Programmed-response cross-linked nanocarrier for multidrug-resistant ovarian cancer treatment

Haijing Qu; Jinfan Yang; Shuaijun Li; Ji Xu; Xin Zhou; Xiangdong Xue; Dalin Zhang; Hongxu Du; Yingbin Shen; Mythili Ramachandran; Hongbo Zheng; Yi Wu; Yifan Ding; Hao Wu; Xiaobin Ma; Tzu-Yin Lin; Yuanpei Li

doi:10.1016/j.jconrel.2023.03.031

Programmed-response cross-linked nanocarrier for multidrug-resistant ovarian cancer treatment

J Control Release. 2023 May:357:274-286. doi: 10.1016/j.jconrel.2023.03.031. Epub 2023 Apr 5.

Authors

Haijing Qu¹, Jinfan Yang², Shuaijun Li³, Ji Xu³, Xin Zhou³, Xiangdong Xue⁴, Dalin Zhang⁵, Hongxu Du⁵, Yingbin Shen⁵, Mythili Ramachandran⁵, Hongbo Zheng⁵, Yi Wu⁵, Yifan Ding⁶, Hao Wu⁷, Xiaobin Ma⁸, Tzu-Yin Lin⁹, Yuanpei Li¹⁰

Affiliations

¹ Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA; School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
² Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA; National Demonstration Center for Experimental Light Chemistry Engineering Education (Shaanxi University of Science & Technology), Shaanxi Provincial Key Laboratory of Papermaking Technology and Specialty Paper Development, College of Bioresources Chemical and Materials Engineering, Shaanxi University of Science & Technology, Xi'an 710021, China.
³ Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Department of Biophysics, School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
⁴ Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA; School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
⁵ Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA.
⁶ Department of Biophysics, School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
⁷ Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China; Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA; Department of Biophysics, School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China. Electronic address: lfshwu@xjtu.edu.cn.
⁸ Department of Oncology, The Second Affiliated Hospital, Medical School of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. Electronic address: binbinmxb@sohu.com.
⁹ Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA. Electronic address: tylin@ucdavis.edu.
¹⁰ Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA. Electronic address: lypli@ucdavis.edu.

PMID: 36958401
DOI: 10.1016/j.jconrel.2023.03.031

Abstract

The application of numerous chemotherapeutic drugs has been limited due to poor solubility, adverse side effects, and even multidrug resistance in patients. Polymeric micelles with reversibly cross-linked structures provide a promising solution to these issues. Herein, we optimized and synthesized programable-released disulfide cross-linked micelle (PDCM) based on our previous well-defined dendrimers to deliver the antitumor drug betulinic acid (BA) and paclitaxel (PDCM@PTX) and evaluated the therapeutic efficacy of multidrug-resistant (MDR) simulative orthotopic intraperitoneal ovarian cancer mice models. Comprehensive results demonstrated that PDCM@PTX formed stable nanoparticles able to improve the pharmacokinetic profile and circulation time of PTX, allowing for increased tumor penetration. Furthermore, in the tumor microenvironment, the programable-switches (ester bonds and disulfide cross-linking) of PDCM@PTX were cleaved by the high concentration of glutathione (tumor microenvironment) and esterase (intracellular) present in the tumor, allowing for in situ release of PTX and BA, resulting in intensive therapeutic efficacy in MDR ovarian cancer.

Keywords: Cross-linking; Esterase response; GSH response; Multidrug resistant; Ovarian cancer.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Cell Line, Tumor
Disulfides
Drug Delivery Systems / methods
Drug Resistance, Neoplasm
Female
Humans
Mice
Micelles
Ovarian Neoplasms* / drug therapy
Ovarian Neoplasms* / pathology
Paclitaxel / chemistry
Tumor Microenvironment

Substances

Paclitaxel
Antineoplastic Agents
Micelles
Disulfides