Rational design of mitochondria targeted thiabendazole-based Ir(III) biscyclometalated complexes for a multimodal photodynamic therapy of cancer

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. New Thiabendazole-based Ir(III) Biscyclometalated complexes have been rationally designed and synthetised for photodynamic therapy of cancer. Complexes [1a]Cl and [3a]Cl yielded a relevant photocytotoxic activity upon blue light irradiation though a mitochondria-targeted multimodal mechanism that involves NADH oxidation, mitochondrial membrane depolarization and DNA damage. [Display omitted] •New thiabendazole-based Ir(III) biscyclometalated complexes as PDT agents.•Modulation of electronic effects on the ligands have a great impact on activity.•[1a]Cl and [3a]Cl display phototoxicity indexes higher than 20 in cancer cells.•They are uptaken by the cells by endocytosis and mainly accumulate in mitochondria.•Upon irradiation, they trigger a multimodal mitochondrial damage and cell death.