Drift Correction Method In Super-resolution Localization Imagin

Oxidative stress and inflammation caused by excessive reactive oxygen species(ROS)have become the key pathogenic factor of atherosclerosis.ROS induces low density lipoprotein to become oxidized low-density lipoprotein,thus promoting the formation of foam cells,leading to the continuous deterioration of the disease.ROS leads to apoptosis and oxidative damage of protein and other biomolecules.ROS also disrupts redoxdependent signaling in the vascular wall to promote the progression of atherosclerosis.The existing clinical treatment methods mainly include lipid-lowering drugs and antiplatelet drugs,but pay less attention to the oxidative microenvironment and inflammation,and there is no effective treatment.The results of preclinical studies of known antioxidants are also disappointing.Therefore,it is necessary to study suitable preparations to ameliorate the oxidative microenvironment of atherosclerosis.In this study,we first designed a red blood cell membrane biomimetic nano delivery system(RPP-PU)by the polylactic acid glycolic acid diphenyl cyclic peroxyoxalate bond polyethylene glycol(6s-PLGA-DAr-PO-PEG)material loaded with probucol and with high sensitivity of ROS scavenging ability to treat atherosclerosis more effectively.The preparation,cell and animal experiments were carried out by using oxalyl chloride as a key component to prepare new materials,ultrasonic emulsification-solvent evaporation method to prepare nano preparation,in vitro detection of drug release under the condition of hydrogen peroxide,HPLC measurement of drug content and blood drug concentration,immunofluorescence detection of cellular ROS content,establishment of apolipoprotein E deficiency(APOE-/-)atherosclerosis mouse model,in vivo imaging observation of the distribution,aortic oil red and masson staining and other experimental methods.The results showed that 6s-PLGA-DAr-PO-PEG had high sensitivity to ROS,and the response sensitivity reached 10 μmol/L,closing to the lowest ROS concentration level in the pathological microenvironment.RPP-PU had good stability for 14 days in vitro,high drug loading and encapsulation efficiency,good biocompatibility and blood safety.RPP-PU possessed obvious ROS responsiveness and scavenging function in hydrogen peroxide liquid and cell in vitro.RPP-PU delayed the release of probucol in vivo and prolonged its action time and had good retention effect in the aorta and liver.In APOE-/-model mice,RPP-PU effectively eliminated pathological ROS,reduced lipid levels and related enzyme levels,and significantly reduced the area of vascular plaques and fibers.Our study showed that the ROS scavenging biomimetic nano delivery system could clear rich ROS in atherosclerotic lesions,thereby reducing the oxidative stress microenvironment and achieving a more ideal therapeutic goal for atherosclerosis.In order to achieve better atherosclerosis targeting and inhibition of foam cells,this study continued to design another bionic nano delivery system,which used monocytes to phagocytize hydrogen peroxide responsive nanoparticles containing M2 macrophage secretion and atorvastatin to form "carriers"(MAMS).It was designed to regulate immune responses and make better use of the functions of cells themselves.In this study,we observed the activity of monocytes by dying or alive staining,induced M2 macrophages,observed the migration of monocytes to foam cells by Transwell chamber,detected the lipid and its efflux of foam cells,detected the lipid of aorta and blood,and detected the M2 macrophage markers induced by immunofluorescence and flow cytometry to observe the therapeutic effect in vivo and in vitro.The results showed that MAMS could induce M2 macrophages and maintained good activity after phagocytizing nanoparticles.MAMS also significantly scavenged ROS in vitro.MAMS inhibited the formation of foam cells and promoted lipid efflux in vitro.MAMS promoted the transformation of monocytes into M2 macrophages and migration to foam cells.In atherosclerosis model mice,MAMS effectively reduced blood lipids,regulated the level of relevant enzymes,reduced the area of foam cells and fibers,induced M2 macrophages,reduced inflammation and regulated the proliferation of smooth muscle.In short,this study mainly focuses on the oxidative microenvironment of local atherosclerotic lesions,the formation of foam cells and other key disease problems.Two cell-based biomimetic nano delivery systems were designed.While removing excessive ROS,they achieved multiple effects such as "lipid-lowering,anti-inflammatory and antioxygen,targeting,microenvironment amelioration and immunorestoration",enhanced the treatment of free drugs for atherosclerosis.The combination of this responsive material and biomimetic nano delivery system will become a new research strategy of atherosclerotic treatment by taking advantage of the circulating and targeting of cells,cooperating with pathological repairing,and meeting the physiological needs of the disease.