Moderately Heavy Atom-Substituted BODIPY Photosensitizer with Mitochondrial Targeting Ability for Imaging-Guided Photodynamic Therapy.

Advanced photodynamic therapy requires photosensitizers with targeting, diagnostic, and therapeutic properties. To fulfill this multifunctionality, we report the synthesis of two triphenylphosphonium (TPP)-functionalized boron-dipyrromethene (BODIPY) dyes, TPPB-H and TPPB-Br, which incorporate a hydrogen atom and dibrominated vinyl moiety at the 6-position of the BODIPY core, respectively. The heavy-atom effect of the moderately heavy bromine atoms allowed TPPB-Br to achieve a proper balance between the toxic singlet oxygen (O) production and fluorescence efficiencies. In this dye, the bromine atom-induced stimulation of the singlet-to-triplet intersystem crossing dynamics resulted in an approximately 45-fold increase in the O quantum yield with respect to that of the nonbrominated counterpart (0.0059 and 0.28 for TPPB-H and TPPB-Br, respectively). This increase was accompanied only a 2-fold reduction in the fluorescence quantum yield (0.54 and 0.22 for TPPB-H and TPPB-Br, respectively). During multicolor confocal laser scanning microscopy observations conducted using two carcinomas, MCF-7 and HeLa, both BODIPY dyes exhibited high targeting specificity toward cancer cell mitochondria owing to the TPP cation functionalization. The two dyes also showed the feasibility of fluorescence cell imaging; however, only the dibrominated BODIPY TPPB-Br manifested pronounced photocytotoxicity with half-maximal inhibitory concentrations of 0.12 and 0.77 μM obtained for MCF-7 and HeLa cells, respectively. These findings demonstrate the potential applicability of TPPB-Br as an imaging-guided photodynamic therapy agent with mitochondrial specificity.