Negi Monika, Dixit Tejal, Venkatesh V
Department of Chemistry, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand 247667, India.
Inorg Chem. 2023 Dec 11;62(49):20080-20095. doi: 10.1021/acs.inorgchem.3c02942. Epub 2023 Nov 22.
Organelle-targeted photosensitizers (PSs) for photodynamic therapy (PDT) are considered as an effective therapeutic strategy for the development of next generation PSs with the least side effects and high therapeutic efficacy. However, multiorganelle targeted PSs eliciting PDT via both type I and type II mechanisms are scarce. Herein, a series of cyclometalated iridium(III) complexes were formulated [Ir(CN)(SS)] (CN = 2-phenylpyridine (ppy) and 2-(thiophen-2-yl)pyridine (thpy); SS = diethyldithiocarbamate (DEDTC), morpholine--dithiocarbamate (MORDTC) and methoxycarbonodithioate (MEDTC)) and the newly designed complexes Ir2@DEDTC and Ir1@MEDTC were characterized by single crystal X-ray crystallography. Complexes containing thpy as CN ligand exhibit excellent photophysical properties such as red-shifted emission, high singlet oxygen quantum yield (ϕ) and longer photoluminescence lifetime when compared with complexes containing ppy ligands. Ir2@DEDTC exhibits the highest ϕ and photoluminescence lifetimes among the synthesized complexes. Therefore, Ir2@DEDTC was chosen to evaluate the photosensitizing ability to produce reactive oxygen species (ROS). Upon blue light irradiation (456 nm), it efficiently produces ROS, i.e., hydroxy radical (OH) and singlet oxygen (O), which was confirmed by electron paramagnetic resonance (EPR) spectroscopy. photocytotoxicity toward HCT116, HeLa, and PC3 cell lines showed that out of all the synthesized complexes, Ir2@DEDTC has the highest photocytotoxic index (PI > 400) value. Ir2@DEDTC is efficiently taken up by the HCT116 cell line and accumulated mainly in the lysosome and mitochondria of the cells, and after PDT treatment, it elicits cell shrinkage, membrane blebbing, and DNA fragmentation. The phototherapeutic efficacy of Ir2@DEDTC has been investigated against 3D spheroids considering its ability to mimic some of the basic features of solid tumors. The morphology was drastically altered in the Ir2@DEDTC treated 3D spheroid after the light irradiation unleashed the potential of the Ir(III) dithiocarbamate complex as a superior PS for PDT. Hence, mitochondria and lysosome targeted photoactive cyclometalated Ir(III) dithiocarbamate complex exerting oxidative stress via both type I and type II PDT can be regarded as a dual-organelle targeted two-pronged approach for enhanced PDT.
用于光动力疗法（PDT）的细胞器靶向光敏剂（PSs）被认为是开发具有最小副作用和高治疗效果的下一代PSs的有效治疗策略。然而，通过I型和II型机制引发PDT的多细胞器靶向PSs却很稀缺。在此，我们制备了一系列环金属化铱（III）配合物[Ir(CN)(SS)]（CN = 2-苯基吡啶（ppy）和2-（噻吩-2-基）吡啶（thpy）；SS = 二乙基二硫代氨基甲酸盐（DEDTC）、吗啉二硫代氨基甲酸盐（MORDTC）和甲氧基羰基二硫代酸盐（MEDTC）），并通过单晶X射线晶体学对新设计的配合物Ir2@DEDTC和Ir1@MEDTC进行了表征。与含有ppy配体的配合物相比，含有thpy作为CN配体的配合物表现出优异的光物理性质，如发射红移、高单线态氧量子产率（ϕ）和更长的光致发光寿命。Ir2@DEDTC在合成的配合物中表现出最高的ϕ和光致发光寿命。因此，选择Ir2@DEDTC来评估其产生活性氧（ROS）的光敏能力。在蓝光照射（456 nm）下，它能有效地产生活性氧，即羟基自由基（OH）和单线态氧（O），这通过电子顺磁共振（EPR）光谱得到了证实。对HCT116、HeLa和PC3细胞系的光细胞毒性研究表明，在所有合成的配合物中，Ir2@DEDTC具有最高的光细胞毒性指数（PI > 400）值。Ir2@DEDTC能被HCT116细胞系有效摄取，并主要积累在细胞的溶酶体和线粒体中，在PDT处理后，它会引发细胞收缩、膜泡化和DNA片段化。考虑到Ir2@DEDTC模拟实体瘤一些基本特征的能力，我们研究了其对3D球体的光治疗效果。在光照射后，Ir2@DEDTC处理的3D球体的形态发生了显著改变，这释放了铱（III）二硫代氨基甲酸盐配合物作为一种优异的PDT光敏剂的潜力。因此，线粒体和溶酶体靶向的光活性环金属化铱（III）二硫代氨基甲酸盐配合物通过I型和II型PDT发挥氧化应激作用，可以被视为一种增强PDT的双细胞器靶向双管齐下的方法。
