Disulfide‐Linked Dendritic Oligomeric Phthalocyanines as Glutathione‐Responsive Photosensitizers for Photodynamic Therapy

• Published in: Chemistry : a European journal 2018-04, Vol.24 (22), p.5779-5789
• Main Authors: Chow, Sun Y. S., Wong, Roy C. H., Zhao, Shirui, Lo, Pui‐Chi, Ng, Dennis K. P.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Alkynes; Chemical synthesis; Chemistry; Citric acid; Colon; Cycloaddition; dendrimers; Dimethylformamide; Disulfide bonds; Fluorescence; Glutathione; Irradiation; Oxygen; Permeability; Photodynamic therapy; photosensitizers; phthalocyanines; Quenching; Radiation; self-quenching; Singlet oxygen; Tumors; Zinc
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201706128

A series of disulfide‐linked dendritic phthalocyanines were synthesized by using the CuI‐catalyzed alkyne–azide cycloaddition reaction as the key step. Whereas these compounds were essentially nonaggregated in N,N‐dimethylformamide, they were stacked in citrate solution (pH 7.4, with 1 % Cremophor EL), as shown by the broad appearance of their Q‐band absorption. Having two‐to‐six zinc(II) phthalocyanine units in a molecule, these compounds were significantly self‐quenched, particularly in citrate solution. Both the fluorescence intensity and singlet‐oxygen generation efficiency were significantly lower than those of the monomeric counterparts, and the self‐quenching efficiency increased as the number of phthalocyanine units increased. Upon interaction with 5 mm glutathione (GSH) in citrate solution, the fluorescence intensity of these compounds increased as a result of cleavage of the disulfide linkages and separation of the phthalocyanine units, which thereby reduced the self‐quenching effect. The “on/off” ratios were found to be 7, 18, 23, and 21 for the dimeric (PC2), trimeric (PC3), tetrameric (PC4), and hexameric (PC6) systems, respectively. GSH also enhanced the fluorescence emission inside human colon adenocarcinoma HT29 cells and promoted the formation of singlet oxygen of these compounds. Upon irradiation, their half maximal inhibitory concentration (IC50) values were found to be in the range of 0.18 to 0.38 μm. Finally, the biodistribution and activation of PC2 and PC6 were also examined in HT29 tumor‐bearing nude mice. For both compounds, the fluorescence intensity per unit area at the tumor was found to grow gradually during the first 24 h. Whereas the intensity then dropped for PC2, the intensity for PC6 remained steady over the following 6 d, which might have been a result of the enhanced permeability and retention effect arising from the larger molecular mass of the hexameric system. Six pack: A series of self‐quenched dendritic phthalocyanines are synthesized and activated by glutathione (GSH) in citrate solution, inside HT29 cells, and in tumor‐bearing nude mice. The effects of the number of phthalocyanine units in these molecules on the photophysical and photobiological properties are also examined. Among the series, the hexameric system shows prolonged fluorescence intensity in vivo (see scheme; PS=photosensitizer).