Photothermal-Enhanced Inactivation of Glutathione Peroxidase for Ferroptosis Sensitized by an Autophagy Promotor
Photothermal-Enhanced Inactivation of Glutathione Peroxidase for Ferroptosis Sensitized by an Autophagy Promotor
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DOI：
10.1021/acsami.9b16124
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发表时间：
2019-11-20
影响因子：
9.5
通讯作者：
Sun, Baiwang
中科院分区：
文献类型：
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作者：
An, Peijing;Gao, Zhiguo;Sun, Baiwang
到目前为止，铁凋亡的治疗策略仍然很简单，虽然铁凋亡引起了广泛的兴趣，由于它的逃逸，从传统的治疗方式的生物载体。在此，我们构建了一种基于MnO2@HMCu2-xS纳米复合材料（HMCMs）的光热（PT）和自噬增强的铁蛋白治疗模式，用于有效的肿瘤消融。HMCM具有PT增强的谷胱甘肽（GSH）耗竭能力，从而通过谷胱甘肽过氧化物酶4（GPX 4）的增强失活诱导PT增强的铁凋亡。此后，GSH响应的Mn 2+释放可通过Fenton样反应产生活性氧（ROS），以加强细胞内的氧化应激，从而导致脂质过氧化氢（LPO）积聚。此外，由于自噬在铁细胞凋亡过程中不可或缺的作用，自噬促进剂雷帕霉素（Rapa）被加载到HMCM中，以使细胞对铁细胞凋亡敏感。体内外实验结果表明，HMCM在人乳腺癌模型中表现出上级抗癌作用，其联合治疗体系为下一代抗恶性肿瘤的铁毒性治疗提供了可能。
Until now, ferroptotic therapeutic strategies remain simple, although ferroptosis has aroused extensive interest owing to its escape from the biocarriers of conventional therapeutic modalities. Herein, we construct a photothermal (PT)- and autophagy-enhanced ferroptotic therapeutic modality based on MnO2@HMCu2-xS nano-composites (HMCMs) for efficient tumor ablation. The HMCMs possess PT-enhanced glutathione (GSH) depletion capability, thereby inducing PT-enhanced ferroptosis via the reinforced inactivation of glutathione peroxidase 4 (GPX4). Thereafter, the GSH-responsed Mn2+ release could generate reactive oxygen species (ROS) by a Fenton-like reaction to reinforce the intracellular oxidative stress for the lipid hydroperoxide (LPO) accumulation in ferroptosis. Additionally, an autophagy promotor rapamycin (Rapa) was loaded into HMCM for sensitizing cells to ferroptosis due to the indispensable role of autophagy in the ferroptosis process. The in vitro and in vivo data demonstrated that the HMCM exhibited superior anticancer effect in human breast cancer models and that the combined therapeutic system afforded the next generation of ferroptotic therapy for combatting malignant tumors.