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    Home > Angelw: a new photodynamic photosensitizer based on iridium (Ⅲ) complex and coumarin

    Angelw: a new photodynamic photosensitizer based on iridium (Ⅲ) complex and coumarin

    • Last Update: 2019-04-23
    • Source: Internet
    • Author: User
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    Because of the ability to produce reactive oxygen species (ROS) under light, iridium (Ⅲ) complexes have become a potential photodynamic therapy (PDT) photosensitizers (PS) However, it is difficult for the existing iridium (Ⅲ) complex photosensitizers to reach the phototherapy window, resulting in poor tissue penetration and miss target toxicity, which seriously limits its clinical application In order to solve these problems, some researchers have combined organic fluorescence molecules with metal complexes to develop new PDT reagents This method takes advantage of the rich photophysical properties of organic fluorescence molecules and the known anticancer activity of metal complexes A class of fluorescent molecules (coupys) emitting far infrared / near infrared light was synthesized by the Vicente March á n team of the University of Barcelona in Spain This kind of fluorescence molecule is based on coumarin, whose carbonyl is replaced by N alkylated cyano (4-pyridyl) methylene (scheme1a), thus increasing the push-pull properties of aromatic system This kind of molecule has strong luminescence, good light stability and large Stokes displacement Based on this, a new type of PDT photosensitizer (scheme1) was developed by combining the coupy fluorescent molecule with iridium (Ⅲ) complex C Compound 6), which can exist stably in water and cell culture medium, can selectively produce superoxide anion radical (SAR) under visible light irradiation, and the phototoxicity of PS is closely related to the generation of SAR Recently, the related research results were published in angel Chem Int ed (DOI: 10.1002 / anie 201901268), entitled "rewards novelphotodynamic agent generating superoxide anion Radios: acylometalized IR (III) complex adjusted to a far red sending coumarin" (image source: angelw Chem Int ed.) firstly, the optical properties and optical stability of compound 6 were tested (Figure 1) The results show that the new PS has the strongest phosphorescence at 660 nm When iridium (Ⅲ) complex is activated, coumarin will also emit fluorescence This indicates that there is energy transfer from iridium (Ⅲ) complex to coumarin In the presence of oxygen, iridium (Ⅲ) complexes can produce singlet oxygen in organic solvents, but not in PBS In conjugates, the ability of coumarin to produce singlet oxygen increased by an order of magnitude The photostability of PS is better than that of rose red, which is commonly used in biological system (image source: angelw Chem Int ed.) next, the authors studied the uptake of compound 6 by HeLa cells The results of confocal experiments show that the cells can effectively absorb compound 6, which is widely distributed in the cytoplasm, while coumarin 2 is mainly concentrated in mitochondria and nucleus (Figure 2) The results of quantitative analysis of iridium showed that the uptake of compound 6 by cells was stronger than that of compound 3, and the uptake of compound 6 by cells was independent of temperature (Table 1) These results showed that the cells absorbed compound 6 and compound 3 in different ways, which resulted in the different distribution of the two in the cells The authors then studied the killing effect of compound 6 on cancer cells (Table 2) MTT results showed that the cytotoxicity of compound 6 was lower than that of two parent molecules, and blue light could significantly enhance the antitumor effect of compound 6 However, due to the lower toxicity of compound 6 under dark conditions, the light toxicity index of compound 6 under green light and blue light is higher, which are 85 and 161 respectively (image source: angelw Chem Int ed.) (image source: angelw Chem Int ed.) (image source: angelw Chem Int ed.) then, the author studied the ROS production of various compounds in cells under light and dark conditions (Figure 3) Under dark conditions, the levels of ROS produced by the three compounds were similar Once irradiated by visible light, the level of ROS produced by compound 6 was significantly higher than that of compound 2 and compound 3 This indicated that the photocellular toxicity of compound 6 was related to the ROS produced in the cells The cytotoxic test showed that compound 6 had the same cytotoxicity under normal and hypoxic conditions, which indicated that compound 6 was also suitable for the treatment of hypoxic tumors Then, the author analyzed the types of ROS that lead to cell death (Figure 4) By treating cells with selective ROS scavenger, the author found that only the reagent (Tiron) that can selectively scavenge SRA can inhibit the ROS produced by the compound Under the light condition, compound 6 can produce SRA in cells, and its cytotoxicity can be completely eliminated after SRA removal, which indicates that compound 6 can induce tumor cell death by producing SRA under the light In addition, compounds 2 and 3 could not significantly enhance the production of intracellular ROS under light These results show that the combination of coupy fluorescent molecules and iridium (Ⅲ) complexes not only enhances the uptake of PS, but also enhances the phototoxicity of PS by producing highly toxic SRA under light (image source: angelw Chem Int ed.) (image source: angelw Chem Int ed.) all in all, this study is the first time to synthesize a new PS based on the coopy fluorescence molecule and iridium (Ⅲ) ring metal complex, and tumor cells have a strong uptake of this compound The compound can produce SRA which is highly cytotoxic under light, no matter whether it is lack of oxygen or not, leading to the death of tumor cells Therefore, this new near-infrared fluorescent dye complex can overcome the problems of poor tissue permeability and high dependence on local oxygen concentration faced by PDT It can be regarded as a model of fluorescent PS for the diagnosis and treatment of hypoxic tumors.
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