Synthesis Of Multifunctional Nano Carrier And Study Of Diagnosis And Treatment For Atherosclerosis

Atherosclersis has threatened human health for a long time.However,there is a lack of accurate and effective means for diagnosis and treatment because of concealment in the early atherosclerosis stage.The pathological process and predisposing factors of this chronic disease have reached a uniform conclusion in the world of medicine.At present,the effective means of operation such as vascular stenting and surgery can be performed on it.But the means of detection and treatment can be used in late stage of this disease.This is due to the vascular wall thickening and lesion to the outside of the tube wall rather than lumen the early stage of the disease.Therefore,the current diagnosis and treatment are lagging behind.Diagnosis and treatment of this disease in the early stage is a fundamental way to avoid the effective method of treatment.In order to achieve this goal,nanoparticles diagnosis and treatment system has been widely studied and can be used as a promising alternative solution.In the early stages of atherosclerosis,a variety of biological factors gather in the affected area and further release other biological factors to induce a series of disease,so,these factors can be used as biological targets of the nanoparticles diagnosis and treatment system.In this work,we have selected macrophages and macrophage migration inhibitory factor as the target and designed a variety of multifunctional nanoparticles for the early diagnosis and treatment.Here,a kind of new mutifunctional polymer(PHEMA-Sim-FPEG-ISO-1)was designed by Poly(2-hydroxyethyl methacrylate)(PHEMA),simvastatin prodrug(Sim),florescence polyethylene glycol(FPEG)and a kind of targeting molecule of macrophages(ISO-1),which is appropriate for atherosclerosis and has the ability of imaging,controling release of drug and targeting diseased sites.PHEMA was prepared with hydroxymethyl methacrylate(HEMA)by atom transfer radical polymerization(ATRP).Hydrophobic oxalyl simvastatin prodrug(Sim)was prepared by simvastatin,a kind of antiarteriosclerotic drug,and oxalyl chloride to response in hydrogen peroxide;Hydrophilic florescence polyethylene glycol(FPEG)was synthetized originally by citric acid,polyethylene glycol monomethyl ether and L-cysteine to possess fluorescence without other probe;Finally,PHEMA was decorated with drug,FPEG and targeting molecule to form amphiphilic multifunctional nanomicelles.The synthesis of nanoparticles was confirmed by nuclear magnetic resonance(1H-NMR),Fourier transform infrared spectroscopy(FTIR)and gel permeation chromatography(GPC).The particle size and morphology of nanoparticles were determined by dynamic light scattering(DLS)and transmission electron microscopy(TEM).It was shown the size of the nanoparticle was about 100 nm and formed a spherical structure.The results of fluorescence characteristic of the nanoparticles obtained by the photoluminescence spectra(PL)demonstrated that it had good fluorescence intensity and fluorescence stability.The UV-Vis absorption spectra(UV)indicated it owned a high release efficiency at a certain concentration of hydrogen peroxide.The MTT method proved that the nanoparticles had little cytotoxicity.Good fluorescence and targeting properties of macrophages was observed by through confocal Laser Scanning microscopy(CLSM).The results demonstrated that the water-soluble nanoparticles presented good biocompatibility,hydrogen peroxide sensitivity and self-luminous ability,as the same as provided new ideas for the treatment of atherosclerosis.Another diagnostic system,hydrogen peroxide-sensitive and fluorescence-enhanced complex liposomes,was designed on the basis of the previous system.This system stands in the hope of retaining the advantages of the former,such as the sensitive controlled release of hydrogen peroxide for atherosclerosis,the idea of the multifunctionality of the polymer itself,and the improvement in detection methods.Single fluorescence imaging is limited in biological applications.We have introduced superparamagnetic iron oxides to form bimodal probes to improve detection capabilities.In addition,in order to fully tap the idea of multifunctionality,we hope that active oxygen will not only serve as a response switch for drug release,and we hope it will interact with our fluorescence detection.Based on the above ideas,we chose a biocompatible phospholipid as a carrier to prepare this multifunctional nano-system.First,we synthesized a kind of amphiphilic polymer named M12P5,which has the ability to target macrophages and a certain therapeutic function.We combine it with phospholipids to form composite liposomes and form nanovesicles that can carry diverse substances.Second,we used the STOBER method to coat the surface of oil-soluble iron oxides with a layer of silica in order to increase the water solubility of superparamagnetic iron oxides and reduce their effect on quenching after associating with fluorescein,.In addition,we combined the hydrogen peroxide-sensitive simvastatin prodrug with fluorescein to synthesize a kind of fluorescence-drug molecule.The micromolecule not only can release the drug under a certain concentration of hydrogen peroxide,but also has the effect of enhancing fluorescence.Finally,we used composite nanovesicles to coat IONPs@Si O2 and the fluorescence-drug molecule to form a dual-mode optical-magnetic detection,hydrogen peroxide sensitive controlled release drug,and certainly targeted nanosystems.We confirmed the synthesis of multifunctional nanosystem by nuclear magnetic and infrared instrument.At the same time,the fluorescence properties,magnetic properties,drug loading ability and drug release ability of the nanovesicles were analyzed by fluorescence spectroscopy,VSM,TGA and UV spectra.In summary,two kinds of multifunctional nanoparticles was synthetized for atherosclerosis.It also provides a new idea for the integration of deep-level diagnosis and treatment,hoping to provide prospective and make contributions to the treatment of atherosclerosis.