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基于谷胱甘肽耗竭和增强活性氧生成的纳米催化诊疗一体化用于高效癌症治疗。

Nanocatalytic Theranostics with Glutathione Depletion and Enhanced Reactive Oxygen Species Generation for Efficient Cancer Therapy.

机构信息

Marshall Laboratory of Biomedical Engineering, International Cancer Center, Laboratory of Evolutionary Theranostics (LET), School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518060, China.

出版信息

Adv Mater. 2021 Feb;33(7):e2006892. doi: 10.1002/adma.202006892. Epub 2021 Jan 4.

Abstract

Chemodynamic therapy (CDT) is an emerging therapy method that kills cancer cells by converting intracellular hydrogen peroxide (H O ) into highly toxic hydroxyl radicals ( OH). To overcome the current limitations of the insufficient endogenous H O and the high concentration of glutathione (GSH) in tumor cells, an intelligent nanocatalytic theranostics (denoted as PGC-DOX) that possesses both H O self-supply and GSH-elimination properties for efficient cancer therapy is presented. This nanoplatform is constructed by a facile one-step biomineralization method using poly(ethylene glycol)-modified glucose oxidase (GOx) as a template to form biodegradable copper-doped calcium phosphate nanoparticles, followed by the loading of doxorubicin (DOX). As an enzyme catalyst, GOx can effectively catalyze intracellular glucose to generate H O , which not only starves the tumor cells, but also supplies H O for subsequent Fenton-like reaction. Meanwhile, the redox reaction between the released Cu ions and intracellular GSH will induce GSH depletion and reduce Cu to Fenton agent Cu ions, and then trigger the H O to generate OH by a Cu -mediated Fenton-like reaction, resulting in enhanced CDT efficacy. The integration of GOx-mediated starvation therapy, H O self-supply and GSH-elimination enhanced CDT, and DOX-induced chemotherapy, endow the PGC-DOX with effective tumor growth inhibition with minimal side effects in vivo.

摘要

化学动力学疗法(CDT)是一种通过将细胞内过氧化氢(H 2 O 2 )转化为高毒性羟基自由基(OH)来杀死癌细胞的新兴治疗方法。为了克服目前内源性 H 2 O 2 不足和肿瘤细胞中谷胱甘肽(GSH)浓度过高的限制,提出了一种智能纳米催化治疗系统(记为 PGC-DOX),该系统具有 H 2 O 2 自供应和 GSH 消除特性,可实现高效的癌症治疗。该纳米平台是通过使用聚乙二醇(PEG)修饰的葡萄糖氧化酶(GOx)作为模板的简便一步生物矿化方法构建的,以形成可生物降解的铜掺杂磷酸钙纳米颗粒,然后负载阿霉素(DOX)。作为酶催化剂,GOx 可有效催化细胞内葡萄糖生成 H 2 O 2 ,不仅使肿瘤细胞饥饿,还为随后的芬顿样反应提供 H 2 O 2 。同时,释放的 Cu 离子与细胞内 GSH 之间的氧化还原反应会诱导 GSH 耗竭并将 Cu 还原为芬顿试剂 Cu 离子,然后通过 Cu 介导的芬顿样反应触发 H 2 O 2 生成 OH ,从而增强 CDT 疗效。GOx 介导的饥饿疗法、H 2 O 2 自供应和 GSH 消除增强 CDT 以及 DOX 诱导的化疗的结合,使 PGC-DOX 具有有效的肿瘤生长抑制作用,体内副作用最小。

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