在光治疗窗口（600-900 nm）内，光动力疗法（PDT）和光热疗法（PTT）的组合可以显著增强治疗效果，在癌症光疗中超过了单独应用PDT或PTT的疗效。在此，我们报道了一种新型小分子混合配体的镍（II）-二硫代烯络合物（Ni-TDD），具有二吡啶菲嗪配体，展示出强大的红光PDT和显著的近红外（NIR）轻度温度PTT活性，对癌细胞和三维多细胞瘤结节（MCTSs）具有作用。四配位的平面四方体络合物在约900 nm处展示出中等强度吸收带（ε ∼ 3700 M-1cm-1），并在水相中展示出良好的暗稳定性和光稳定性。Ni-TDD在HeLa癌细胞上引起了强大的红光（600-720 nm）PDT效应（IC50 = 1.8 μM，光激化系数 = 44），通过高效的单线态氧产生诱导细胞凋亡。Ni-TDD表现出明显的与双螺旋小牛胸腺DNA的扣押结合亲和力，导致结合常数（Kb） ∼ 106 M-1。该配合物在808 nm NIR光照射下诱导轻度高温，并对MDA-MB-231癌细胞表现出显著的轻度温度PTT效应。将经过Ni-TDD处理的HeLa MCTSs同时照射红光和NIR光，通过单线态氧和轻度高温产生引起明显的协同抑制生长效果，超过了单独照射的效果。Ni-TDD对非癌性HPL1D和L929细胞的毒性极低，即使在高微摩尔浓度下也是如此。这是首次报道镍（II）配合物展示红光PDT活性，并且是第一例一价过渡金属配合物在临床相关光治疗窗口内表现出联合PDT和PTT效应的例子。我们的研究结果为设计和开发金属-二硫代烯络合物作为双重作用癌症光疗药物奠定了基础，使用长波长光治疗固体肿瘤。Copyright © 2023 Elsevier Masson SAS. All rights reserved.

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.Copyright © 2023 Elsevier Masson SAS. All rights reserved.