Preparation And Application Of Heparin Based Drug Delivery System

Due to the excellent anti-coagulation ability as well as wonderful modifiability,heparin is widely used as the biomaterials.The in vivo retention time is vital for the retrieve vena cava filters.However,the retention time of current RVCF usually can’t meet the clinical requirements due to on site thrombosis and intimal hyperplasia,which causes the patient to experience multiple filter placement and removal process.The antithrombotic and anti-intimal hyperplasia coating is thought to be a feasible solution to this problem.A biodegradable hydrogel loaded with heparin and paclitaxel was prepared by Michael addition reaction under physiological conditions(37 ℃,p H=7.4)in this paper.The fastest gelation time was determined as 5 min with 20 wt%concentration by reverse vial method.It was further found that higher the mass concentration of hydrogel,denser the structure of cross-linked network was.And the larger the storage modulus and loss modulus,the smaller the swelling ratio was.The in vitro degradation test showed the hydrogel could be degraded within several weeks depending on different gelation concentrations,whereas in vitro release test showed the loaded heparin and paclitaxel both possessed controlled and sustainable release behavior.The APTT test showed the hydrogel possessed excellent antithrombotic properties,while in vitro cell test exhibited it can obviously inhibited the growth and the proliferation of smooth muscle and endothelial cells which were responsible for the intimal hyperplasia.Consequently,as-prepared hydrogels has promising potential to be applied as the coating of the retrieve vena cava filters.Drug delivery systems have attracted more and more attention as they can encapsulate hydrophobic drugs and endow sustainable release as well as stimuli-response release and tumor targeting ability.In our previous work,heparin can form polyion with doxorubicin(DOX)which can self-assemble into micelle and serve as drug carrier.The heparin-DOX drug carrier exhibited p H sensitive drug release,but its storage and in vivo stability were poor.In this paper,thiol group was firstly introduced heparin via he EDCI/NHS catalytic system.Then,negative charged thiolate heparin and positive charged DOX could self-assemble into micelle in water as well.Finally,the thiol group could be oxided into disulfide bond to crosslink micelle’s shell by oxygen gas.The thiol-based crosslink can not only significantly increase the micelle’s storage and in vivo stability,but also endow p H and glutathione(GSH)sensitive drug release which were meaningful for anti-tumor drug carrier as the tumor cell usually possessed acidic and GSH-rich environment so that p H and GSH sensitivity can confirm the drug carrier release much more drug in tumor site.Drug loading amount was determined as 31.5% by UV,while the particle size was measured as 150-200 nm by TEM and DLS.Its particle size remained unchanged in a week showing its excellent storage stability,whereas the micelle didn’t experience dissociation against dilution as demonstrated by fluorescence microscope with pyrene probe exhibiting potential in vivo stability.The in vitro release behavior showed the release rate of DOX was significantly depended on the p H and the concentration of the GSH,indicating micelle’s p H and GSH sensitivity.Furthermore,the cytotoxicity of as-prepared micelle against HUVEC(normal cell)and MDA-MB-231(tumor cell)showed that this micelle was nontoxic for normal cells but possessed significant cytotoxicity against tumor cells.Cellular uptake and intracellular distribution were further revealed by fluorescent inverted microscope.In conclusion,the thiolate heparin-DOX micelle showed promising potential in chemotherapy.