Study On Nano-drugs Combined With Photodynamic Therapy And Glutamine Metabolism Intervention

In triple negative breast cancer(TNBC),glutamine metabolism is extremely active,which can provide energy source for tumor cells,promote the synthesis of biological macromolecules and maintain intracellular redox balance,and play an important role in supporting tumor cell proliferation and metastasis.Therefore,the intervention of glutamine metabolism in TNBC cells is a very potential method for the treatment of TNBC.Although glutamine metabolism inhibitors can effectively block glutamine metabolism and inhibit the proliferation and metastasis of TNBC cells,TNBC cells can maintain their own proliferation needs through other compensatory metabolic pathways,affecting the efficacy of glutamine metabolism intervention.Photodynamic therapy(PDT)is a new type of minimally invasive tumor therapy,which relies on excessive reactive oxygen species(ROS)produced by photosensitizer(PSs)under laser irradiation,resulting in irreversible damage to tumor cells and inhibition of tumor activity.Therefore,when PDT is combined with glutamine metabolism intervention,PDT can inhibit the activity of tumor cells and increase the consumption of glutathione(GSH),which is an antioxidant metabolite,while the regulation of glutamine metabolism can not only reduce the energy supply of tumor cells,but also inhibit the production of GSH,thus comprehensively reduce the content of tumor GSH,aggravate the damage of ROS to cells,and reduce the tolerance of tumor cells to glutamine inhibition.Produce synergistic anti-tumor effect.Based on the above related research,we designed a nano-platform(BCH NPs)based on glutaminase inhibitor(BPTES)and photosensitizer Chlorin e6(Ce6),which cooperated with glutamine metabolic inhibition and photodynamic therapy to combat triple negative breast cancer.BCH NPs is composed of BPTES,Ce6 and HSA.BPTES and Ce6 are formed by hydrophobic interaction and π-π stacking interaction with the help of HSA,and the addition of HSA can increase the stability and biocompatibility of the nanoparticles.The main research contents,methods and conclusions are as follows:Preparation and characterization of BCH NPs.BCH NPs were prepared by nanoprecipitation method.Ultraviolet-visible absorption(UV-vis)spectra indicated that the nanoparticles were successfully prepared.The chemical composition of BCHNPs was analyzed by scanning electron microscopy(SEM)combined with energy dispersive X-ray spectroscopy(EDS),which once again proved the successful preparation of nanoparticles.The results of transmission electron microscopy(TEM)showed that the nanoparticles were spherical.Dynamic light scattering(DLS)showed a mean particle size of 120.8± 1.3 nm and a charge of-22.4±1.7 mV.In vitro photodynamic experiments showed that the nanoparticles can efficiently produce singlet oxygen(1O2).The hemolysis rate of nanoparticles was less than 5%,which proved that nanoparticles could be administered intravenously.MDA-MB-231 human breast cancer cells were used as model cells to verify the antitumor effect of nanoparticles at the cellular level.Uptake experiments showed that the uptake efficiency of BCH NPs by MDA-MB-231 cells was higher than that of Ce6.In the experiment of intracellular reactive oxygen production,the reactive oxygen production of BCH NPs +Laser group was much higher than that of Ce6+Laser group due to the increase of intake.In addition,the intracellular GSH content of BCH NPs+Laser group was also significantly reduced.MTT experiment showed that the nanoparticles had superior antitumor effect under laser.Finally,BALB/CA-nu female mice were used as model animals to verify the antitumor effect of nanoparticles at the animal level.The distribution of BCHNPs in mice showed that BCH NPs accumulated in tumor sites.In vivo tumor inhibition and anti-metastasis experiments,the BCH NPs+Laser group showed the best effect.In addition,the tissue sections and blood biochemical indexes proved that the nanoparticles had no tissue toxicity and good biocompatibility.In summary,a self-assembled nanoparticle of glutamine metabolism regulation combined with photodynamic therapy was prepared in this study.The treatment strategy greatly reduces the amount of glutathione in tumors,synergistically enhances the effect of glutamine metabolism inhibition and photodynamic therapy,and provides great potential for clinical transformation of TNBC therapy.