Engineering dual catalytic nanomedicine for autophagy-augmented and ferroptosis-involved cancer nanotherapy

Zhifang Li; Chunmei Wang; Chen Dai; Ruizhi Hu; Li Ding; Wei Feng; Hui Huang; Yin Wang; Jianwen Bai; Yu Chen

doi:10.1016/j.biomaterials.2022.121668

Engineering dual catalytic nanomedicine for autophagy-augmented and ferroptosis-involved cancer nanotherapy

Biomaterials. 2022 Aug:287:121668. doi: 10.1016/j.biomaterials.2022.121668. Epub 2022 Jul 5.

Authors

Zhifang Li¹, Chunmei Wang¹, Chen Dai², Ruizhi Hu², Li Ding³, Wei Feng⁴, Hui Huang⁴, Yin Wang⁵, Jianwen Bai⁶, Yu Chen⁷

Affiliations

¹ Department of Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, PR China.
² Department of Ultrasound in Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, PR China.
³ Tongji University School of Medicine, Tongji University Cancer Center, Shanghai Engineering Research Center of Ultrasound Diagnosis and Treatment, National Clinical Research Center of Interventional Medicine, Shanghai, 200072, PR China.
⁴ Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai, 200444, PR China.
⁵ Department of Ultrasound, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, 200433, PR China. Electronic address: lpbbl@aliyun.com.
⁶ Department of Emergency Medicine and Critical Care, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, PR China. Electronic address: baijianwen1019@163.com.
⁷ Materdicine Lab, School of Life Sciences, Shanghai University, Shanghai, 200444, PR China. Electronic address: chenyuedu@shu.edu.cn.

PMID: 35834999
DOI: 10.1016/j.biomaterials.2022.121668

Abstract

Chemodynamic therapy represents a distinct anti-tumor strategy by activating intratumoral chemical catalytic reactions to produce highly toxic reactive oxygen species (ROS) from non-/limited-toxic nanocatalysts. However, the low efficacy of ROS generation still remains a major challenge for further clinical translation. Herein, a liposomal nanosystem which simultaneously encapsulated copper peroxide nanodots (CPNs) and artemisinin (ART) was constructed for autophagy-enhanced and ferroptosis-involved cancer cell death owing to Cu-based dual catalytic strategy. To be specific, the CPN components, served as a H₂O₂ self-supplying platform, release H₂O₂ and Cu²⁺ under acidic tumor environment and endogenously generate ^.OH via Fenton-like reaction (catalytic reaction I). In addition, Cu²⁺ species catalyze ART components to produce ROS radicals (catalytic reaction II), further augmenting the intracellular oxidative damage and lipid peroxide accumulation, leading to cancer cell death. Specifically, ART also acted as a potent autophagy inducer increasing the level of intracellular iron pool through degradation of ferritin, which could promote cancer cell ferroptosis, producing the best antineoplastic effect. After accumulation into the tumor sites, ultrasound irradiation was applied to trigger the release of CPNs and ART from liposomal nanosystems, and amplify the efficacy of catalytic reaction for maximum therapeutic effect. Both in vitro and in vivo therapeutic outcomes suggest the outstanding autophagy-augmented ferroptosis-involved cancer-therapeutic efficacy, which was further corroborated by transcriptome sequencing. In this work, Cu was firstly proven to trigger ART to produce ROS species, but also provide a TME-responsive nanoplatform for potentially suppressing tumor growth by autophagy-augmented ferroptosis-involved cancer nanotherapy.

Keywords: Artemisinin; Autophagy; Chemodynamic therapy; CuO(2); Ferroptosis.