Intracellular Redox Regulation Of Cyclometallic Iridium Complexes And Research On Anti-tumor Diagnosis And Treatment

Currently,the worldwide burden of cancer incidence and death is rapidly increasing,posing a serious threat to human health.Cyclometalated iridium complexes have very superior anticancer activity and unique antitumor mechanism.At the same time,they are also a class of excellent photosensitizers,which can be used in photodynamic therapy of cancer.Based on the unique redox environment in tumor tissue,the development of cyclometalated iridium complexes that can regulate the redox environment of cells is of great significance for antitumor research.The research of this paper is mainly divided into the following four aspects:（1）During photodynamic therapy（PDT）,the excess H₂S in cancer cells reduces the PDT effect,because H₂S indirectly depletes the reactive oxygen species（ROS）on which PDT depends.Therefore,H₂S-responsive photosensitizers can improve the efficiency of photodynamic therapy by consuming H₂S.In this work,two H₂S-responsive cyclometalated iridium complexes（Ir-DNB,Ir-MMB）have been designed and synthesized.They shown high sensitivity and selectivity to H₂S,and could locolize in the mitochondria These complexes have been successfully applied to exogenous and endogenous H₂S response in vitro and in vivo imaging.Further antitumor studies display that Ir-MMB can decrease intracellular GSH level.Under light,Ir-MMB can catalyze the oxidation of NADH to NAD⁺and produce H₂O₂,and ultimately results in cell apoptosis through mitochondrial membrane potential（MMP）depolarization and ROS production.（2）In order to increase the residence time of the drug in the cell,three bromine-containing cyclometalated iridium complexes（Ir-ppy-Br,Ir-pq-Br and Ir-bt Br-bpy）have been designed and synthesized.All of the complexes enter cells through energy-dependent pathways,mainly localized in mitochondria and can be fixed on mitochondrial proteins.They show higher antiproliferative activity than cisplatin in both 2D monolayers and 3D spheroids.The mechanism study shown that these complexes can induce mitochondrial depolarization,elevate ROS levels and inhibit Trx R activity,and inhibit tumor cell colony formation and angiogenesis.Further study display that complex Ir-pq-Br can trigger apoptosis via the activation of caspase-3,increase in the protein levels of Bax and decreased expression levels of KI67.（3）Two H₂S-responsive cyclometalated iridium complexes（Ir-pb-N₃,Ir-ppy-N₃）have been designed as targeted tumor imaging and mitochondrial DNA agents.They have good sensitivity and high selectivity for H₂S,and can be applied to the exogenous and endogenous H₂S imaging of H₂S-rich tumor tissue in vivo.Mechanism studies show that Ir-ppy-N₃can embed in mitochondrial DNA and cause DNA damage to cause autophagy ferroptosis,and induce aseries of events associated with mitochondrial damage,such as ROS production,the reduction of ATP and apoptosis.The in vivo antitumor activity showed that Ir-ppy-N₃can significantly inhibit the tumor growth in light and display excellent potency as PDT agent,and increase the expression ofγ-H2AX in the tumor.Meanwhile,Ir-ppy-N₃treatment did not result in mortality or significant change in body weight and normal tissues during this experiment,indicating that Ir-ppy-N₃has no severe side effects under these conditions and induce DNA damage.（4）In this work,two dinuclear cyclometalated iridium complexes（Ir-ppy-2S,Ir-pq-2S）were designed to decrease in GSH levels by depleting intracellular GSH.Mechnism studies found that Ir-pq-2S display higher anticancer activity and can cause apoptosis through increase for ROS levels,mitochondrial damage and activation of caspase-3 under light.Meanwhile,complex Ir-pq-2S can induce ferroptosis by downregulating GPX4 level and massive accumulation of lipid peroxides.