trans-Bisglycoconjugation is an Efficient and Robust Architecture for PDT Photosensitizers Based on 5,10,15,20-Tetrakis(pentafluorophenyl)porphyrin Derivatives

To examine the versatility of the trans-bisglycoconjugation architecture for 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TFPP) derivative-based photodynamic therapy (PDT), 25 porphyrin derivatives bearing D-glucopyranose moieties were prepared, and their in vitro photocytotoxicities were examined. trans-Bisglycoconjugated TFPP derivatives exerted the best photocytotoxicity among TFPP derivatives in the same category, regardless of the central metal ion and the type of glycoconjugation. trans-Bisglycoconjugated free-base TFPP bearing β-D-glucopyranosylthio groups (trans-H22SGlc) was found to be the most potent photosensitizer, not only in HeLa cells (EC50 < 5 nM), but also in highly metastatic cancer cell lines such as B16-BL6 melanoma cells (EC50 < 10 nM). UV–vis and dynamic light-scattering measurements suggested that trans-bisglycoconjugated TFPP derivatives formed relatively large J-aggregates in an aqueous solution. trans-Bisglycoconjugated TFPP derivatives exhibited greater uptake by HeLa cells than those with different glycoconjugation patterns, with the exception of Zn(II) complexes. trans-Bisglycoconjugated TFPP derivatives efficiently generated hydrogen peroxide and hydroxyl radical by a type I photoreaction, while no significant differences were found in the efficiency of singlet oxygen generation by a type II photoreaction. These unique characteristics of trans-bisglycoconjugated TFPP derivatives support the conclusion that trans-bisglycoconjugation is a highly efficient and robust architecture for TFPP-based PDT development.