Key Structural Factors Governing the Photodynamic Activity of Phthalocyanines

Phthalocyanines (Pcs) are promising photosensitizers (PSs) for photodynamic therapy (PDT) due to their strong absorption in the red part of the visible spectrum and ability for singlet oxygen generation. However, variability of experimental conditions in in vitro experiments among published derivatives complicates clear comparisons. In this study, we systematically evaluated a diverse set of over forty Pcs including cationic, anionic, nonionic Zn, Mg or metal-free Pc or axially substituted silicon Pcs and compared them with clinically approved PSs (PpIX, ver-teporfin, temoporfin, Photosens) under standardized conditions. Their spectral and photophysical properties (ΦΔ, ΦF, τF), interactions with bovine serum albumin (BSA), subcellular localization, and in vitro PDT efficacy (EC₅₀ values) in three human cancer cell lines were assessed. Key structural features influencing PDT efficacy include their existence in monomeric state through axial substitution (e.g., in silicon Pcs) or rigid bulky peripheral groups, with the latter enhancing activity in cationic while reducing it in nonionic derivatives. Amphiphilic, low-symmetry structures significantly improved PDT efficacy, especially for nonionic and anionic Pcs. While BSA binding can help monomerization, it may also partially quench excited states, and overall, cationic Pcs showed higher EC₅₀ values (typically dozens of nM), likely due to reduced protein interactions and other contributing factors. The re-sults of this study provide clear design principles for future development of highly efficient PSs for PDT.