A redox-responsive nanosystem to suppress chemoresistant lung cancer through targeting STAT3

Qiyi Feng; Jie Chen; Jinxing Huang; Xiaojie Li; Xinyi Liu; Chunxiu Xiao; Xiuli Zheng; Xuanming Chen; Jue Li; Zhongwei Gu; Kui Luo; Kai Xiao; Weimin Li

doi:10.1016/j.jconrel.2023.09.044

A redox-responsive nanosystem to suppress chemoresistant lung cancer through targeting STAT3

J Control Release. 2023 Nov:363:349-360. doi: 10.1016/j.jconrel.2023.09.044. Epub 2023 Sep 28.

Authors

Qiyi Feng¹, Jie Chen¹, Jinxing Huang¹, Xiaojie Li¹, Xinyi Liu¹, Chunxiu Xiao¹, Xiuli Zheng², Xuanming Chen¹, Jue Li¹, Zhongwei Gu², Kui Luo³, Kai Xiao⁴, Weimin Li⁵

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Precision Medicine Center, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, Department of Respiratory Medicine, and Department of Radiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
² Department of Pulmonary and Critical Care Medicine, Precision Medicine Center, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, Department of Respiratory Medicine, and Department of Radiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Sichuan Provincial Key Laboratory of Precision Medicine, Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China.
³ Department of Pulmonary and Critical Care Medicine, Precision Medicine Center, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, Department of Respiratory Medicine, and Department of Radiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Sichuan Provincial Key Laboratory of Precision Medicine, Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China. Electronic address: luokui@scu.edu.cn.
⁴ Department of Pulmonary and Critical Care Medicine, Precision Medicine Center, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, Department of Respiratory Medicine, and Department of Radiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Sichuan Provincial Key Laboratory of Precision Medicine, Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China. Electronic address: xiaokaikaixiao@scu.edu.cn.
⁵ Department of Pulmonary and Critical Care Medicine, Precision Medicine Center, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, Department of Respiratory Medicine, and Department of Radiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Sichuan Provincial Key Laboratory of Precision Medicine, Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China. Electronic address: weimi003@scu.edu.cn.

PMID: 37748583
DOI: 10.1016/j.jconrel.2023.09.044

Abstract

Cancer stem cells (CSCs) have been demonstrated to be involved in tumor initiation and relapse, and the presence of CSCs in the tumor tissue often leads to therapeutic failure. BBI608 has been identified to eliminate CSCs by inhibiting signal transducer and activator of transcription 3 (STAT3). In this study, we confirm that BBI608 can efficiently suppress the proliferation and migration of non-small cell lung cancer (NSCLC) cells, and specifically kill the stemness-high population in chemoresistant NSCLC cells. To improve its bioavailability and tumor accumulation, BBI608 is successfully encapsulated into redox-responsive PEGylated branched N-(2-hydroxypropyl) methacrylamide (HPMA)-deoxy cholic acid (DA) polymeric nanoparticles (BBI608-SS-NPs). The BBI608-SS-NPs can release the drug in response to high concentrations of intracellular glutathione, and exhibit cytotoxicity against lung cancer cells and CSCs comparable to the free drug BBI608. Furthermore, the BBI608-SS-NPs preferentially accumulate in tumor sites, resulting in a superior anti-tumor efficacy in both cisplatin-resistant cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of NSCLC. Mechanistic studies demonstrate that BBI608-SS-NPs not only directly inhibit the downstream genes of the STAT3 pathway, but also indirectly inhibit the Wnt pathway. Overall, this stimuli-responsive polymeric nanoformulation of BBI608 shows great potential in the treatment of chemoresistant NSCLC by targeting CSCs.

Keywords: Drug delivery; Drug resistance; Non-small cell lung cancer; Patient-derived xenograft; STAT3; Stimuli-responsive polymer.

Publication types

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

MeSH terms

Carcinoma, Non-Small-Cell Lung* / metabolism
Cell Line, Tumor
Cell Proliferation
Humans
Lung Neoplasms* / pathology
Neoplastic Stem Cells / metabolism
Oxidation-Reduction
STAT3 Transcription Factor / metabolism

Substances

napabucasin
STAT3 Transcription Factor
STAT3 protein, human