Novel Azole-Modified Porphyrins for Mitochondria-Targeted Photodynamic Therapy

Photodynamic therapy is a non-invasive treatment strategy for various types of cancer, based on the use of light to activate a photosensitizer which triggers processes leading to cell death. Given the increasing interest in the development of mitochondria-targeted photosensitizers, in this study we synthesized two novel thiadiazol-substituted porphyrins, 5,10,15,20-tetra(2,1,3-benzothiadiazol-5-yl) porphyrin (C1) and 5,10,15,20-tetra(1,2,3-thiadiazol-4-yl) porphyrin (C2), designed to target mitochondria in cancer cells thanks to the azole residues present in their structure. The two porphyrinic compounds were characterized in terms of structural and photophysical properties, revealing high yields of singlet oxygen production. Their interaction with biological structures was analyzed in a triple-negative human breast carcinoma cell line (MDA-MB-231), either as free compounds or delivered via mitochondriotropic liposome formulations. Both newly synthesized porphyrins entered MDA-MB-231 cells, with compound C2 demonstrating more efficient localization in the cytoplasm and in mitochondria. Dark and phototoxicity tests were also performed: both compounds proved to be effective phototoxic agents, with C2 showing the highest activity, making it a promising photosensitizer for mitochondria-targeted photodynamic therapy.