Mitochondria and DNA Targeting of 5,10,15,20-Tetrakis(7-sulfonatobenzo[b]thiophene) Porphyrin-Induced Photodynamic Therapy via Intrinsic and Extrinsic Apoptotic Cell Death

摘要

Photodynamic therapy (PDT) selectively targets subcellular organelles and promises an excellent therapeutic strategy for cancer treatment. Here, we report the synthesis of a new water-soluble photosensitizer, 5,10,15,20-tetralds (7-sulfonatobenzo[b]-thiophene) porphyrin (SBTP). Rational design of the porphyrinic molecule containing benzo[b]thiophene moiety at the meso-position led to selective accumulation in both mitochondria and nucleus of MCF-7 cells. This multitarget ability of SBTP can cause damage to mitochondria as well as DNA simultaneously. FACS analysis showed rapid cellular uptake of SBTP. High-content cell-based assay was executed to concurrently monitor increase of cytosolic Ca2+ levels, mitochondrial permeability transition (MPT), and caspase-3/7/8 activation in MCF-7 cells under the pathological condition caused by PDT action of SBTP. The study of cell death dynamics showed that PDT action of SBTP caused an increase in the MPT followed by an increase in cytosolic Ca2+ level. The localization of SBTP in the mitochondria activated the intrinsic apoptotic pathway. Additionally, localization of SBTP in the nucleus led to DNA damage in MCF-7 cells. The DNA fragmentation that occurred by PDT action of SBTP was thought to be responsible for extrinsic apoptosis of MCF-7 cells. SBTP demonstrated effective PDT activity of 5 mu M IC50 value to MCF-7 cells by bitargeting mitochondria and DNA.