Study On Stimulus-responsive Functional Nanocarrier For High Radioprotection Activity

With wide application of nuclear energy and radiation technology in various fields such as industry,medicine,military,food etc,various nuclear accidents have occurred from time to time,such as nuclear reactor accidents,loss of radioactive sources and radiotherapy accidents.Moreover,worldwide terrorist attacks such as radioactive “dirty bombs” present an enormous challenge for biological and medical safety.In this way radiation poses a great threat to people's lives,leading to acute radiation sickness on organs and the whole body,such as bone marrow type radiation sickness(1-10 Gy),acute intestinal type radiation sickness(10-50 Gy)and acute cerebral radiation sickness(> 50 Gy).These diseases including anemia,infection and bleeding complications.It is difficult to cure and recover from these diseases.Thus this situation has received more and more attention.In order to deal with the radiation hazards in nuclear radiation emergencies,nuclear terrorism,and radiation diagnosis and treatment,it is of great significance to carry out in-depth research on basic applications of radiation protection and treatment.Studies have found that ionizing radiation acts directly on water,causing water molecules to produce a series of highly reactive oxygen species such as hydroxyl radicals,hydrogen,and hydrogen peroxide.The radiation degradation products of water then act on biological macromolecules,causing changes in their physical and chemical properties.Thus when humans are exposed to radiation,a large amount of highly reactive oxygen free radicals were produced through radiation hydrolysis.Reactive oxygen-responsive groups in these carriers could fall apart and then release radioprotective drugs once arriving such environments.As a result,tissue damage caused by free radical attack is greatly reduced,and a high radioative activity could be reached.Besides,the use of red blood cell membranes(RBCs)can avoid the clearance of reticuloendothelial system(RES)thus achieve long-circulating drug delivery.Furthermore,RBCs modified with targeting ligand could achieve accuracy of the medication.In this dissertation,we employed a ROS-responsive polymer carrier and erythrocyte membrane to deliver drugs with radioprotective effect and explore the mechanism for their radioprotective effects.Specific studies of this paper are as follows:(1)A strategy for high radioprotective activity by the assembly of PprI protein with a ROS-sensitive polymeric carrierThis chapter shows a strategy for high radioprotective activity of PprI protein by a ROS-sensitive polymeric carrier.CS-CP5K-PEG was prepared by the reaction of PEG-CP5K-NHS with CS.The graft copolymer could self-assemble in PBS displaying core-shell morphology with a narrow size distribution,and shows good ROS-responsive property due to the linkage of CP5 K.CS-CP5K-PEG could assemble with PprI protein,protect PprI protein from enzymolysis by lysozyme,and lower the cytotoxicity of PprI protein by improving its biocompatibility.Importantly,the polymeric carrier could improve the cell viability after 6 Gy of X-ray radiation in comparison with PprI protein at high concentrations(> 8 ?g m L-1).In vivo experiments showed that CS(PprI)-CP5K-PEG could improve the overall survival rate of radiated C57BL/6 mice and show good protection for the hematological system.A similar concept could be applicable to the delivery of other radioprotective agents by ROS-sensitive nanocarriers.This study may provide a new approach for highly effective radioprotection.(2)Erythrocyte membrane coated Ce O2 and Cu nanoparticles for radioprotection and radiotherapy.Whole blood was first withdrawn from male C57BL/6 mice.The resulting packed RBCs were treated with hypotonic medium for hemolysis.The RBC membranes were then incubated with Folate-PEG2000-DSPE to obtain folate-inserted RBC membranes.The mixture of folate-inserted RBC membranes and Cu nanoparticles were sonicated in a bath sonicator for 10 s,and then extruded several times back and forth through 100 nm extrusion membranes to obtain FA targeted red blood cells coated Cu(FA-RBC-Cu).The process for obtain the erythrocyte membrane coated Ce O2(RBC-Ce O2)were the same to RBC-Cu.Closer examination through SEM And DLS reveals a polymeric core approximately 215 nm in diameter and an outer lipid shell 8 nm thickness.The thickness of the lipid layer is in agreement with the reported membrane width of RBCs,suggesting a successful membrane translocation to the polymeric particle surface.The cytotoxicity of RBC-Cu and RBC-Ce O2 nanoparticles on HUVECs were much lower than the naked nanoparticles.Meanwhile RBC-Ce O2 nanoparticle show high radioprotection on HUVECs and RBC-Cu nanoparticle exhibit enhanced radiothearpy effect on SW1990 s.This study shows that the red blood cell membrane-coated Ce O2 and Cu nanoparticles have a great clinical application prospect on radioprotection and radiotherapy.