A dipyridophenazine Ni(II) dithiolene complex as a dual-acting cancer phototherapy agent activatable within the phototherapeutic window

A combination of photodynamic therapy (PDT) and photothermal therapy (PTT) within the phototherapeutic window (600-900 nm) can lead to significantly enhanced therapeutic outcomes, surpassing the efficacy observed with PDT or PTT alone in cancer phototherapy. Herein, we report a novel small-molecule mixed-ligand Ni(II)-dithiolene complex (Ni-TDD) with a dipyridophenazine ligand, demonstrating potent red-light PDT and significant near-infrared (NIR) light mild-temperature PTT activity against cancer cells and 3D multicellular tumour spheroids (MCTSs). The four-coordinate square planar complex exhibited a moderately intense absorption band (ε ∼ 3700 M-1cm-1) centered around 900 nm and demonstrated excellent dark and photostability in an aqueous phase. Ni-TDD induced a potent red-light (600-720 nm) PDT effect on HeLa cancer cells (IC50 = 1.8 μM, photo irritation factor = 44), triggering apoptotic cell death through efficient singlet oxygen generation. Ni-TDD showed a significant intercalative binding affinity towards double-helical calf thymus DNA, resulting in a binding constant (Kb) ∼ 106 M-1. The complex induced mild hyperthermia and exerted a significant mild-temperature PTT effect on MDA-MB-231 cancer cells upon irradiation with 808 nm NIR light. Simultaneous irradiation of Ni-TDD-treated HeLa MCTSs with red and NIR light led to a remarkable synergistic inhibition of growth, exceeding the effects of individual irradiation, through the generation of singlet oxygen and mild hyperthermia. Ni-TDD displayed minimal toxicity towards non-cancerous HPL1D and L929 cells, even at high micromolar concentrations. This is the first report of a Ni(II) complex demonstrating red-light PDT activity and the first example of a first-row transition metal complex exhibiting combined PDT and PTT effects within the clinically relevant phototherapeutic window. Our findings pave the way for designing and developing metal-dithiolene complexes as dual-acting cancer phototherapy agents using long wavelength light for treating solid tumors.