谷胱甘肽
癌细胞
葡萄糖氧化酶
癌症治疗
化学
癌症
体内
活性氧
生物化学
细胞内
纳米颗粒
生物物理学
纳米技术
材料科学
生物
医学
酶
内科学
生物传感器
生物技术
作者
Xingyu Fan,Botao Chen,Hui Xu,Anqiang Pan,Shuquan Liang,Songwen Tan,Yongju He
标识
DOI:10.1021/acs.chemmater.2c03612
摘要
Depleting intracellular glutathione (GSH) has emerged as a potent strategy to combat cancer. However, the existing GSH-depleting agents are too toxic or ineffective and standalone GSH depletion fails to yield a satisfactory curative effect. Herein, we present an intelligent nanoparticle that possesses GSH depletion, glucose consumption accompanied with H2O2 production, and NO generation properties for multimodal cancer therapy. The nanoparticle is constructed by synthesis of tetrasulfide bond-doped mesoporous silica nanoparticles followed by conjugating glucose oxidase (GOx) on the surface and loading l-arginine (l-Arg) into the mesopores. In this nanoparticle, the doped tetrasulfide bonds can quickly deplete GSH, which increases the cellular reactive oxygen species concentration to induce ferroptosis and meanwhile triggers particle biodegradation to expose the loaded l-Arg. Moreover, the elevated H2O2 level activates l-Arg to release NO for NO therapy. GOx consumes glucose to initiate starvation therapy and simultaneously produces a large amount of H2O2. Importantly, the produced H2O2 can not only potentiate ferroptosis but also promote NO release to enhance NO therapy. Besides, NO could in turn improve the efficacy of starvation therapy by damaging the mitochondria to block energy supply. In vitro and in vivo studies demonstrate that the nanoparticles show a great synergistic effect of ferroptosis/starvation/NO therapy, which can significantly kill cancer cells and remarkably inhibit tumor growth without obvious side effects. Therefore, we think that the designed nanoparticles may provide a promising paradigm for synergistic cancer therapy and hold a prospect in clinical trials.
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