| Atherosclerosis,as one of the cardiovascular diseases,has attracted widespread attention in recent years.Its main pathological features are endothelial damage,lipid accumulation and progressive local inflammation.As atherosclerosis progresses and worsens,advanced lesions of plaques can cause restriction or blockage of blood flow,leading to more serious cardiovascular diseases.In contrast,although early-stage atherosclerosis has a relatively simple pathologic environment which is less difficult to treat,early lesions are difficult to diagnose timely without obvious symptoms.Therefore,accurate diagnosis and effective therapy of early atherosclerosis are of great importance to reduce the risk of cardiovascular disease.In this thesis,a series of nano drug carriers with aggregation-induced emission(AIE)properties and antiinflammatory function were constructed by combining fluorescence imaging and antiinflammatory therapy using nanodrug carriers as a medium and applying them to the integration of early atherosclerosis diagnosis and therapy.This thesis detaily explores the accumulation ability of nano-drug carriers in atherosclerosis and designs various stimulus-responsive structures to achieve specific release of drugs.At the same time,this thesis also combines AIE fluorescent probes with nanocarriers to achieve fluorescence diagnosis of atherosclerosis,and develops novel AIE fluorophores for more accurate identification and imaging of atherosclerotic plaques.In addition,this thesis continues to improve the nanocarrier system from three aspects of accumulation,diagnosis and therapy,and explores its potential for clinical application in atherosclerotic diseases.The research of this thesis includes the following parts:1.A theranostic nanocarrier TPP@PMM with serial reactive oxygen species(ROS)responsiveness and two-photon AIE properties has been constructed,which has good stability during blood transport and can accumulate at atherosclerotic tissues through broken endothelium.Under the influence of overexpressed ROS generated by the inflammatory response of diseased plaques,TPP@PMM can disassemble and release the two-photon fluorescent probe TP and the anti-inflammatory drug prednisolone(Pred),thus performing the two-photon fluorescent diagnosis and antiinflammatory therapy.In vitro studies have shown that TPP@PMM has good ROS responsiveness and two-photon AIE properties,and can effectively inhibit cellular inflammation and foam cell formation.In addition,TPP@PMM can be used for in vivo tracing as well as identification and imaging of atherosclerotic plaques.Furthermore,it also performs a good anti-atherosclerosis ability,exhibiting the great theranostic effect.2.Based on the previous work,the lipid removal function is further introduced into the nanocarrier construction.TPCDP@PMM,a theranostic nanocarrier,has been constructed based on the two-photon fluorophore,Pred drug and cyclodextrin,which can respond to the high local ROS concentration,perform the two-photon AIE diagnosis and achieve a two-pronged therapy for atherosclerosis through antiinflammatory and lipid removal.TPCDP@PMM has good two-photon AIE properties,which can be used to track the distribution and accumulation of nanocarriers in vivo to identify atherosclerotic plaques.In addition,the good ROS responsiveness of nanocarriers can enable the efficient release of drug and cyclodextrin for two-pronged treatment of atherosclerosis.In vitro and in vivo experiments demonstrate that TPCDP@PMM can achieve the fluorescent diagnosis and effective therapy of atherosclerosis.3.A new AIE fluorescent probe with lipid specificity,LFP,has been designed and synthesized to address the problem of non-specific imaging of the fluorescent probes applied in our previous work.LFP has good AIE properties and shows bright orange-red fluorescence in aqueous solution.In addition,the fluorescence emission wavelength of LFP can be blue-shifted with the change of aggregation state.Based on this,the probe shows green fluorescence in oil solution,demonstrating its lipidspecific fluorescence properties.In vitro studies have revealed that LFP can provide clear and specific fluorescence imaging of lipid droplets in foam cells.Furthermore,LFP has been used for the specific identification of atherosclerotic plaques,which can be found to accurately locate the plaques and enable distinct fluorescence imaging.Thus,the lipid-specific imaging characteristics of LFP set up the foundation for enhancing the accuracy of nanocarriers for atherosclerosis diagnosis.4.Based on the specific fluorescent probe LFP designed in the previous work,a theranostic nanosized prodrug carrier RBC/LFP@PMMP with a biomimetic shell has been constructed.Firstly,LFP is encapsulated in a ROS-responsive prednisolone prodrug polymer to form a prodrug micelle.Furthermore,the pro-drug micelles are coated with the red blood cell membrane to form the biomimetic nanocarrier.Due to the biomimetic surface and the pro-drug structure,RBC/LFP@PMMP shows less drug leakage and longer circulation time during blood transport,thus promoting its accumulation effect at atherosclerosis.In addition,it can rapidly respond to overexpression ROS,enabling the release of anti-inflammatory drugs and fluorescent probes LFP.In vivo experiments have demonstrated the good accumulation of RBC/LFP@PMMP in lesions by fluorescence imaging,as well as its precise localization and imaging of atherosclerotic plaques.In addition,its good stability and outstanding anti-inflammatory therapeutic effect also provide the clinical possibility of the theranostic nanocarriers on atherosclerosis. |
