National & Local Joint Biomedical Engineering Research Center on Photodynamic Technologies, College of Chemistry, Fuzhou University, Fuzhou, 350108, China.
National & Local Joint Biomedical Engineering Research Center on Photodynamic Technologies, College of Chemistry, Fuzhou University, Fuzhou, 350108, China; Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry, Fuzhou University, Fuzhou, 350108, China; State Key Laboratory of Photocatalysis on Energy and Environment, College of Chemistry, Fuzhou University, Fuzhou, 350108, China.
Eur J Med Chem. 2020 May 1;193:112203. doi: 10.1016/j.ejmech.2020.112203. Epub 2020 Mar 6.
Here, we have synthesized and characterized a novel activatable photosensitizer (PS) 8a in which two well-designed boron dipyrromethene (BODIPY) derivatives are utilized as the photosensitizing fluorophore and quencher respectively, which are connected by a disulfide linker via two successive Cu (І) catalyzed click reactions. The fluorescence emission and singlet oxygen production of 8a are suppressed via intramolecular fluorescence resonance energy transfer (FRET) from the excited BODIPY-based PS part to quencher unit, but both of them can be simultaneously switched on by cancer-related biothiol glutathione (GSH) in phosphate buffered saline (PBS) solution with 0.05% Tween 80 as a result of cleavage of disulfide. Also, 8a exhibits a bright fluorescence image and a substantial ROS production in A549 human lung adenocarcinoma, HeLa human cervical carcinoma and H22 mouse hepatoma cells having a relatively high concentration of GSH, thereby leading to a significant photocytotoxicity, with IC values as low as 0.44 μM, 0.67 μM and 0.48 μM, respectively. In addition, the photosensitizer can be effectively activated and imaged in H22 transplanted hepatoma tumors of mice and shows a strong inhibition on tumor growth. All these results suggest that such a GSH-responsive photosensitizer based on FRET mechanism may provide a new strategy for tumor-targeted and fluorescence imaging-guided cancer therapy.
在这里，我们合成并表征了一种新型的可激活光动力剂（PS）8a，其中两个经过精心设计的硼二吡咯甲烷（BODIPY）衍生物分别用作光敏荧光团和猝灭剂，它们通过两个连续的 Cu（І）催化点击反应通过二硫键连接。8a 的荧光发射和单线态氧产生通过来自激发的基于 BODIPY 的 PS 部分到猝灭单元的分子内荧光共振能量转移（FRET）被抑制，但由于二硫键的断裂，它们都可以同时在磷酸盐缓冲盐水（PBS）溶液中的癌症相关生物硫醇谷胱甘肽（GSH）中被同时打开，其中含有 0.05%吐温 80。此外，8a 在 A549 人肺腺癌细胞、HeLa 人宫颈癌细胞和 H22 小鼠肝癌细胞中表现出明亮的荧光图像和大量 ROS 产生，这些细胞具有相对较高浓度的 GSH，从而导致显著的光细胞毒性，其 IC 值分别低至 0.44 μM、0.67 μM 和 0.48 μM。此外，该光敏剂可在小鼠 H22 移植肝癌肿瘤中有效激活和成像，并对肿瘤生长表现出强烈的抑制作用。所有这些结果表明，这种基于 FRET 机制的 GSH 响应型光动力剂可能为肿瘤靶向和荧光成像引导的癌症治疗提供新策略。
