Liposome-encapsulated iridium(III) complexes significantly enhance antitumor efficiency through immunogenic cell...

Iridium(III) complexes become a research hotspot due to their unique chemical properties and biological activities. Herein, we synthesized two iridium(III) complexes: [Ir(bzq)₂(BDIP)]PF₆ (bzq = benzo[h]quinoline, BDIP = 2-(6-bromobenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline, Ir10a) and [Ir(piq)₂(BDIP)]PF₆ (piq = 1-phenylisoquinoline, Ir10b). The antitumor activities and mechanisms of the complexes and liposome-loaded complexes Ir10alip and Ir10blip were studied. Through the cellular uptake, we found that complexes and liposomes enter cells, but the less amount of Ir10a and Ir10b in the cells was observed. Ir10a, Ir10b, Ir10alip and Ir10blip inhibit the formation of cell colonies and cell invasion, cause a decrease in the mitochondrial membrane potential, and induce a release of cytochrome C. Ir10a, Ir10b, Ir10alip and Ir10blip cause apoptosis through p38-MAPK pathway. We also found that the expression of CRT, HSP70, and HMGB1 increased, proving that Ir10a, Ir10b, Ir10alip and Ir10blip caused immunogenic cell death, which further activates immune response to increase CD8⁺ T cells. The decrease of GSH, the increase of MDA, as well as the decreased expression of GPX4 and ferritin, provide strong evidence for ferroptosis. We further investigated the in vivo antitumor activities of Ir10b and Ir10blip through xenograft tumor experiments. The tumor inhibition rates of Ir10b and Ir10blip reached 33.02% and 67.92%, respectively, which proved that Ir10blip had a better antitumor effect in vivo. The above results demonstrate that Ir10a, Ir10b, Ir10alip and Ir10blip are expected to provide an efficient and low-toxicity treatment option for patients with cervical cancer, and this work plays an important role in the future development of antitumor drugs.