Abstract：
The relentless increase in drug resistance of platinum-based chemotherapeutics has opened the scope for other new cancer therapies with novel mechanisms of action (MoA). Recently, photocatalytic cancer therapy, an intrusive catalytic treatment, is receiving significant interest due to its multitargeting cell death mechanism with high selectivity. Here, we report the synthesis and characterization of three photoresponsive Ru(II) complexes, viz., [Ru(ph-tpy)(bpy)Cl]PF6 (Ru1), [Ru(ph-tpy)(phen)Cl]PF6 (Ru2), and [Ru(ph-tpy)(aip)Cl]PF6 (Ru3), where, ph-tpy = 4\'-phenyl-2,2\':6\',2″-terpyridine, bpy = 2,2\'-bipyridine, phen = 1,10-phenanthroline, and aip = 2-(anthracen-9-yl)-1H-imidazo[4,5-f][1,10] phenanthroline, showing photocatalytic anticancer activity. The X-ray crystal structures of Ru1 and Ru2 revealed a distorted octahedral geometry with a RuN5Cl core. The complexes showed an intense absorption band in the 440-600 nm range corresponding to the metal-to-ligand charge transfer (MLCT) that was further used to achieve the green light-induced photocatalytic anticancer effect. The mitochondria-targeting photostable complex Ru3 induced phototoxicity with IC50 and PI values of ca. 0.7 μM and 88, respectively, under white light irradiation and ca. 1.9 μM and 35 under green light irradiation against HeLa cells. The complexes (Ru1-Ru3) showed negligible dark cytotoxicity toward normal splenocytes (IC50s > 50 μM). The cell death mechanistic study revealed that Ru3 induced ROS-mediated apoptosis in HeLa cells via mitochondrial depolarization under white or green light exposure. Interestingly, Ru3 also acted as a highly potent catalyst for NADH photo-oxidation under green light. This NADH photo-oxidation process also contributed to the photocytotoxicity of the complexes. Overall, Ru3 presented multitargeting synergistic type I and type II photochemotherapeutic effects.
摘要：
铂类化疗药物耐药性的不断增加为其他具有新作用机制（MoA）的新癌症疗法开辟了前景。最近,光催化癌症疗法，侵入性催化处理，由于其具有高选择性的多靶向细胞死亡机制，因此受到了极大的关注。这里,我们报道了三种光响应Ru（II）配合物的合成和表征，viz.,[Ru(ph-tpy)(bpy)Cl]PF6(Ru1)，[Ru(ph-tpy)(phen)Cl]PF6(Ru2)，和[Ru(ph-tpy)(aip)Cl]PF6(Ru3)，where,ph-tpy=4\'-苯基-2,2\':6\'，2″-三吡啶,bpy=2,2'-联吡啶,phen=1,10-菲咯啉，和aip=2-（蒽醌-9-基）-1H-咪唑并[4,5-f][1,10]菲咯啉，表现出光催化抗癌活性。Ru1和Ru2的X射线晶体结构揭示了具有RuN5Cl核心的八面体几何形状。配合物在440-600nm范围内显示出强烈的吸收带，对应于金属-配体电荷转移（MLCT），可进一步用于实现绿光诱导的光催化抗癌作用。靶向线粒体的光稳定复合物Ru3诱导的光毒性，IC50和PI值约为。分别为0.7μM和88μM，在白光照射和ca。1.9μM和35在绿光照射下针对HeLa细胞。复合物(Ru1-Ru3)对正常脾细胞显示可忽略的暗细胞毒性(IC50>50μM)。细胞死亡机制研究表明，Ru3在白光或绿光暴露下通过线粒体去极化诱导ROS介导的HeLa细胞凋亡。有趣的是,Ru3还充当绿光下NADH光氧化的高效催化剂。这种NADH光氧化过程也有助于配合物的光细胞毒性。总的来说,Ru3具有多靶向协同的I型和II型光化学治疗作用。
