Novel 2‑(2′-Benzothiazolyl)-benzimidazole-Based Iridium(III) Photocatalysts Exhibit Antiproliferative Effects in 2D and 3D Cancer Cells to Bypass Hypoxia-Induced Resistance

This study explores
the therapeutic potential of seven bis-cyclometalated
Ir(III) complexes (1–7), derived from the 2,2′-(benzothiazolyl)benzimidazole
scaffold, as highly promising next-generation photoactivatable agents
for type I and type II-guided photodynamic therapy (PDT) in lung and
colorectal cancers. Their high phototoxicity in 2D and 3D cancer cell
models, achieving IC50 values in the nanomolar region,
was closely linked to the generation of singlet oxygen and type I
reactive oxygen species (ROS) and the photooxidation of NADH, with
complex 4 identified as the strongest ROS inducer and
the most photocytotoxic complex. Notably, the iridium complexes proved
to maintain their phototoxicity in hypoxic conditions. Using 3D spheroids,
complex 4 demonstrated deep tissue penetration sought
to overcome PDT limitations in solid tumors. Overall, the synthesized
complexes showcase high efficacy and favorable pharmacological profiles,
positioning them as promising candidates for the ROS-guided photodynamic
treatment of cancers, including those located within hypoxic environments.