Fluorescein-Functionalized Iridium(III) Complexes as Dual-Mode Type I Photosensitizers for Hypoxia-Tolerant Photodynamic and X-ray-Induced Therapy.

The development of photosensitizers that function effectively in hypoxic environments and enable deep-tissue treatment remains a significant challenge in photodynamic therapy (PDT). Here, we report two novel Ir(III) complexes functionalized with fluorescein designed as efficient Type I photosensitizers for both light-driven PDT and X-ray-induced PDT (X-PDT). By populating the triplet state of the fluorescein ligands, these complexes facilitate the generation of reactive oxygen species (ROS) through electron transfer, producing superoxide anion radicals (O) and hydroxyl radicals (OH) under irradiation. The complexes exhibit pronounced phototoxicity against cancer cells, particularly under hypoxic conditions, where oxygen-dependent Type II photosensitizers are less effective. Remarkably, these complexes also demonstrate direct X-ray activation, offering a solution for deep-tissue cancer treatment. The lead complex, , outperforms existing systems by efficiently generating both singlet oxygen O(Δ) and free radicals, enabling synergistic Type I and II PDT effects. This work represents a major advancement in the design of oxygen-independent PDT agents by using fluorescein's triplet state, with potential applications in deep-tissue and hypoxic tumor environments.