Multienzyme-like Reactivity Cooperatively Impairs Glutathione Peroxidase 4 and Ferroptosis Suppressor Protein 1 Pathways in Triple-Negative Breast Cancer for Sensitized Ferroptosis Therapy
Multienzyme-like Reactivity Cooperatively Impairs Glutathione Peroxidase 4 and Ferroptosis Suppressor Protein 1 Pathways in Triple-Negative Breast Cancer for Sensitized Ferroptosis Therapy
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DOI：
10.1021/acsnano.1c08664
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发表时间：
2022-01-18
期刊：
影响因子：
17.1
通讯作者：
Cai, Kaiyong
中科院分区：
文献类型：
--
作者：
Li, Ke;Lin, Chuanchuan;Cai, Kaiyong
铁凋亡是最近发现的一种调节性细胞死亡途径，为化疗耐药肿瘤适应症的治疗提供了机会，但其疗效可能受到谷胱甘肽过氧化物酶4（GPX 4）和铁凋亡抑制蛋白1（FSPI）抗氧化机制的影响，为其临床转化带来了重大挑战。在这项研究中，我们报告了一个铜-四（4-羧基苯基）卟啉氯化物（Fe（III））（Cu-TCPP（Fe））金属有机框架（MOF）为基础的纳米系统的有效纳入Au纳米粒子（NPs）和RSL 3，它可以表现出酶样活性，普遍抑制肿瘤细胞中的抗铁毒性途径，放大铁毒性损伤。在本文中，Cu-TCPP（Fe）MOF纳米片通过原位成核与Au NPs整合，并通过7 r-x堆叠负载RSL 3，其最终用聚乙二醇（PEG）和iRGD修饰用于肿瘤靶向药物递送。具体地，Au NP可以表现出葡萄糖氧化酶样活性以有效地消耗葡萄糖，从而破坏戊糖磷酸途径以阻碍还原型谷胱甘肽（GSH）生物合成并防止辅酶QI 0（CoQI 0）再循环为CoQI 0 H2，而Cu物质可以将GSH氧化为氧化型谷胱甘肽（GSSG）。这些纳米催化活性可以导致GPX 4/GSH和FSPI/CoQI 0 H2途径的同时抑制，并与RSL 3的GPX 4失活功能合作，引起明显的铁凋亡损伤，从而为临床应用铁凋亡治疗提供了强有力的理论基础。
Ferroptosis is a recently discovered route of regulated cell death that offers the opportunities for the treatment of chemotherapy-resistant tumor indications, but its efficacy can be affected by the glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSPI) antioxidant mechanisms, posing significant challenges for its clinical translation. In this study, we report a Cu-tetra(4-carboxyphenyl)porphyrin chloride(Fe(III)) (Cu-TCPP(Fe)) metal organic framework (MOF)-based nanosystem for the efficient incorporation of Au nanoparticles (NPs) and RSL3, which can demonstrate enzyme-like activities to universally suppress the antiferroptotic pathways in tumor cells for amplifying ferroptotic damage. Herein, Cu-TCPP(Fe) MOF nanosheets were integrated with Au NPs via in situ nucleation and loaded with RSL3 via 7r-x stacking, which were eventually modified with polyethylene glycol (PEG) and iRGD for tumor-targeted drug delivery. Specifically, the Au NPs can demonstrate glucose oxidase-like activities for efficient glucose depletion, thus disrupting the pentose phosphate pathway to impede reduced glutathione (GSH) biosynthesis and prevent the recycling of coenzyme QI0 (CoQI0) to CoQI0H2, while Cu species can oxidize GSH into oxidized glutathione (GSSG). These nanocatalytic activities can lead to the simultaneous inhibition of the GPX4/GSH and FSPI/CoQI0H2 pathways and cooperate with the GPX4-deactivating function of RSL3 to cause pronounced ferroptotic damage, thereby providing a strong rationale for the application of ferroptosis therapy in the clinic.