Boosting ferroptosis and microtubule inhibition for antitumor therapy via a carrier-free supermolecule nanoreactor

Min Mu; Xiaoyan Liang; Na Zhao; Di Chuan; Bo Chen; Shasha Zhao; Guoqing Wang; Rangrang Fan; Bingwen Zou; Bo Han; Gang Guo

doi:10.1016/j.jpha.2022.09.003

Boosting ferroptosis and microtubule inhibition for antitumor therapy via a carrier-free supermolecule nanoreactor

J Pharm Anal. 2023 Jan;13(1):99-109. doi: 10.1016/j.jpha.2022.09.003. Epub 2022 Oct 7.

Authors

Min Mu¹, Xiaoyan Liang¹, Na Zhao², Di Chuan¹, Bo Chen¹, Shasha Zhao¹, Guoqing Wang³, Rangrang Fan³, Bingwen Zou⁴, Bo Han², Gang Guo¹

Affiliations

¹ State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
² Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi, Xinjiang, 832002, China.
³ Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, 610041, China.
⁴ Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.

Abstract

Traditional microtubule inhibitors fail to significantly enhance the effect of colorectal cancer; hence, new and efficient strategies are necessary. In this study, a supramolecular nanoreactor (DOC@TA-Fe³⁺) based on tannic acid (TA), iron ion (Fe³⁺), and docetaxel (DOC) with microtubule inhibition, reactive oxygen species (ROS) generation, and glutathione peroxidase 4 (GPX4) inhibition, is prepared for ferroptosis/apoptosis treatment. After internalization by CT26 cells, the DOC@TA-Fe³⁺ nanoreactor escapes from the lysosomes to release payloads. The subsequent Fe³⁺/Fe²⁺ conversion mediated by TA reducibility can trigger the Fenton reaction to enhance the ROS concentration. Additionally, Fe³⁺ can consume glutathione to repress the activity of GPX4 to induce ferroptosis. Meanwhile, the released DOC controls microtubule dynamics to activate the apoptosis pathway. The superior in vivo antitumor efficacy of DOC@TA-Fe³⁺ nanoreactor in terms of tumor growth inhibition and improved survival is verified in CT26 tumor-bearing mouse model. Therefore, the nanoreactor can act as an effective apoptosis and ferroptosis inducer for application in colorectal cancer therapy.

Keywords: Carrier-free nanoreactor; Colorectal cancer; Ferroptosis; Microtubule.