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“火上浇油”策略使铁死亡-铜死亡自加速循环,增强抗肿瘤治疗效果。

A strategy of "adding fuel to the flames" enables a self-accelerating cycle of ferroptosis-cuproptosis for potent antitumor therapy.

机构信息

School of Biomedical Engineering, Southern Medical University, 1023 Sha-Tai South Road, Guangzhou, Guangdong, 510515, China.

Medical Imaging Center, Nanfang Hospital, Southern Medical University, 1023 Sha-Tai South Road, Guangzhou, Guangdong, 510515, China.

出版信息

Biomaterials. 2024 Dec;311:122701. doi: 10.1016/j.biomaterials.2024.122701. Epub 2024 Jul 6.


DOI:10.1016/j.biomaterials.2024.122701
PMID:38981152
Abstract

Cuproptosis in antitumor therapy faces challenges from copper homeostasis efflux mechanisms and high glutathione (GSH) levels in tumor cells, hindering copper accumulation and treatment efficacy. Herein, we propose a strategy of "adding fuel to the flames" for potent antitumor therapy through a self-accelerating cycle of ferroptosis-cuproptosis. Disulfiram (DSF) loaded hollow mesoporous copper-iron sulfide (HMCIS) nanoparticle with conjugation of polyethylene glycol (PEG) and folic acid (FA) (i.e., DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, HS, Cu, and Fe in the acidic tumor microenvironment (TME). The hydrogen peroxide (HO) levels and acidity within tumor cells enhanced by the released HS induce acceleration of Fenton (Fe) and Fenton-like (Cu) reactions, enabling the powerful tumor ferroptosis efficacy. The released DSF acts as a role of "fuel", intensifying catalytic effect ("flame") in tumor cells through the sustainable Fenton chemistry (i.e., "add fuel to the flames"). Robust ferroptosis in tumor cells is characterized by serious mitochondrial damage and GSH depletion, leading to excess intracellular copper that triggers cuproptosis. Cuproptosis disrupts mitochondria, compromises iron-sulfur (Fe-S) proteins, and elevates intracellular oxidative stress by releasing free Fe. These interconnected processes form a self-accelerating cycle of ferroptosis-cuproptosis with potent antitumor capabilities, as validated in both cancer cells and tumor-bearing mice.

摘要

在抗肿瘤治疗中,铜蛋白细胞死亡面临着来自铜稳态外排机制和肿瘤细胞中高谷胱甘肽(GSH)水平的挑战,这阻碍了铜的积累和治疗效果。在此,我们提出了一种通过铁死亡-铜死亡自加速循环进行有力抗肿瘤治疗的策略。我们开发了载有二硫化物(DSF)的中空介孔铜铁硫化物(HMCIS)纳米颗粒,并用聚乙二醇(PEG)和叶酸(FA)进行了连接(即 DSF@HMCIS-PEG-FA),以在酸性肿瘤微环境(TME)中快速释放 DSF、HS、Cu 和 Fe。释放的 HS 增强了肿瘤细胞内的过氧化氢(HO)水平和酸度,加速了 Fenton(Fe)和类 Fenton(Cu)反应,从而实现了强大的肿瘤铁死亡疗效。释放的 DSF 作为“燃料”,通过可持续的 Fenton 化学(即“添加燃料以助燃”)在肿瘤细胞中增强催化作用(“火焰”)。肿瘤细胞中的强烈铁死亡表现为严重的线粒体损伤和 GSH 耗竭,导致过量的细胞内铜引发铜死亡。铜死亡通过释放游离铁破坏线粒体、损害铁硫(Fe-S)蛋白并增加细胞内氧化应激。这些相互关联的过程形成了具有强大抗肿瘤能力的铁死亡-铜死亡自加速循环,在癌细胞和荷瘤小鼠中均得到了验证。

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