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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

77 Citations (Scopus)

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.

Original language	English
Pages (from-to)	3680-3689
Number of pages	10
Journal	Nano Letters
Volume	21
Issue number	8
DOIs	https://doi.org/10.1021/acs.nanolett.0c04468
Publication status	Published - 28 Apr 2021

Keywords

block polymer
cancer immunotherapy
endosomal escape
pH-response
siRNA delivery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1021/acs.nanolett.0c04468

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Li, C., Zhou, J., Wu, Y., Dong, Y., Du, L., Yang, T., Wang, Y., Guo, S., Zhang, M., Hussain, A., Xiao, H., Weng, Y., Huang, Y., Wang, X., Liang, Z., Cao, H., Zhao, Y., Liang, X. J., Dong, A., & Huang, Y. (2021). Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA. Nano Letters, 21(8), 3680-3689. https://doi.org/10.1021/acs.nanolett.0c04468

@article{e52ef3b8f53948b1bd1265b81ee8da0a,

title = "Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA",

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",

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

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year = "2021",

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doi = "10.1021/acs.nanolett.0c04468",

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T1 - Core Role of Hydrophobic Core of Polymeric Nanomicelle in Endosomal Escape of siRNA

AU - Li, Chunhui

AU - Zhou, Junhui

AU - Wu, Yidi

AU - Dong, Yanliang

AU - Du, Lili

AU - Yang, Tongren

AU - Wang, Yongheng

AU - Guo, Shuai

AU - Zhang, Mengjie

AU - Hussain, Abid

AU - Xiao, Haihua

AU - Weng, Yuhua

AU - Huang, Yong

AU - Wang, Xiaoxia

AU - Liang, Zicai

AU - Cao, Huiqing

AU - Zhao, Yongxiang

AU - Liang, Xing Jie

AU - Dong, Anjie

AU - Huang, Yuanyu

PY - 2021/4/28

Y1 - 2021/4/28

N2 - 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.

AB - 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.

KW - block polymer

KW - cancer immunotherapy

KW - endosomal escape

KW - pH-response

KW - siRNA delivery

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SN - 1530-6984

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EP - 3689

JO - Nano Letters

JF - Nano Letters

IS - 8

ER -

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

Abstract

Keywords

UN SDGs

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