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Critical Overview of the Use of Ru(II) Polypyridyl Complexes as Photosensitizers in One-Photon and Two-Photon Photodynamic Therapy
Accounts of Chemical Research ( IF 18.3 ) Pub Date : 2017-10-23 00:00:00 , DOI: 10.1021/acs.accounts.7b00180
Franz Heinemann 1 , Johannes Karges 1 , Gilles Gasser 1
Affiliation  

Photodynamic Therapy (PDT) is an emerging technique to treat certain types of cancer, bacterial, fungal, and viral infections, and skin diseases. In past years, different research groups developed new ruthenium-containing photosensitizers (PSs) with tuned photophysical and biological properties to better fit the requirements of PDT. In this Account, we report and discuss the latest results in this research area, emphasizing particularly our own research. For example, inspired by the DNA intercalating complex [Ru(bpy)2(dppz)]2+ (bpy = 2,2′-bipyridine; dppz = (dipyrido[3,2-a:2′,3′-c]phenazine), a series of ruthenium complexes bearing differently functionalized dppz ligands were synthesized to target DNA. The introduction of the substituents on the dppz ligand did not reduce much the affinity of the complexes to DNA but highly affected their cellular uptake. The most effective complex in this series, [Ru(bpy)2(dppz-7-OMe)]2+, showed IC50 values in the low micromolar range against several types of cancer cells upon light irradiation and, importantly, a high phototoxic index (PI) of >150. This value is comparable to or even better than several PSs used in clinics under comparable experimental conditions. This compound was found to localize in the nucleus and to induce DNA damage in HeLa cells upon light irradiation. Interestingly, cells in the mitotic phase were found to be more affected and to have a different mechanism of cell death (apoptosis) upon light irradiation than those in the interphase (paraptosis). To take advantage of that, the PS was combined with a cell cycle inhibitor to synchronize cells in the mitotic phase, further improving the phototoxicity by a factor of 3.6. In addition, our group recently demonstrated that [Ru(bphen)2(benzene-1,2-dislufinate)] (bphen = 4,7-diphenyl-1,10-phenanthroline) localizes in mitochondria and has an IC50 value of 0.62 μM with a PI of over 80 in HeLa cells upon light irradiation at 420 nm. Interestingly, this complex was also found to efficiently kill Gram-positive Staphylococcus aureus under light irradiation. Antimicrobial PDT (aPDT) is another field of research where Ru(II) polypyridyl complexes can play an interesting role to fight antibiotics resistance. [Ru(dqpCO2Me)(ptpy)]2+ (dqpCO2Me = 4-methylcarboxy-2,6-di(quinolin-8-yl)pyridine), ptpy = 4′-phenyl-2,2′:6′,2″-terpyridine) is additionally efficient against Gram-negative Escherichia coli. The efficacy of positively charged Ru(II) PSs is related to their affinity to the negatively charged membrane of Gram-negative bacteria.

中文翻译:

在单光子和两光子光动力疗法中使用Ru(II)聚吡啶配合物作为光敏剂的关键概述

光动力疗法(PDT)是一种新兴技术,用于治疗某些类型的癌症,细菌,真菌和病毒感染以及皮肤疾病。在过去的几年中,不同的研究小组开发了新的含钌光敏剂(PSs),它们具有经过调整的光物理和生物特性,以更好地满足PDT的要求。在此报告中,我们报告并讨论了该研究领域的最新成果,特别强调了我们自己的研究。例如,受到DNA嵌入复合物[Ru(bpy)2(dppz)] 2+(bpy = 2,2'-联吡啶; dppz =(dipyrido [3,2- a:2',3'- c[phenazine]),合成了一系列带有不同功能化dppz配体的钌配合物,以靶向DNA。在dppz配体上引入取代基并不会大大降低复合物对DNA的亲和力,但会极大地影响其细胞吸收。该系列中最有效的络合物[Ru(bpy)2(dppz-7-OMe)] 2+的IC 50在光辐照下,对几种类型的癌细胞的微摩尔浓度值低,重要的是,> 150的高光毒性指数(PI)。在可比较的实验条件下,该值可与临床上使用的几种PS相当甚至更好。发现该化合物位于细胞核中,并在光照射下诱导HeLa细胞中的DNA损伤。有趣的是,发现有丝分裂期的细胞受光照射的程度比中间期的细胞(致死症)受到的影响更大,并且具有不同的细胞死亡(凋亡)机制。为了利用这一优势,将PS与细胞周期抑制剂结合使用,以使细胞在有丝分裂期同步化,从而将光毒性进一步提高了3.6倍。此外,我们小组最近证明了[Ru(bphen)2(苯-1,2- dislufinate)](=的BPhen 4,7-二苯基-1,10-菲咯啉)在局部化的线粒体和具有IC 50 0.62μM的值与80在HeLa细胞中时的光照射在一个PI 420纳米 有趣的是,还发现这种复合物在光照射下能有效杀死革兰氏阳性金黄色葡萄球菌。抗菌PDT(aPDT)是另一个研究领域,其中Ru(II)聚吡啶基复合物可以在对抗抗生素耐药性方面发挥有趣的作用。[Ru(dqpCO 2 Me)(ptpy)] 2+(dqpCO 2 Me = 4-甲基羧基-2,6-二(喹啉-8-基)吡啶),ptpy = 4'-苯基-2,2':6 ',2''-三联吡啶)对革兰氏阴性大肠杆菌也有效。带正电的Ru(II)PS的功效与其对革兰氏阴性菌带负电的膜的亲和力有关。
更新日期:2017-10-23
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