Chiaroscuro of P(V) porphyrins cytotoxicity: Balancing light and dark effects

In order to search for new more effective photosensitizers for photodynamic therapy, three phosphorus(V) porphyrins with donor meso-substituents (p-methoxyphenyl, p-methylphenyl, p-tert-butylphenyl) and axial ethoxy groups were synthesized. All complexes were sufficiently photostable and capable of effectively generating singlet oxygen with quantum yields of 0.68-0.74 in ethanol. The study revealed that complexes with meso-p-methylphenyl and meso-p-methoxyphenyl fragments demonstrated pico- and nanomolar photocytotoxicity both upon 450 nm (IC_{50 light} = 330 pM - 150 nM) and 660 nm (IC_{50 light} = 14-147 nM) light irradiation against human breast adenocarcinoma MCF-7 cells and human lung adenocarcinoma A-549 cells. The complexes also demonstrated high dark cytotoxicity, precisely in hypoxic conditions, which is atypical for photosensitizers. Therefore, a dual cytotoxicity mechanism was proposed: membrane damage in the dark followed by necrosis and light-induced ROS generation followed by apoptosis, which increases P(V) porphyrins activity in hypoxic conditions. Considering that solid tumors in vivo have a low oxygen supply, this could be an effective strategy for targeting tumor hypoxic cells, which are generally resistant to PDT.