Tumor microenvironments self-activated nanoscale metal-organic frameworks for ferroptosis based cancer chemodynamic/photothermal/chemo therapy

• Published in: Acta pharmaceutica Sinica. B 2021-10, Vol.11 (10), p.3231-3243
• Main Authors: Liang, Yu, Zhang, Li, Peng, Chao, Zhang, Shiyu, Chen, Siwen, Qian, Xin, Luo, Wanxian, Dan, Qing, Ren, Yongyan, Li, Yingjia, Zhao, Bingxia
• Format: Article
• Language: English
• Subjects: Drug delivery; Fenton reaction; Ferroptosis; GSH depletion; Metal-organic frameworks (MOFs); Original; Tumor microenvironments
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2021.01.016

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. [Display omitted]