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Evoking Ferroptosis by Synergistic Enhancement of a Cyclopentadienyl Iridium-Betulin Immune Agonist |
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| Authors: | Mengdi Lv Yue Zheng Jian Wu Zhengqi Shen Binglian Guo Guojing Hu Yuanlei Huang Jingyue Zhao Prof. Yong Qian Prof. Zhi Su Prof. Chao Wu Prof. Xuling Xue Prof. Hong-Ke Liu Prof. Zong-Wan Mao |
| Affiliation: | 1. National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023 P. R. China These authors contributed equally to this work.;2. MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, GBRCE for Functional Molecular Engineering, Sun Yat-Sen University, Guangzhou, 510275 P. R. China;3. National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing, 210023 P. R. China;4. Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080 P. R. China |
| Abstract: | Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation (LPO) with the potential for antitumor immunity activation. In this study, a nonferrous cyclopentadienyl metal-based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl ( Ir-Bet ) was developed by a metal-ligand synergistic enhancement (MLSE) strategy involving the reaction of [Ir(Cp*)Cl]2Cl2 with the natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir-Cp*) species as Ir-Bet not only tremendously enhanced the antiproliferative activity toward cancer cells, but also activated ferritinophagy for iron homeostasis regulation by PI3K/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evoked an immune response by nuclear factor kappa-B (NF-κB) activation of Ir-Cp* species. Further immunogenic cell death (ICD) occurred by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. An in vivo vaccination experiment demonstrated desirable antitumor and immunogenic effects of Ir-Bet by increasing the ratio of cytotoxic T cells (CTLs)/regulatory T cells (Tregs). |
| Keywords: | Cyclopentadienyl Ligands Ferroptosis Immunochemotherapy Iridium Complexes Synergistic Strategy |