Iridium(III) complexes as type I photosensitizers for hypoxic two-photon photodynamic therapy

Photodynamic therapy (PDT), a non-invasive therapeutic modality, has significantly improved skin cancer treatment in recent years. Nonetheless, the limitations associated with conventional photosensitizers, such as their substantial dependence on oxygen and restricted light penetration, continue to pose considerable challenges for clinical applications. Herein, five Iridium(III) complexes have been developed as type I photosensitizers for two-photon PDT targeting melanoma. These complexes exhibit notable two-photon absorption (TPA) cross-sections (σ2 ≥ 100 GM) and high yields of reactive oxygen species (ROS) under hypoxic conditions, leading to mitochondrial damage and subsequent apoptosis through ROS generation with low doses of single or two-photon excitation. Notably, Ir4@PEG exhibits an IC₅₀ value of 2.1 μM and a phototoxicity index (PI) of 47 under hypoxic conditions. Cellular assays indicate that Ir4@PEG initially targets and localizes within lysosomes, where the lysosomal membrane is subsequently compromised upon light stimulation, resulting in Ir4 transferring and damaging mitochondria, causing cell apoptosis. Additionally, Ir4@PEG demonstrates improved tumor penetration, significant ROS production, and marked phototoxicity in hypoxic three-dimensional tumor spheroids. These findings provide new insights into designing oxygen-independent, metal-based two-photon photodynamic therapies against hypoxic melanoma.