Despite their outstanding properties as potential photosensitizers for photodynamic therapy (PDT), Ir(III) biscyclometalated complexes need both further developments to overcome remaining limitations and in-depth
investigations into their mechanisms of action to reach clinic application in the treatment of cancer. This
work describes the synthesis of a family of Ir(III) complexes of general formula [Ir(C^N)2(N^N′
)]Cl (N^N′ =
thiabendazole-based ligands; C^N = ppy (2-phenylpyridinate) (Series A), or dfppy (2-(2,4-difluorophenyl)pyridinate) (Series B)) and their evaluation as potential PDT agents. These complexes are partially soluble in water
and exhibit cytotoxic activity in the absence of light irradiation versus several cancer cell lines. Furthermore, the
cytotoxic activity of derivatives of Series A is enhanced upon irradiation, particularly for complexes [1a]Cl and
[3a]Cl, which show phototoxicity indexes (PI) above 20. Endocytosis was established as the uptake mechanism
for [1a]Cl and [3a]Cl in prostate cancer cells by flow cytometry. These derivatives mainly accumulate in the
mitochondria as shown by colocalization confocal microscopy experiments. Presumably, [1a]Cl and [3a]Cl
induce death on cancer cells under irradiation through apoptosis triggered by a multimodal mechanism of action,
which likely involves damage over mitochondrial DNA and mitochondrial membrane depolarization. Both
processes seem to be the result of photocatalytic oxidation processes.
