(Oxidopyridyl)Porphyrins of Different Lipophilicity: Photophysical Properties, ROS Production and Phototoxicity on Melanoma Cells Under CoCl(2)-Induced Hypoxia.

One of the main limitations of photodynamic therapy (PDT) is hypoxia, which is caused by increased tumour proliferation creating a hypoxic tumour microenvironment (TME), as well as oxygen consumption by PDT. Hypoxia-activated prodrugs (HAPs), such as molecules containing aliphatic or aromatic N-oxide functionalities, are non-toxic prodrugs that are activated in hypoxic regions, where they are reduced into their cytotoxic form. The (oxido)pyridylporphyrins tested in this work were synthesised as potential HAPs from their AB(3) pyridylporphyrin precursors, using m-chloroperbenzoic acid (m-CPBA) as an oxidising reagent. Their ground-state and excited-state spectroscopic properties, singlet oxygen ((1)O(2)) production by the photodegradation of 1,3-diphenylisobenzofurane (DPBF) and theoretical lipophilicity were determined. In vitro analyses included cellular uptake, localisation and (photo)cytotoxicity under normoxia and CoCl(2)-induced hypoxia. The CoCl(2) hypoxia model was used to reveal their properties, as related to HIF-1 activation and HIF-1α accumulation. (Oxido)pyridylporphyrins showed promising properties, such as the long lifetime of the excited triplet state, a high quantum yield of intersystem crossing, and high production of ROS/(1)O(2). Lower cellular uptake resulted in an overall lower phototoxicity of these N-oxide porphyrins in comparison to their N-methylated analogues, and both porphyrin series were less active on CoCl(2)-treated cells. (Oxido)pyridylporphyrins showed higher selectivity for pigmented melanoma cells, and the antioxidant activity of melanin pigment seemed to have a lower impact on their PDT activity compared to their N-methylated analogues in both CoCl(2)-induced hypoxia and normoxia. Their potential HAP activity will be evaluated under conditions of reduced oxygen concentration in our future studies.