Preparation Of Hyaluronic Acid-based Multifunctional Drug Delivery System And Its Application In The Treatment Of Atherosclerosis

Atherosclerosis is a progressive disease with clinically inapparent lesions and a long incubation period.The detailed pathological progression of atherosclerosis has been primely studied,and there are various pathological theories.Inflammation is considered to be closely related to the pathogenesis of atherosclerosis,and macrophages are the representative inflammatory cells in the inflammatory microenvironment and accumulate in large numbers at the atherosclerosis lesions.Meanwhile,inflammation-related biochemical signals such as pH,high reactive oxygen species(ROS)have also attracted much attention,as they are the pathological basis for rational design of biostimuli-responsive vectors.Photothermal therapy(PTT)has also emerged in the treatment of atherosclerosis due to its minimally invasive and less invasive features.In this paper,two multifunctional smart nano-delivery systems that can target macrophages are prepared respectively.The work is as follows:(1)A ROS-sensitive and macrophage-targeted nanomicelle(HASC@Cur)was designed.It is self-assembled from the amphiphilic material hyaluronic acid-2’-(propane-2,2-dialkyl(thio))diacetate-curcumin.The HASC@Cur nanomicelles have appropriate size and morphology,suitable for in vivo applications,and have good stability and dispersibility.Due to the existence of ROS-sensitive thioketal bonds,the nanomicelles can achieve ROS-stimulated drug release in vitro.Cytotoxicity shows that HASC@Cur nanomicelles have excellent biocompatibility.In addition to being used as a therapeutic drug,the drug in the HASC@Cur nanomicelles can also be used as a fluorescent probe to realize self-monitoring.The in vitro cellular uptake verifies its ability and proves that the HASC@Cur nanomicelles can target macrophages.(2)We designed a hyaluronic acid-targeting and pH-responsive chemophotothermal synergistic multifunctional nanocarriers(CuS@DMSN-N=C-HA)by using PTT to address the deficiency of monotherapy.Uniform dendritic mesoporous silica nanoparticles are generated on the surface of copper sulfide(CuS)through the oil-water two-phase layering reaction,and then used as a drug-loading system to load the anticoagulant thrombolytic drug heparin(Hep).Finally,hyaluronic acid(HA)with the ability to target macrophages was modified on the surface of the carrier with pHsensitive Schiff base bonds.The HA modification endows the nanocomposite with pH responsiveness and the ability to target macrophages,while reducing drug leakage and increasing drug loading.In vitro drug release results reveal that the nanosystem exhibited excellent controlled drug release properties and could release drugs slowly and efficiently in a weakly acidic environment.Cytotoxicity and hemolysis rate tests shows the excellent biosafety of CuS@DMSN-N=C-HA.Cell imaging revealed that HA endowed the nanocarriers with superior targeting ability,and CuS@DMSN-N=CHA could be efficiently internalized by macrophages compared with the nanocarriers without the target modified.Compared with monotherapy,the synergistic treatment of H-CuS@DMSN-N=C-HA,based on the excellent photothermal conversion ability of CuS,showed excellent thrombolytic ability in vitro and in vivo thrombolysis experiments.Based on this multifunctional intelligent system,we realized precise drug delivery,controlled release and chemo-photothermal synergistic treatment of atherosclerosis.