Low molecular weight chitosan based GSH-responsive self-assembled cationic micelle with enhanced anti-tumor effect by combining oxidative damage and chemotherapy

Yuting Yuan; Qiuhong Chen; Zhenhua Wang; Yingqi Mi; Fang Dong; Wenqiang Tan; Zhanyong Guo

doi:10.1016/j.ijbiomac.2024.131736

Low molecular weight chitosan based GSH-responsive self-assembled cationic micelle with enhanced anti-tumor effect by combining oxidative damage and chemotherapy

Int J Biol Macromol. 2024 Apr 21;268(Pt 2):131736. doi: 10.1016/j.ijbiomac.2024.131736. Online ahead of print.

Authors

Yuting Yuan¹, Qiuhong Chen², Zhenhua Wang³, Yingqi Mi², Fang Dong¹, Wenqiang Tan⁴, Zhanyong Guo⁵

Affiliations

¹ Key Laboratory of Coastal Biology and Bioresource Utilization, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China; University of Chinese Academy of Sciences, Beijing 100049, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China.
² Key Laboratory of Coastal Biology and Bioresource Utilization, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China.
³ College of Life Sciences, Yantai University, Yantai 264005, China.
⁴ Key Laboratory of Coastal Biology and Bioresource Utilization, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China; University of Chinese Academy of Sciences, Beijing 100049, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China. Electronic address: wqtan@yic.ac.cn.
⁵ Key Laboratory of Coastal Biology and Bioresource Utilization, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China; University of Chinese Academy of Sciences, Beijing 100049, China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao 266071, China. Electronic address: zhanyongguo@hotmail.com.

PMID: 38653433
DOI: 10.1016/j.ijbiomac.2024.131736

Abstract

A novel cationic lipoic acid grafted low molecular weight chitosan (LCNE-LA) conjugate was constructed and further self-assembled into GSH-responsive cationic nanocarrier to achieve better antitumor effect by combining encapsulated chemotherapy and oxidative damage induced by ROS. The resultant LCNE-LA cationic micelle exhibited favorable physicochemical properties (low CMC, small size, positively zeta potential and good stability), excellent biosafety and desired redox sensitivity. Next, doxorubicin (Dox) was embedded into hydrophobic core to form stable Dox/LCNE-LA micelle that had superior loading capacity. The GSH-induced release behavior, cellular uptake ability, ROS generation and GSH consumption capacity and in vitro antitumor activity of Dox/LCNE-LA micelle were systematically evaluated. Consequently, Dox/LCNE-LA cationic micelle with positively charged could efficiently enter into cancer cell and redox-sensitive release Dox via disulfide-thiol exchange reaction, which usually expend abundant GSH and disrupt redox homeostasis. Studies further confirmed that Dox/LCNE-LA micelle could increase ROS and reduced GSH content which might cause oxidative damage to tumor cell. Antitumor activity indicated that Dox/LCNE-LA micelle achieved an excellent cancer-killing effect, which might be attributed to combination treatment of Dox and ROS induce oxidative damage. Overall, this research was expected to provide a platform for antitumor treatment by triggering Dox release and promoting ROS generation.

Keywords: Amphiphilic conjugate; GSH-responsive cationic micelle; Low molecular weight chitosan.