Tumor microenvironments self-activated nanoscale metal-organic frameworks for ferroptosis based cancer chemodynamic/photothermal/chemo therapy.
Tumor microenvironments self-activated nanoscale metal-organic frameworks for ferroptosis based cancer chemodynamic/photothermal/chemo therapy.
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肿瘤微环境自激活纳米级金属有机框架用于基于铁死亡的癌症化学动力学/光热/化疗治疗
DOI：
10.1016/j.apsb.2021.01.016
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发表时间：
2021-10
期刊：
影响因子：
--
通讯作者：
Zhao B
中科院分区：
文献类型：
--
作者：
Liang Y;Zhang L;Peng C;Zhang S;Chen S;Qian X;Luo W;Dan Q;Ren Y;Li Y;Zhao B
铁下垂作为一种新发现的细胞死亡形式，已成为精准癌症治疗的靶点。基于纳米技术的几种铁下垂治疗策略已被报道，要么通过提高细胞内铁水平，要么通过抑制依赖谷胱甘肽(GSH)的脂氢过氧化物酶谷胱甘肽过氧化物酶4(Gpx4)。然而，通过同时传递铁和抑制Gpx4的策略很少被报道。因此，我们开发了一种新型的肿瘤微环境(TME)激活的金属-有机骨架，该骨架中的铁和铜离子通过二硫键与聚乙二醇化反应(FCSP MOF)桥联，在氧化还原TME作用下被特异性降解，同时实现GSH耗竭诱导的Gpx4失活，并通过Fenton反应释放Fe离子产生ROS，从而引起铁下垂。FCSP MOF的本征光热能力和释放的铜离子加速了Fenton反应，从而产生了更多的ROS。TME中过表达的GSH和H_2O_2可以保证特异性的TME自激活治疗。阿霉素(DOX)负载不仅能诱导细胞凋亡，还能间接产生过氧化氢，放大Fenton反应，从而获得更好的肿瘤治疗效果。体外和体内实验均证实了所合成的FCSP@DOX MOF具有显著的抗肿瘤作用。FCSP@DOX通过GSH耗竭辅助剂Gpx4失活和Fenton/Fenton样反应诱导的基于铁下垂的化疗/光热/化疗的协同作用，在体外和体内都取得了良好的抗肿瘤效果，对正常组织的损害最小。
Ferroptosis, as a newly discovered cell death form, has become an attractive target for precision cancer therapy. Several ferroptosis therapy strategies based on nanotechnology have been reported by either increasing intracellular iron levels or by inhibition of glutathione (GSH)-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4). However, the strategy by simultaneous iron delivery and GPX4 inhibition has rarely been reported. Herein, novel tumor microenvironments (TME)-activated metal-organic frameworks involving Fe & Cu ions bridged by disulfide bonds with PEGylation (FCSP MOFs) were developed, which would be degraded specifically under the redox TME, simultaneously achieving GSH-depletion induced GPX4 inactivation and releasing Fe ions to produce ROS via Fenton reaction, therefore causing ferroptosis. More ROS could be generated by the acceleration of Fenton reaction due to the released Cu ions and the intrinsic photothermal capability of FCSP MOFs. The overexpressed GSH and H2O2 in TME could ensure the specific TME self-activated therapy. Better tumor therapeutic efficiency could be achieved by doxorubicin (DOX) loading since it can not only cause apoptosis, but also indirectly produce H2O2 to amplify Fenton reaction. Remarkable anti-tumor effect of obtained FCSP@DOX MOFs was verified via both in vitro and in vivo assays. FCSP@DOX achieved excellent anti-tumor efficiency both in vitro and in vivo with minimized damage to normal tissues by taking the synergy of GSH-depletion assistant GPX4 inactivation and Fenton/Fenton-like reaction induced ferroptosis-based chemodynamic/photothermal/chemo therapy.
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