Investigation Of Manganese-based Nanoliposomes Loaded With Dihydroartemisinin Construction And Its Anti-pancreatic Cancer Effect

Pancreatic cancer is one of the most malignant tumors in the digestive system,known as the "king of cancers",which seriously endangers human life and health.Novel therapies mediated by reactive oxygen species(ROS)have been widely studied in the biological field because of their excellent anti-tumor effects.For example,photodynamic therapy(PDT),chemodynamic therapy(CDT)and sonodynamic therapy(SDT)can produce cytotoxic ROS for tumor treatment through different pathways under the stimulation of light,chemistry and sound.However,the efficiency of ROS is limited by hypoxia,insufficient endogenous Fenton reaction substrate,and the ROS scavenger glutathione(GSH)in the tumor microenvironment(TME),which seriously affects the effectiveness of ROS-like mediated tumor therapy.Based on this,this study constructs a manganese-based nanoliposome drug delivery platform to load relevant therapeutic agents to improve the efficiency of intracellular ROS production through both enhanced production and reduced consumption strategies.In this thesis,we designed and prepared manganese-based liposome nanoparticles(MLP@DHA&Ce6)with peroxide and oxygen self-supply.First,the hydrophobic drugs dihydroporphyrin e6(Ce6)and dihydroartemisinin(DHA)were loaded in the hydrophobic cavities of liposomes through hydrophobic interaction with phospholipid bilayers,and then a layer of manganese dioxide nanoparticles were obtained by coating the liposomal surface with manganese nanoparticles using the redox reaction of potassium permanganate(KMn O4)and polyethylene glycol-2000(PEG-2000).Then,the MLP@DHA&Ce6 were characterized by using transmission electron microscopy(TEM)and ultraviolet-visible spectrophotometer(UV-vis)and X-ray photoelectron spectroscopy(XPS).The results showed that MLP@DHA&Ce6 has a rough spherical structure on the surface.The successful preparation of MLP@DHA&Ce6 was further demonstrated by the tetravalent characteristic peak of manganese element in XPS results and the characteristic peak of Ce6 in UV-vis results.The in vitro results demonstrated that the manganese dioxide in MLP@DHA&Ce6 could catalyze the generation of oxygen and manganese ions from hydrogen peroxide to enhance PDT therapy and activate CDT,synergizing PDT and CDT.In addition,the MLP@DHA&Ce6 nanoparticles had a destructive effect on glutathione,further protecting ROS from glutathione scavenging.The uptake of MLP@DHA&Ce6 by human-derived pancreatic cancer Bx PC-3 cells was investigated by laser confocal microscopy,and the results showed that MLP@DHA&Ce6 could be effectively taken up by Bx PC-3 cells.The cytotoxicity of the nanodelivery platform MLP was investigated using MTT assay,and the results showed that the cells did not exhibit significant damage even at ultra-high concentrations of 2 mg/m L,indicating that our manganese-based nanoliposome drug delivery platform has excellent biosafety,and its toxicity increases with increasing concentration after drug loading.The efficient intracellular ROS induction efficiency of MLP@DHA&Ce6 was then demonstrated using a ROS probe.The results of in vivo anti-tumor assay showed that the tumor volume of MLP@DHA&Ce6 group was significantly decreased and the growth of tumor cells was effectively inhibited.In summary,the MLP@DHA&Ce6 designed and prepared in this paper released loaded drug,manganese ions and oxygen under the stimulation of 660 nm NIR light irradiation and tumor microenvironment(TME).Oxygen enhanced Ce6-mediated PDT,while manganese ions catalyzed the breakage of the internal peroxide bridge in the DHA structure to activate CDT.in addition,MLP@DHA&Ce6 nanoparticles had efficient GSH destruction properties.Therefore,manganese-based nanoliposomes significantly enhanced the production of ROS in pancreatic cancer cells,which in turn inhibited the growth of pancreatic cancer cells.In this paper,we have synergized PDT and CDT with simple carriers for efficient ROS generation in pancreatic cancer cells through rational design,which provides a theoretical basis and design ideas for synergistic therapy of pancreatic cancer.