Lin Huang , Jiaoyang Zhu , Guochao Wu , Wei Xiong , Jie Feng , Chenggong Yan , Jing Yang , Zongheng Li , Qingdeng Fan , Bin Ren , Yan Li , Chaomin Chen , Xiangrong Yu , Zheyu Shen
{"title":"\"火上浇油 \"的策略使铁褐斑病-杯状褐斑病的自我加速循环成为有效的抗肿瘤疗法。","authors":"Lin Huang , Jiaoyang Zhu , Guochao Wu , Wei Xiong , Jie Feng , Chenggong Yan , Jing Yang , Zongheng Li , Qingdeng Fan , Bin Ren , Yan Li , Chaomin Chen , Xiangrong Yu , Zheyu Shen","doi":"10.1016/j.biomaterials.2024.122701","DOIUrl":null,"url":null,"abstract":"<div><p>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) (<em>i.e.</em>, DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, H<sub>2</sub>S, Cu<sup>2+</sup>, and Fe<sup>2+</sup> in the acidic tumor microenvironment (TME). The hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) levels and acidity within tumor cells enhanced by the released H<sub>2</sub>S induce acceleration of Fenton (Fe<sup>2+</sup>) and Fenton-like (Cu<sup>2+</sup>) 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 (<em>i.e.</em>, “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<sup>3+</sup>. 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.</p></div>","PeriodicalId":254,"journal":{"name":"Biomaterials","volume":null,"pages":null},"PeriodicalIF":12.8000,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A strategy of “adding fuel to the flames” enables a self-accelerating cycle of ferroptosis-cuproptosis for potent antitumor therapy\",\"authors\":\"Lin Huang , Jiaoyang Zhu , Guochao Wu , Wei Xiong , Jie Feng , Chenggong Yan , Jing Yang , Zongheng Li , Qingdeng Fan , Bin Ren , Yan Li , Chaomin Chen , Xiangrong Yu , Zheyu Shen\",\"doi\":\"10.1016/j.biomaterials.2024.122701\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>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) (<em>i.e.</em>, DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, H<sub>2</sub>S, Cu<sup>2+</sup>, and Fe<sup>2+</sup> in the acidic tumor microenvironment (TME). The hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) levels and acidity within tumor cells enhanced by the released H<sub>2</sub>S induce acceleration of Fenton (Fe<sup>2+</sup>) and Fenton-like (Cu<sup>2+</sup>) 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 (<em>i.e.</em>, “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<sup>3+</sup>. 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.</p></div>\",\"PeriodicalId\":254,\"journal\":{\"name\":\"Biomaterials\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2024-07-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biomaterials\",\"FirstCategoryId\":\"5\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0142961224002357\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENGINEERING, BIOMEDICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomaterials","FirstCategoryId":"5","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0142961224002357","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENGINEERING, BIOMEDICAL","Score":null,"Total":0}
A strategy of “adding fuel to the flames” enables a self-accelerating cycle of ferroptosis-cuproptosis for potent antitumor therapy
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, H2S, Cu2+, and Fe2+ in the acidic tumor microenvironment (TME). The hydrogen peroxide (H2O2) levels and acidity within tumor cells enhanced by the released H2S induce acceleration of Fenton (Fe2+) and Fenton-like (Cu2+) 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 Fe3+. 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.
期刊介绍:
Biomaterials is an international journal covering the science and clinical application of biomaterials. A biomaterial is now defined as a substance that has been engineered to take a form which, alone or as part of a complex system, is used to direct, by control of interactions with components of living systems, the course of any therapeutic or diagnostic procedure. It is the aim of the journal to provide a peer-reviewed forum for the publication of original papers and authoritative review and opinion papers dealing with the most important issues facing the use of biomaterials in clinical practice. The scope of the journal covers the wide range of physical, biological and chemical sciences that underpin the design of biomaterials and the clinical disciplines in which they are used. These sciences include polymer synthesis and characterization, drug and gene vector design, the biology of the host response, immunology and toxicology and self assembly at the nanoscale. Clinical applications include the therapies of medical technology and regenerative medicine in all clinical disciplines, and diagnostic systems that reply on innovative contrast and sensing agents. The journal is relevant to areas such as cancer diagnosis and therapy, implantable devices, drug delivery systems, gene vectors, bionanotechnology and tissue engineering.