Research On Drug Delivery System With Dual Response Of Reactive Oxygen Species And Shear Stress For Atherosclerosis Treatment

Atherosclerosis is a key pathogenesis of cardiovascular diseases,which can lead to cardiovascular diseases such as myocardial infarction,angina pectoris,ischemic heart disease,ischemic stroke,and stroke.Atherosclerotic cardiovascular disease has become a major public health problem in the world.Even when the medical level is very advanced,the global mortality rate of cardiovascular disease has not decreased,but has become the main cause of the highest morbidity and mortality in the global population.In the next 10 years,the number of cardiovascular patients will continue to grow rapidly,which has attracted more and more researchers to participate in this"battle"to curb the development of atherosclerosis.Studies have shown that inflammation runs through the entire process of atherosclerosis development,and lipids also play an important role in promoting its development.These factors endow atherosclerosis with a special microenvironment,such as high reactive oxygen species（ROS）levels,high shear stress and high lipids content.The reduction of ROS and lipid levels plays a role in delaying the progression of atherosclerosis.This thesis takes high ROS levels and high shear stress as the research object,and uses red blood cells（RBCs）as bionic carriers to explore the construction methods of drug-loaded nanoparticles and drug-loaded micelles with ROS and shear stress response,and the therapeutic effect on atherosclerosis..The main research contents are as follows:（1）Constructed a biomimetic nano drug delivery system with a dual response of shear stress and ROS,which was composed of atherosclerosis drug anionic simvastatin acid（SA）,sulfhydryl-modified cationic polyethyleneimine（PEI-SH）and RBCs,using electrostatic adsorption and self-assembly to obtain drug-loaded nanoparticles SA PEI,and adsorbed them on the red blood cell membrane to obtain SA PEI@RBCs.The drug loading of SA PEI was 44.4±2.7%,which could achieve drug release in response to ROS.The in vitro shear model proved that SA PEI@RBCs had a shear stress response and the Fe Cl3 model proved that SA PEI@RBCs possessed the best therapeutic effect and had good in vivo safety.（2）The cross-linked dendrimer nanoparticles（SA PAM）loaded with simvastatin acid（SA）were designed to be adsorbed on the red blood cells（RBCs）surface to obtain SA PAM@RBCs,successfully prepared a drug delivery system with dual sensitivity to ROS and shear stress for the atherosclerosis treatment.Compared with SA PEI@RBCs,the drug loading of SA PAM nanoparticles in SA PAM@RBCs system was increased to 65.3±2.1%,and SA could be continuously released by H2O2 triggering,which could significantly reduce the H2O2 level in LPS-stimulated RAW 264.7 cells.The shear sensitivity model proved that under the action of low shear stress（20 dynes/cm²）,SA PAM in SA PAM@RBCs rarely desorbed,while the desorption of SA PAM was relatively complete under the stimulation of high shear stress（100 dynes/cm²）,and only a small amount of SA PAM was still adsorbed on red blood cells,indicating that SA PAM had better desorption ability in response to shear stress stimulation.Both the rabbit Fe Cl3 model and Apo E^-/-mouse model showed that SA PAM@RBCs had a better therapeutic effect and excellent safety in vivo than that of SA.The above results indicated that a biomimetic drug delivery system with dual sensitivity to ROS and shear stress could provide a promising strategy for the atherosclerosis treatment.（3）Developed an intelligent response system（SV MC@RBCs）that could simultaneously respond to ROS and the shear stress microenvironment of atherosclerotic plaque,which was consisted of RBCs and cationic micelles（SV MC）formed by loading simvastatin（SV）with polyglycidyl methacrylate-polypropylene sulfide（PGED-PPS）.Compared with SA PEI@RBCs and SA PAM@RBCs,the drug-carrying system with PGED-PPS as a carrier also had the effect of reducing ROS,and could cooperate with simvastatin to treat atherosclerosis.The in vitro and in vivo experiments results showed that SV MC@RBCs could effectively treat atherosclerosis,which not only avoided the risk of bleeding,but also had excellent in vivo safety.These results indicated that SV MC@RBCs was a promising therapeutic nanomedicine for the treatment of ROS-related diseases.