A bimetallic Ru(ii)–Ru(ii) complex as an effective non-small cell lung cancer photosensitizer with potential ferroptosis photoinduction

Abstract

Three polypyridyl bimetallic photosensitizers of Ru–Ru, Os–Os, and Ru–Os with the general formula of [(DIP)₄M₂(L-1)](PF₆)₄, where DIP is 4,7-diphenyl-1,10-phenanthroline and L-1 is the bridging ligand, were developed and fully characterized. Electronic property study by DFT and TD-DFT calculations indicated a polarized electron distribution tendency and an intra-molecular charge transfer effect. The complex Ru–Ru generated high amounts of reactive oxygen species (¹O₂ and O₂˙⁻), and the ¹O₂ generation efficiency of Ru–Ru was approx. 24 fold (in acetonitrile) and 6.6 fold (in PBS/DMSO (95/5, v/v)) higher than that of [Ru(bpy)₃]Cl₂ under low-power blue light exposure. These complexes exhibited moderate to great photocytotoxicity against A549 and MGC-803 cancer cell lines under blue LED light irradiation, and the IC₅₀ values of Ru–Ru were as low as 2.33 μM (phototherapeutic index (PI) > 21) and 3.10 μM (PI > 16), respectively; while it was relatively less cytotoxic against HaCaT normal cells (Ru–Ru, IC₅₀ value of 6.10 μM) and almost noncytotoxic in the dark. The cellular singlet oxygen detection in A549 cancer cells was in a concentration-dependent manner. Ru–Ru can also induce potent photo-oxidation of NADH (turnover frequency of 462 h⁻¹ in PBS) and glutathione in PBS/DMSO (95/5, v/v), interfere with the balance of NADH (41%) and GSH (66%) in A549 cells, and cause accumulated lipid peroxidation, which indicated that such a complex can be a candidate catalytic type I and type II photosensitizer and potentially induce ferroptosis in cancer cells.