A ferroptosis amplifier based on triple-enhanced lipid peroxides accumulation strategy for effective pancreatic cancer therapy

Mengyao Chen; Xiaohan Tong; Yanting Sun; Chunyan Dong; Chen Li; Chunhui Wang; Minyi Zhang; Yixuan Wen; Pinting Ye; Ruihao Li; Jie Wan; Shujing Liang; Shuo Shi

doi:10.1016/j.biomaterials.2024.122574

A ferroptosis amplifier based on triple-enhanced lipid peroxides accumulation strategy for effective pancreatic cancer therapy

Biomaterials. 2024 Apr 21:309:122574. doi: 10.1016/j.biomaterials.2024.122574. Online ahead of print.

Authors

Mengyao Chen¹, Xiaohan Tong¹, Yanting Sun¹, Chunyan Dong¹, Chen Li¹, Chunhui Wang¹, Minyi Zhang¹, Yixuan Wen¹, Pinting Ye¹, Ruihao Li¹, Jie Wan¹, Shujing Liang², Shuo Shi³

Affiliations

¹ School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China.
² School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China. Electronic address: liangshujing2016@163.com.
³ School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China. Electronic address: shishuo@tongji.edu.cn.

PMID: 38670032
DOI: 10.1016/j.biomaterials.2024.122574

Abstract

As an iron dependent regulatory cell death process driven by excessive lipid peroxides (LPO), ferroptosis is recognized as a powerful weapon for pancreatic cancer (PC) therapy. However, the tumor microenvironment (TME) with hypoxia and elevated glutathione (GSH) expression not only inhibits LPO production, but also induces glutathione peroxidase 4 (GPX4) mediated LPO clearance, which greatly compromise the therapeutic outcomes of ferroptosis. To address these issues, herein, a novel triple-enhanced ferroptosis amplifier (denoted as Zal@HM-PTBC) is rationally designed. After intravenous injection, the overexpressed H₂O₂/GSH in TME induces the collapse of Zal@HM-PTBC and triggers the production of oxygen and reactive oxygen species (ROS), which synergistically amplify the degree of lipid peroxidation (broaden sources). Concurrently, GSH consumption because of the degradation of the hollow manganese dioxide (HM) significantly weakens the activity of GPX4, resulting in a decrease in LPO clearance (reduce expenditure). Moreover, the loading and site-directed release of zalcitabine further promotes autophagy-dependent LPO accumulation (enhance effectiveness). Both in vitro and in vivo results validated that the ferroptosis amplifier demonstrated superior specificity and favorable therapeutic responses. Overall, this triple-enhanced LPO accumulation strategy demonstrates the ability to facilitate the efficacy of ferroptosis, injecting vigorous vitality into the treatment of PC.

Keywords: Ferroptosis amplifier; Lipid peroxides; Pancreatic cancer; Triple-enhanced strategy.