Synthesis And In Vitro Photodynamic Activities Of Reduction-responsive Boron Dipyrromethene Photosensitizer

Photodynamic therapy(PDT)is a promising minimally invasive clinical modality,which has many advantages over traditional therapeutic methods.PDT requires three elements:light,a photosensitizer(PS)and oxygen.The therapeutic outcome depends greatly on the behavior of the photosensitizer.Boron dipyrromethene(BODIPY)is a new type of fluorescent dye that has a broad application with its excellent photothermal stability,high molar extinction coefficient and readily modified precursor structure.In order to improve the selectivity of PDT and achieve the aim therapeutic with highly effective and low-toxic,here a novel reductive GSH/DTT-responsive Boron Dipyrromethene photosensitizer was synthesized based o photo-induced electron transfer(PET)mechanism.The conjugated is a combination of a quencher,linker and PS,namely,electron accepter fullerene C60 as quencher,GSH-responsive disulfide bond as linker and BODIPY derivatives as PS.It is expected that the photodynamic activity of the photosensitizer at the tumor site will be improved.In addition,its photophysical,photochemical properties and in vitro biological activities have been evaluated.Chapter 1 briefly introduce PDT,photosensitizers and the recently emerged strategies of targeting photodynamic therapy.And an overview of BODIPY including synthesis,properties,and applications for PDT.Chapter2 describes the synthesis and characterization of the compound DBSC and the control one DBCC,then we study their photophysical,photochemical properties.Results show that DBSC and DBCC have photophysical and photochemical properties of ideal photosensitizers,they exist in the cell culture medium with monomeric form mainly and the well photo-stability;inactivated DBSC and DBCC have almost no fluorescence quantum yield as a result of quenching by the C60 moiety(0.06 and 0.08,respectively),only DBSC can be activated when the concentration of DTT meets the concentration of GSH in tumor cells,with emitting fluorescence and producing a higher singlet quantum yield while DBCC does not exhibit the comparable properties.Chapter 3 explores the in vitro photodynamic activities of the activated photosensitizer DBSC and the control DBCC.The MTT and DCF assay for intracellular reactive oxygen species showed that DBSC had fine photodynamic targeting capability.It was not reduced by the micromolar concentration of GSH in HELF cells,and that DBSC in the"Turn off" state had no photodynamic activity;in H1299 and HeLa cells,DBSC was activated by the GSH-reduced response of tumor cells.DBSC in the "Turn on" state released photodynamic activity;Intense photodynamic activity is exhibited in DTT-pretreated H1299,HeLa and HELF cells.The ICs50 values were 0.06?M(H1299 and HELF cells)and 0.05 ?M(HeLa cells),respectively.DBCC in the HELF,H1299,and HeLa cells has been in a "turn off"state due to the stability of carbon-carbon bonds,and has no photodynamic activity.Subcellular localization experiments showed that DBSC mainly distributed in lysosomes and mitochondria in H1299 and HeLa cells.