Biotin-modified cyclometalated iridium-based photosensitizers as mitochondria-targeted theranostic agents for tumor photodynamic therapy in vitro and in vivo

Photodynamic therapy (PDT) is a promising non-invasive treatment technique for various types of cancer. Photoluminescent cyclometalated Ir(III) complexes, a distinctive genre of photosensitizers (PSS), have garnered significant interest due to their exceptional selective toxicity towards cancerous cells and minimal cytotoxicity towards normal cells. This study aimed to investigate the application of three newly designed biotin-modified cyclometalated Ir(III) complexes (Ir1-Ir3) for the treatment of cancer. The three complexes were found to have good photocatalytic activity, with singlet oxygen (1O2) yields ranging from 0.24 to 0.65 in aqueous solutions. The results suggest that these complexes have the potential as phototherapeutic and photodiagnostic agents for cancer treatment. Additionally, the biotin fragments in the Ir1-Ir3 structures enable their selective targeting of tumor cells. Notably, Ir3 displayed negligible dark toxicity towards A549 human lung cancer cells (IC50 > 100 μM), but its value decreased to 0.25 μM after 15 min of 425 nm (40 mW/cm2) light exposure. Furthermore, these complexes exhibited low phototoxicity towards non-cancerous BHK mouse kidney cells. Further investigation demonstrated that Ir3 had potent targeting abilities for mitochondria, and could trigger cell apoptosis through the activation of ROS-mediated mitochondrial signaling pathways under 425 nm light irradiation. In vivo studies revealed that Ir3 effectively suppressed tumor growth in A549 xenograft-bearing mice when exposed to 425 nm light. These results indicate that Ir3 has the potential to be a valuable photosensitizer drug for the photodynamic treatment of tumors.