GSH-responsive degradable nanodrug for glucose metabolism intervention and induction of ferroptosis to enhance magnetothermal anti-tumor therapy

作者全名："Liao, Zhen; Wen, E.; Feng, Yi"

作者地址："[Liao, Zhen] Univ Elect Sci & Technol China, Sch Life Sci & Technol, Dept Biomed Engn, Chengdu 61173, Sichuan, Peoples R China; [Feng, Yi] Third Mil Med Univ, Army Med Univ, Southwest Hosp, Inst Burn Res, Chongqing 400038, Peoples R China; [Wen, E.] Chongqing Med Univ, Affiliated Hosp 2, Precis Med Ctr, Chongqing, Peoples R China"

通信作者："Feng, Y (通讯作者)，Third Mil Med Univ, Army Med Univ, Southwest Hosp, Inst Burn Res, Chongqing 400038, Peoples R China."

来源：JOURNAL OF NANOBIOTECHNOLOGY

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001197033600002

JCR分区：Q1

影响因子：10.6

年份：2024

卷号：22

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Magnetothermal therapy; Ferroptosis; Metabolic interference; Redox homeostasis; Mesoporous silica nanoparticle

摘要："The challenges associated with activating ferroptosis for cancer therapy primarily arise from obstacles related to redox and iron homeostasis, which hinder the susceptibility of tumor cells to ferroptosis. However, the specific mechanisms of ferroptosis resistance, especially those intertwined with abnormal metabolic processes within tumor cells, have been consistently underestimated. In response, we present an innovative glutathione-responsive magnetocaloric therapy nanodrug termed LFMP. LFMP consists of lonidamine (LND) loaded into PEG-modified magnetic nanoparticles with a Fe3O4 core and coated with disulfide bonds-bridged mesoporous silica shells. This nanodrug is designed to induce an accelerated ferroptosis-activating state in tumor cells by disrupting homeostasis. Under the dual effects of alternating magnetic fields and high concentrations of glutathione in the tumor microenvironment, LFMP undergoes disintegration, releasing drugs. LND intervenes in cell metabolism by inhibiting glycolysis, ultimately enhancing iron death and leading to synthetic glutathione consumption. The disulfide bonds play a pivotal role in disrupting intracellular redox homeostasis by depleting glutathione and inactivating glutathione peroxidase 4 (GPX4), synergizing with LND to enhance the sensitivity of tumor cells to ferroptosis. This process intensifies oxidative stress, further impairing redox homeostasis. Furthermore, LFMP exacerbates mitochondrial dysfunction, triggering ROS formation and lactate buildup in cancer cells, resulting in increased acidity and subsequent tumor cell death. Importantly, LFMP significantly suppresses tumor cell proliferation with minimal side effects both in vitro and in vivo, exhibiting satisfactory T2-weighted MR imaging properties. In conclusion, this magnetic hyperthermia-based nanomedicine strategy presents a promising and innovative approach for antitumor therapy."

基金机构："Chongqing Natural Science Foundation for postdoctoral [2023M734260, 2023TQ0147, GZC20233608]; China Postdoctoral Science Foundation [CSTB2023NSCQ-BHX0028, CSTB2023NSCQ-BHX0205]; Chongqing Natural Science Foundation"

基金资助正文："This research was supported, in part or in whole, by the China Postdoctoral Science Foundation (Grant No. 2023M734260, Grant No. 2023TQ0147, Grant No. GZC20233608), and the Chongqing Natural Science Foundation for postdoctoral (Grant No. CSTB2023NSCQ-BHX0028, Grant No. CSTB2023NSCQ-BHX0205)"