Study On The DNA Interaction And Photodynamic Antitumor Activity Of Halogenated Gallium Corroles

Nowadays,cancer is one of the most deadly diseases.Traditional cancer treatments,including surgery,radiation and chemotherapy,can cause serious side effects,resulting in the loss of normal organ function.By contrast,photodynamic therapy(PDT)is more controlled and can selectively destroy tumor cells with less damage to normal tissue.PDT involves injecting photosensitizers into cancer patients either intravenously or intraperitoneally.According to the pharmacokinetic properties of the drug,the tumor is illuminated at the time of maximum drug uptake.The process ultimately produces singlet oxygen,a cytotoxin,which is a key factor in tumor destruction.Therefore,the choice of photosensitizer plays a decisive role in the efficacy of PDT.As porphyrin analogs,corroles also have great potential as PDT photosensitizers,and gallium corroles have been reported to have good photodynamic antitumor activity.In addition,the heavy atom effect can enhance the ability of photosensitizer to produce singlet oxygen and improve the efficacy of PDT.Based on the above analysis,in this paper,we have designed and synthesized a series of halogenated gallium(III)corroles,studied their interaction with DNA and photodynamic antitumor activity.The research contents are as follows:1?Four halogenated free base corroles and their gallium(III)complexes were synthesized and well characterized by using UV-visible electron absorption spectroscopy(UV-Vis),high resolution mass spectrum(HRMS),nuclear magnetic resonance spectrometer(NMR)and fourier transform infrared spectrum(FT-IR).2?The interaction between four halogenated gallium(III)complexes and CT-DNA was studied by UV-Vis and fluorescence spectrophotometry titration.The results showed that these gallium corroles bound to DNA via an outside binding mode,and compared to other gallium corroles,1-Ga had a stronger interaction with CT-DNA.3?The photostability and self-aggregation behavior of four halogenated gallium(III)complexes in different solvent systems were measured by electron absorption spectroscopy.The results showed that the photostability of 3-Ga was the best.In DMF,four gallium corroles did not show self-aggregation behavior within the tested concentration range,but 4-Ga showed self-aggregation behavior when the concentration reached 40 ?M in DMF/Tris-HCl.In addition,The ability to produce singlet oxygen of four halogenated gallium(III)complexes was measured by EPR,and the results showed that 3-Ga had the strongest ability to produce singlet oxygen.4?The in vitro cytotoxicity of four halogenated gallium(III)complexes toward three kinds of tumor cells(A549,231 and HepG2)and two kinds of normal cells(HSF and Huvec)under dark and light conditions was studied by MTT assay.The results showed that the cytotoxicity of gallium corroles depend on the cell type,and 3-Ga had the best photodynamic activity to HepG2 cells.5?The uptake of 3-Ga by HepG2 cells was investigated by confocal microscopy and flow cytometry,and the results showed that 3-Ga could efficiently penetrate HepG2 cells without the addition of any external carrier protein.Under light conditions,3-Ga could effectively produce reactive oxygen species in HepG2 and cause the decrease of mitochondrial membrane potential.Flow cytometry results showed that 3-Ga could induce apoptosis of HepG2 cells and lead to an increase of cells at the sub-G0 phase.6?The acute toxicity of 3-Ga in vivo was simply evaluated in BALB/c mice,and the results showed 3-Ga had very low acute toxicity at a dose of 10 mg/kg.