A rhodamine-coordinated iridium complex to overcome cisplatin-resistant cancer via regulating mitochondrial function triggered apoptosis and ferroptosis
Juanjuan Li, Juanjuan Li, Gui‐Bin Gao, Wenrui Ouyang, Jinkun Huang, Hongxing Liu, Jin Li, Jin Li
Abstract
Modulating mitochondrial activity to regulate cancer cell homeostatic recycling presents a promising approach to overcome tumor resistance. Consequently, there is an urgent need for novel mitochondria-targeting agents and innovative strategies. We have developed [((η 5 -Cp∗)Ir(rhod)] 2+ 2PF 6 − ( Ir-rhod ), a new mitochondria-targeted iridium complex that exhibits greater cytotoxicity towards A549R (cisplatin-resistant human lung cancer) cells compared to the ligand rhod. Ir-rhod 's mitochondrial targeting ability stems from both rhodamine's inherent mitochondrial affinity and the complex's positive bivalent nature. The positively charged Ir-rhod enters cells and is drawn to mitochondria due to the high transmembrane potential in tumor cells. Notably, rhodamine enables real-time observation of Ir-rhod 's dynamic distribution in vivo. Ir-rhod influences mitochondrial function, triggering tumor cell ferroptosis and apoptosis by modulating ACSL4 and GPX4. The targeting effect of Ir-rhod reduces its systemic toxicity in vivo, enhancing its biosafety profile. To our knowledge, Ir-rhod is an effective mitochondria-targeted Ir complex capable of inducing tumor cell death by disrupting mitochondrial function, offering a potent strategy to suppress cisplatin resistance in non-small cell lung cancer. • Iridium complex Ir-rhod with rhodamine as the ligand, which possesses imaging and mitochondrial targeting capabilities. • The iridium complex Ir-rhod regulating mitochondrial function by upregulating the expression and activity of ACSL4. • The Ir-rhod suppresses cisplatin-resistant non-small-cell lung cancer by triggering ferroptosis and apoptosis.