A glutathione-responsive photosensitizer with fluorescence resonance energy transfer characteristics for imaging-guided targeting photodynamic therapy

• Published in: European journal of medicinal chemistry Vol. 193; p. 112203
• Main Authors: Cao, Jing-Jing, Zhang, Ming-Shan, Li, Xiao-Qiang, Yang, De-Chao, Xu, Gan, Liu, Jian-Yong
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.05.2020; Elsevier
• Subjects: Activatable photosensitizers; Chemistry, Medicinal; Fluorescence resonance energy transfer (FRET); GSH-Responsive; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Photodynamic therapy; Science & Technology; QZWPIKQUUSBXCI-CWOUNDQWSA-N; WRSAPHZETIZPIQ-RNIAWFEPSA-N; YGFGCDHXBBWLDH-LQGKIZFRSA-N; Photodynamic therapy; GSH-Responsive; Activatable photosensitizers; LGJDQYJOPPMHPY-QAOXQPSNSA-N; Fluorescence resonance energy transfer (FRET); BODIPY; DESIGN; PH; OPTIMIZATION; COMBINATION; ZINC(II) PHTHALOCYANINE; DERIVATIVES; PROBES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112203

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 IC50 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. [Display omitted] •A novel glutathione-responsive photosensitizer has been synthesized.•The photosensitizer can be activated by glutathione in solution and cancer cells.•The photosensitizer exhibits a high photodynamic activity to cancer cells.•The photosensitizer can be efficiently accumulated and activated in tumor.•The photosensitizer shows a strong inhibition on tumor growth.