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

Autor: Chen M; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Tong X; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Sun Y; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Dong C; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Li C; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Wang C; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Zhang M; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Wen Y; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Ye P; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Li R; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Wan J; School of Chemical Science and Engineering, Department of Oncology, East Hospital Affiliated to Tongji University, School of Medicine, Tongji University, Shanghai, 200092, PR China., Liang S; 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., Shi S; 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.
Jazyk: angličtina
Zdroj: Biomaterials [Biomaterials] 2024 Sep; Vol. 309, pp. 122574. Date of Electronic Publication: 2024 Apr 21.
DOI: 10.1016/j.biomaterials.2024.122574
Abstrakt: 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 H 2 O 2 /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.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: