Fe-HCOF-PEG2000 as a Hypoxia-Tolerant Photosensitizer to Trigger Ferroptosis and Enhance ROS-Based Cancer Therapy

Hui Peng,1,2,* Qian Jiang,1,* Wenhao Mao,1,3,* Zhonglan Hu,1,* Qi Wang,4 Zhuo Yu,1 Li Zhang,1 Xinyan Wang,5 Chunbo Zhuang,1 Jia Mai,6 Zhiyuan Wang,7 Ting Sun1 1Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 2Center for Clinical Laboratory, General Hospital of the Yangtze River Shipping Wuhan Brain Hospital, Wuhan, Hubei, 430010, People’s Republic of China; 3Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 4Department of Pharmacy, Kaifeng Hospital of Traditional Chinese Medicine, Kaifeng, 475000, People’s Republic of China; 5Department of Obstetrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 6Department of Laboratory Medicine, West China Second Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 7Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ting Sun, Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China, Email [email protected] Zhiyuan Wang, Henan Institute of Advanced Technology, Zhengzhou University, Zhengzhou, 450001, People’s Republic of China, Email [email protected]: The hypoxic tumor microenvironment and single mechanisms severely limit the photodynamic therapy (PDT) efficiency of covalent organic framework (COF) nanoparticles in cancer treatment.Purpose: Here, we propose an iron-loaded, hydrophilic 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (DSPE-PEG2000)-modified hollow covalent organic framework (HCOF), Fe-HCOF-PEG2000, for use in hypoxic PDT and ferroptosis therapy owing to its type I and II photodynamic ability and iron nanoparticle loading property.Results: Fe-HCOF-PEG2000 nanoparticles (Fe-HCOFs-PEG2000) with semiconducting polymers and microporous skeletons allow efficient photophysical properties. Moreover, the iron nanoparticles on Fe-HCOF-PEG2000 caused ferroptosis and further enhanced tumor elimination under normoxic and hypoxic conditions. DSPE-PEG2000 endowed Fe-HCOF-PEG2000 with hydrophilicity, allowing it to circulate and accumulate in organs rich in blood supply, especially tumors. 808 nm NIR activated Fe-HCOF-PEG2000 aggregated in tumors and significantly inhibited tumor growth under hypoxia.Conclusion: To our knowledge, Fe-HCOF-PEG2000 is the leading combination of type I/II PDT and ferroptosis. The strong antitumor effects of this nanomaterial suggest prospects for clinical translation as a tumor nanotherapy drug. Keywords: HCOFs, PDT, ROS, hypoxia, ferroptosis, cancer cells