang; Zicai Liang; Huiqing Cao; Yongxiang Zhao; Xing-Jie Liang; Anjie Dong; Yuanyu Huang

doi:10.1021/acs.nanolett.0c04468

Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA

Nano Lett. 2021 Apr 28;21(8):3680-3689. doi: 10.1021/acs.nanolett.0c04468. Epub 2021 Feb 17.

Authors

Chunhui Li¹, Junhui Zhou², Yidi Wu³, Yanliang Dong², Lili Du³, Tongren Yang¹, Yongheng Wang⁴, Shuai Guo¹, Mengjie Zhang¹, Abid Hussain^{1

5

6}, Haihua Xiao⁴, Yuhua Weng¹, Yong Huang⁷, Xiaoxia Wang³, Zicai Liang^{3

8}, Huiqing Cao³, Yongxiang Zhao⁷, Xing-Jie Liang⁵, Anjie Dong^{2

8}, Yuanyu Huang¹

Affiliations

¹ School of Life Science, Advanced Research Institute of Multidisciplinary Science, Institute of Engineering Medicine, Key Laboratory of Molecular Medicine and Biotherapy, Beijing Institute of Technology, Beijing 100081, China.
² Department of Polymer Science and Technology, School of Chemical Engineering and Technology, Key Laboratory of Systems Bioengineering of the Ministry of Education, Tianjin University, Tianjin 300072, China.
³ Institute of Molecular Medicine, Peking University, Beijing 100871, China.
⁴ Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Polymer Physics and Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
⁵ Chinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China.
⁶ School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
⁷ National Center for International Research of Biological Targeting Diagnosis and Therapy, Guangxi Key Laboratory of Biological Targeting Diagnosis and Therapy Research, Collaborative Innovation Center for Targeting Tumor Diagnosis and Therapy, Nanning, Guangxi 530021, China.
⁸ Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China.

PMID: 33596656
DOI: 10.1021/acs.nanolett.0c04468

Abstract

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.

Keywords: block polymer; cancer immunotherapy; endosomal escape; pH-response; siRNA delivery.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Endosomes*
Gene Silencing
Humans
Hydrophobic and Hydrophilic Interactions
Mice
Polymers*
RNA, Small Interfering / genetics

Substances

Polymers
RNA, Small Interfering