New Encapsulated bis Cyclometalated Ir(III) Complexes with Very Potent Anticancer PDT Activity

Abstract

Photodynamic therapy (PDT) has emerged as a promising approach to cancer treatment, due to its ability to reduce side effects. In the search for luminescent iridium [Ir(C^N)₂(N^N)]⁺ complexes with high ability to generate ROS (reactive oxygen species) under irradiation, we employed C^N ligands with high π-expansion (pbpz (4,9,14-triazadibenzo[a,c]anthracene), 1, or pbpn (4,9,16-triazadibenzo[a,c]naphthacene), 3) that should lead to long excited state lifetimes. The photophysical properties were significantly influenced by the degree of C^N ligand π-expansion. Complex 1 exhibited a long fluorescence lifetime, matching the triplet lifetime observed in TAS, indicating delayed fluorescence. In contrast, the additional ring in complex 3 generated two near-HOMO orbitals, increasing the excited states LC character and reducing spin-orbit coupling (SOC) and intersystem crossing (ISC). They exhibited a notable ability to generate ¹O₂ and O₂^•−. TD-DFT studies nicely explained the differentiated photophysical properties. Both complexes exhibited significant phototoxicity against human cancer cells in both monolayer and multicellular spheroids models, with complex 1 exhibiting higher effect. They effectively photogenerated intracellular ROS, including O₂^•−. The mitochondrial accumulation of 1 and its disruption of mitochondrial functions was verified. Wound healing and clonogenic assays demonstrated their potential as antimetastatic agents. In general, complexes encapsulation significantly facilitated their cellular accumulation and increased photocytotoxic indexes, with NP1 achieving one of the highest IC₅₀ reported in iridium chemistry. Furthermore, the NP showed good anticancer activity even in 3D models. Thus, 1 and 3 and specially NP1 show great promise as type I and II PDT agents with theragnostic potential.