(Oxidopyridyl)Porphyrins of Different Lipophilicity: Photophysical Properties, ROS Production and Phototoxicity on Melanoma Cells Under CoCl2-Induced Hypoxia

Mušković, Martina; Lončarić, Martin; Ratkaj, Ivana; Malatesti, Nela (2025) (Oxidopyridyl)Porphyrins of Different Lipophilicity: Photophysical Properties, ROS Production and Phototoxicity on Melanoma Cells Under CoCl2-Induced Hypoxia. Antioxidants, 14 (8). ISSN 2076-3921

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Official URL: https://www.mdpi.com/2076-3921/14/8/992

Abstract

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 AB3 pyridylporphyrin precursors, using m-chloroperbenzoic acid (m-CPBA) as an oxidising reagent. Their ground-state and excited-state spectroscopic properties, singlet oxygen (1O2) 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 CoCl2-induced hypoxia. The CoCl2 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/1O2. 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 CoCl2-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 CoCl2-induced hypoxia and normoxia. Their potential HAP activity will be evaluated under conditions of reduced oxygen concentration in our future studies.

Item Type:

Article

Uncontrolled Keywords:

(oxidopyridyl)porphyrin; lipophilicity; reactive oxygen species; singlet oxygen; phototoxicity; hypoxia; melanoma cells

Subjects:

NATURAL SCIENCES > Chemistry
NATURAL SCIENCES > Biology
INTERDISCIPLINARY AREAS OF KNOWLEDGE

Divisions:

Division of Experimental Physics

Projects: