Experimental Study On Imageable Drug Sustained Release Vascular Embolic Agent

Transcatheter arterial embolization(TACE)is one of the important methods in the treatment of liver cancer.Therefore,it is very important to find a new embolic agent with multiple functions,such as embolization,imaging,drug release.In recent years,the embolic agent which arrying magnetic nanomaterials and hydrogel have attracted wide attention in the biomedical field,which provides a new research field for the treatment of liver cancer TACE.In order to construct a new embolic agent which can imagable?drug relaese,two new embolic agents,solid and liquid,were prepared in this study.1.Preparation and Magnetocaloric Effect of multimodal imaging gelatain microspheres for embolization in vitroObjective:To present an embolization microsphere with the property of being visible in more than one imaging modality,namely MRI and x-ray/computed tomography(CT),and have magnetocaloric effect.Characterization and testing of the substance in vitro was performed.Methods:Emulsion chemical cross-linking method was used to prepare gelatin microspheres that carried only solid Fe3O4 nanoparticles.Optical microscope was adopted to observe the morphology,particle diameter and the dispersity of the gelatin microspheres.Using Thermogravimetric analysis method,the loading rate of Fe3O4 nanoparticles encapsulated in the gelatin microspheres was calculated..The multimodal visualization ability of the gelatin microspheres was evaluated by radiography,CT and MRI examinations.The heat generation ability of the gelatain microspheres was investigated under Alternating Magnetic Field.Hemolysis test and in vitro cytotoxicity test with cck8.The elastic characteristics and the swelling characteristics of the gelatin microspheres were determined,and the sterile technique was tested.Results:The optimal synthesis condition of microspheres was to use 2:1 of Fe3O4 to gelatin quality ratio,under this situation,the microspheres showed a roundness appearance with satisfactory dispersion,the spherulization rate was high(up to 77%),the drug loading rate was very high(up to 73.27%),the particle diameter was moderate(199.78±142.90 ?m),and the microspheres had multimodal visualization ability for radiography,CT and MRI examinations.The optimization CT value of microspheres could be up to(1028.0±69.5)Hu(concentration=25 mg/ml).Temperature risesed(280s,??>20?)under the alternating magnetic field.Hemolysis test and in vitro cytotoxicity test showed that no statistically significant differences in the hemolysis rate and absorption value existed between the study group and the control group.In acid solution,the microspheres exhibited swelling characteristics,while in ethanol the microspheres showed no swelling phenomenon.Conclusion:Using solid Fe3O4 nanoparticles as visualization material?gelatin as polymer materials,a special gelatin microspheres can be prepared with emulsion chemical cross linking method.This kind of microspheres carries the following features:multimodal visualization ability(radiography?CT and MRI),high drug loading,Magnetocaloric Properties,regular in shape,smooth surface,not easy to agglomerate,high biological safety and convenient disinfection.The microspheres have the functions of multimodal visualization ability,drug loading and synergy.2.Experimental study on imageable drug sustained release hydrogelObjective:In order to solve the problem of unstable dispersion of the lipiodol emulsion and the sudden release of chemotherapeutic drugs in the traditional TACE process,a multifunctional hydrogel embolization agent with stable dispersion of lipiodol(radiopaque)and sustained release epirubicin was constructed.Methods:In this study,methylcellulose(MC)and xanthan gum(XG)were utilized to construct an epirubicin(Epi)and ethiodized poppyseed oil co-loaded hydrogel(Epi/Etpoil@MC/XG)for the TACE.Hydrogel precursor solution was prepared by physical blend of xanthan gum(XG)and methyl-cellulose(MC)in aqueous solution,and blended with oily phase(Ethiodized poppyseed Oil(?))to constitute the blend hydrogel system.The porous structure and the composition of MC/XG hydrogel was characterized by Scanning electron microscope(SEM)?X-ray powder diffraction(XRD)?Circular dichroism(CD)spectra.The Tensor FTIR spectrometer was used to collect fourier-transformed infrared spectroscopy(FTIR)of Epi/Etpoil@MC/XG.X-ray images were scanned via Digital Radiography Systems.The CT images were captured by CT scanner.The DSA images were captured with a DSA machine.The thermo-responsive and injectable properties of Epi/Etpoil@MC/XG was characterized by rheology using a Rheometer under different temp eratures.The drug release rate was calculated by the fluorescence intensity.T he biocompatibility and cytotoxicity towards HepG-2 cells and HUVEC cells w ere detected by MTT assay.The VX2 cells tumor model on the auricle of a r abbit was constructed to evaluate the embolized effect of Epi/Etpoil@MC/XG by digital subtraction angiography(DSA).Results:A radiopaque hydrogel(Epi/Etpoil@MC/XG)was proposed based on methylcellulose(MC)and xanthan gum(XG)stabilized ethiodized poppyseed oil(Etpoil)and chemotherapy drug epirubicin(Epi).The microscopical morphology of MC/XG hydrogel was investigated by SEM,a uniformly interconnected porous structure can be observed;the average size of pores was 3.18±0.75 um,resembling the typical pores' structure of polymer-based hydrogels.The XRD and CD of MC/XG indicates that there is no mutual influence between the MC?XG molecules and double helical structure of XG.The infrared spectrum of Epi/Etpoil@MC/XG hydrogel was measured,the characteristic peaks of EPI,etpoil,MC and XG all were detected.Etpoil can be stably dispersed for at least 20 days in Epi/Etpoil@MC/XG hydrogel.The composite hydrogel(Epi/Etpoil@MC/XG)appeared to be a sustained drug release performance with a release rate of 40%in one day and 50%over 18 days.The results of MTT assay showed that the hydrogel embolic agent has high biocompatibility and obvious tumor inhibition effect.The VX2 cells tumor model on the auricle of a rabbit was constructed to evaluate the embolized effect of Epi/Etpoil@MC/XG by digital subtraction angiography(DSA).Benefiting from its adjusted rheology and stability,Epi/Etpoil@MC/XG can easily be injected into the feeding artery of the tumor and subsequently obstruct blood flow.Histology experiments also prove the embolic effect of the blend hydrogel in tumor blood vessels.Conclusion:In summary,epirubicin and ethiodized poppyseed oil encapsulated by methylcellulose and xanthan gum.The Epi/Etpoil@MC/XG possessed good thermo-responsive and injectable properties,exhibited excellent radiopaque character and sustained drug release performance in the present study.Epi/Etpoil@MC/XG has a great potential for its sustained drug release,thermo-responsive property,less cost,effective embolization.