Efficient photodynamic and photocatalytic anticancer activity of a Ru(II) polypyridyl complex

Ruthenium(II) complexes are considered promising candidates for photodynamic therapy (PDT) owing to their ease of synthesis, low dark toxicity, and favorable photophysical and photochemical properties. However, the therapeutic efficacy of most currently available Ru(II)-based photosensitizers (PSs) is significantly limited by the hypoxic tumor microenvironment and the inherent susceptibility of monotherapy to resistance mechanisms. The development of Ru(II)-based PSs with photocatalytic anticancer activity is expected to solve the above problems. Here, we reported two Ru(II)-based PSs [Ru(dip)₂(dppn)](PF₆)₂ (Ru1) and [Ru(dip)₂(dpb)](PF₆)₂ (Ru2), where, dip = 4,7-diphenyl-1,10-phenanthroline, dppn = benzo[i]dipyrido[3,2-a:2',3'-c]phenazine, dpb = 2,3-diphenylbenzo[ghi]perylene, showing photocatalytic anticancer activity. The results demonstrate that the metal-to-ligand charge transfer (MLCT) absorption bands of Ru1 and Ru2, both featuring extended π-conjugated ligands, are red-shifted relative to that of [Ru(bpy)₃]²⁺. Although Ru1 exhibits comparatively lower cellular uptake, its greater accumulation in nucleus, higher singlet oxygen quantum yield, and superior photocatalytic oxidation efficiency contribute to its higher phototoxicity against human lung cancer cells (A549) than Ru2. This enhanced phototoxic effect is mediated through DNA damage and the activation of mitochondrial apoptosis pathways. Notably, Ru1 retains significant phototoxicity under hypoxic conditions, attributed to its great NADH photo-oxidation capability. The efficient photodynamic and photocatalytic antitumor activity of Ru1, along with its distinctive "low uptake, high activity" profile, offers valuable insights for the rational design of effective and low-toxicity Ru(II)-based photosensitizers.