The literature reports on cationic and anionic phthalocyanines (Pcs) for photodynamic therapy suggest systematically significant differences in activity. In this work, ten different zinc(II) Pcs with carboxylate functions or quaternary nitrogens (hydrophilic anionic, hydrophilic cationic, amphiphilic anionic, and amphiphilic cationic) were investigated, with the aim of revealing reasons for such differences. In vitro assays on HeLa, MCF-7, and HCT-116 cells confirmed higher photoactivity for cationic Pcs (EC50 ∼ 3-50 nM) than for anionic Pcs (EC50 ∼ 0.3-10 μM), the latter being additionally significantly more active in serum-free medium. The environmental pH, binding to serum proteins, interaction with biomembranes, differences in subcellular localization, and relocalization after irradiation were found to be the main factors contributing to the generally lower photoactivity of anionic Pcs than that of the cationic derivatives. This result is not limited only to the presented derivatives and should be considered in the design of novel photosensitizers.

Department of Analytical Chemistry Faculty of Pharmacy in Hradec Kralove Charles University Akademika Heyrovskeho 1203 Hradec Kralove 500 05 Czech Republic

Department of Biochemical Sciences Faculty of Pharmacy in Hradec Kralove Charles University Akademika Heyrovskeho 1203 Hradec Kralove 500 05 Czech Republic

Department of Pharmaceutical Chemistry and Pharmaceutical Analysis Faculty of Pharmacy in Hradec Kralove Charles University Akademika Heyrovskeho 1203 Hradec Kralove 500 05 Czech Republic

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Peripherally Crowded Cationic Phthalocyanines as Efficient Photosensitizers for Photodynamic Therapy