期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 12, 期 3, 页码 502-507出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00045
关键词
Phthalocyanine; singlet oxygen; fluorescence; aggregation; phototoxicity; photodynamic therapy
资金
- Czech Science Foundation [19-14758Y]
- Charles University [PRIMUS/20/SCI/013, GAUK 1620219, SVV 260 550]
- project EFSA-CDN - ERDF [CZ.02.1.01/0.0/0.0/16_019/0000841]
- MINECO-Feder funds [CTQ2017-85393-P, CTQ-2014-53673-P, CTQ-2017-89539-P, PCIN-2017-042/EuroNanoMed2017-191]
- 'Severo Ochoa' Programme for Centres of Excellence in RD (MINECO) [SEV-2016-0686]
This study synthesized zinc phthalocyanine photosensitizers with bulky phenoxy substituents, demonstrating high photodynamic activity and low cytotoxicity against cancer cells. The compounds localized primarily in lysosomes, leading to apoptotic cell death pathway.
Photodynamic therapy is a treatment modality of cancer based on the production of cytotoxic species upon the light activation of photosensitizers. Zinc phthalocyanine photosensitizers bearing four or eight bulky 2,6-di(pyridin-3-yl)phenoxy substituents were synthesized, and pyridyl moieties were methylated. The quatemized derivatives did not aggregate at all in water and retained their good photophysical properties. High photodynamic activity of these phthalocyanines was demonstrated on HeLa, MCF-7, and EA.hy926 cells with a very low EC50 of 50 nM (for the MCF-7 cell line) upon light activation while maintaining low toxicity in the dark (TC50 approximate to 600 mu M), giving thus good phototherapeutic indexes (TC50/EC50) above 1400. The compounds localized primarily in the lysosomes, leading to their rupture after light activation. This induced an apoptotic cell death pathway with secondary necrosis because of extensive and swift damage to the cells. This work demonstrates the importance of a bulky and rigid arrangement of peripheral substituents in the development of photosensitizers.
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