A Reactive Oxygen Scavenging Nucleic Acid Delivery Systems Targeting Atherosclerotic Plaques

Atherosclerosis Atherosclerosis(AS)is considered a major cause of cardiovascular disease(CVD),and unpredictable rupture of vulnerable atherosclerotic plaques can lead to adverse cardiovascular events such as acute myocardial syndrome(ACS)and even sudden cardiac death(SCD).Therefore,assessment of atherosclerotic plaque vulnerability and early intervention are important to reduce cardiovascular disease mortality.Both oxidative stress and inflammatory injury promote the development of atherosclerosis.Many novel therapeutic approaches for gene therapy in atherosclerosis have received widespread attention,and the treatment of atherosclerosis by constructing cationic nucleic acid delivery systems has attracted the interest of many scholars,and interleukin-10(IL-10)has attracted widespread clinical interest as an anti-inflammatory immunomodulator.In addition,the targeting of the atherosclerotic pathological microenvironment is often overlooked,and vascular cell adhesion molecule-1(VCAM-1)expressed by endothelial cells is an important marker of atherosclerotic plaque,and timely diagnosis and treatment can significantly reduce the mortality caused by atherosclerosis.Therefore,how to combine the pathological characteristics of atherosclerosis with the physicochemical properties of the designed delivery system for targeting lesion sites,scavenging reactive oxygen species(ROS)and inhibiting inflammation while achieving in vivo imaging performance of lesion sites is our current problem to be solved.To this end,we have conducted the following studies.In Chapter 2 of the thesis,we constructed reactive oxygen scavenging cationic polymers(PGED-TEMPO)using amino radical quenchers mixed with cationic reagents such as ethylenediamine to open the ring of polyglycidyl methacrylate(PGMA),and then modified it by introducing targeting peptides that can target the location of atherosclerotic lesions to finally construct reactive oxygen scavenging cationic polymers(PGED-TEMPO-VHPK)that can target atherosclerotic lesions in blood vessels.In Chapter 3 of the thesis,a comprehensive evaluation of the in vitro biological performance of the vector was performed by using human umbilical vein endothelial cell(HUVEC)and mononuclear macrophage(RAW264.7)cell lines to demonstrate that in vitro simulated cellular inflammation situations,the designed combination of PGED-TEMPO-VHPK with PIL-10 had,compared to PGED-TEMPO-VHPK better scavenging of reactive oxygen species(ROS)and inhibition of inflammation.In vivo magnetic resonance imaging(MRI)demonstrated better imaging effects of PGED-TEMPO-VHPK compared to PGED-TEMPO.The resulting novel multifunctional polycationic nucleic acid delivery system for AS therapy and in vivo imaging through a combined anti-inflammatory and reactive oxygen species scavenging mechanism can be prepared for subsequent in vivo experiments.The results of the study are of great academic value for improving the theoretical innovation and practical exploration of multifunctional gene delivery carriers.