An electron-accepting half-sandwich iridium(III) complex for the treatment of hypoxic tumors via synergetic chemo- and phototherapy

Tumor hypoxia is believed to be a major bottleneck in the clinical transformation of photodynamic therapy (PDT). Here, a half-sandwich iridium(III) complex [(η⁵-Cp^xbiph)Ir(N^N-NDI)Cl]PF₆ (Ir-NDI, Cp^xbiph = tetramethyl(biphenyl)-cyclopentadienyl) bearing a naphthalene diimide (NDI) modified N^N-chelating ligand was designed to treat hypoxic tumors via synergetic chemo- and phototherapy. In vitro tests showed that Ir-NDI exhibited moderate dark cytotoxicity and potent photo-cytotoxicity against 4T1 murine breast cancer cells under both normoxic and hypoxic conditions. Mechanism studies indicated that Ir-NDI could induce the degradation of endogenous nicotinamide adenine dinucleotide (NADH) and glutathione (GSH) in 4T1 living cells and trigger cellular apoptosis and ferroptosis. In vivo studies demonstrated that Ir-NDI plus laser irradiation achieved significant tumor ablation, with a tumor-growth-inhibition (TGI) rate of up to 89%. Our research here presents a feasible approach for the treatment of hypoxic tumors via chem- and phototherapy of iridium(III) complexes.