Moderately Heavy\nAtom-Substituted BODIPY Photosensitizer\nwith Mitochondrial Targeting Ability for Imaging-Guided Photodynamic\nTherapy

Advanced photodynamic therapy requires photosensitizers\nwith targeting,\ndiagnostic, and therapeutic properties. To fulfill this multifunctionality,\nwe report the synthesis of two triphenylphosphonium (TPP)-functionalized\nboron-dipyrromethene (BODIPY) dyes, TPPB-H and TPPB-Br, which incorporate\na hydrogen atom and dibrominated vinyl moiety at the 6-position of\nthe BODIPY core, respectively. The heavy-atom effect of the moderately\nheavy bromine atoms allowed TPPB-Br to achieve a proper balance between\nthe toxic singlet oxygen (<sup>1</sup>O<sub>2</sub>) production and\nfluorescence efficiencies. In this dye, the bromine atom-induced stimulation\nof the singlet-to-triplet intersystem crossing dynamics resulted in\nan approximately 45-fold increase in the <sup>1</sup>O<sub>2</sub> quantum yield with respect to that of the nonbrominated counterpart\n(0.0059 and 0.28 for TPPB-H and TPPB-Br, respectively). This increase\nwas accompanied only a 2-fold reduction in the fluorescence quantum\nyield (0.54 and 0.22 for TPPB-H and TPPB-Br, respectively). During\nmulticolor confocal laser scanning microscopy observations conducted\nusing two carcinomas, MCF-7 and HeLa, both BODIPY dyes exhibited high\ntargeting specificity toward cancer cell mitochondria owing to the\nTPP cation functionalization. The two dyes also showed the feasibility\nof fluorescence cell imaging; however, only the dibrominated BODIPY\nTPPB-Br manifested pronounced photocytotoxicity with half-maximal\ninhibitory concentrations of 0.12 and 0.77 μM obtained for MCF-7\nand HeLa cells, respectively. These findings demonstrate the potential\napplicability of TPPB-Br as an imaging-guided photodynamic therapy\nagent with mitochondrial specificity.