Mesoporous Titania Nanoparticles(MTNPs) For Drug Loading:Targeting And Light Control Release

Improving the bioavailability of poorly soluble drugs by improving the dissolution rate of poorly water-soluble drug and form?Lations designed to achieve the targeting of the drug delivery system of administration to reduce the dose of chemotherapy drugs,the side effects of chemotherapy drugs,have long been a hot and difficult research in the field of pharmacy.In response to these problems combined with titanium dioxide(TiO2)photochemical characteristics,we have developed mesoporous TiO2 nanospheres(MTNPs).We hope that the spatial constriction of nanometre-sized pores allows the drug molecules to be present in the matrix in microcrystalline or amorphous forms for improving the dissolution rate and bioavailability of water-insoluble drugs.Therefore,the functionalized mesoporous titania nanoparticles were developed in this article.We expect to achieve the targeting cancer cells and light controlled-release drug by the modification of MTNPs to reduce the side effects of drugs and improve the efficacy of drugs and to explore targeting and light trigger controlled release mechanisms on cytology level.The titanium isopropoxide(TIP)was used a titanium source,F127 as a structure-directing agent and ethanol as the reaction solvent.The double-distilled water was used to adjust the rate of hydrolysis of titanium isopropoxide to synthetic F127 dioxide composite nanospheres.The sample was calcined to remove the structure-directing agent F127.According to the results of SEM/TEM,N2 adsorption/desorption experiment,it was found the MTNPs with a well-defined spherical morphology.Particle diameter of is approximately 150 nm,the pores of about 30 nm,a width of 3 nm,specific surface area of 109.26 m2/g and pore volume of 0.1543 cm3/g.The Carvedilol(CAR)was used as model drug.Crystal transition of drugs was explored by differential X-ray diffraction(XRD)and scanning calorimetry(DSC),and the thermogravimetric analysis(TGA)and UV spectrophotometry were used for determination of the drug loading amount of MTNPs to explore the solvent adsorption equilibrium method,melting method and solvent adsorption equilibrium evaporation method for loading drug.Three drug loading methods all make the drug in the carrier in the amorphous state,but the solvent adsorption equilibrium evaporation method was the optimal drug loading method due to its high drug loading amount(23.34%w/w)and rapid dissolute rate in vitro.And the drugIMC and CTL were loaded in the pore of MTNPs by the solvent adsorption equilibrium evaporation method.The XRD and DSC analysis showed that the drug in amorphous state exists in the carrier pore.In vitro dissolution rates of IMC-MTNPs and CTL-MTNPs were significantly higher than the bulk drugs.The bioavailability of the MTNPs-CAR tablet is 1.49 times for the formulation of the commercially available preparations.The establishment of Caco-2 cell monolayer model simulated intestinal epithelial.According to the analysis of cell resistance measurement and confocal laser scanning electron microscopy,the MTNPs do not open the cell gap between the epithelial cells of the small intestine.According to the analysis of flow cytometry and confocal laser scanning electron microscopy,it can be found that Caco-2 cells effectively endocytosis MTNPs.In summary,MTNPs can improve the bioavailability of poorly soluble drugs by changing the rate of drug dissolution and mediated endocytosis of Caco-2 cells.In order to achieve the targeted photodynamic controlled-release drug,the preparation prescription was improved.According to the results of SEM/TEM,N2 adsorption/desorption experiment,it was found the MTNPs with a well-defined spherical morphology.Particle diameter of is approximately 150 nm,the pores of about 3 nm,specific surface area of 555 m2/g and pore volume of 0.294 cm3/g.Polyethyleneimine(PEI)and folic acid(FA)covalently linked and then the FA-PEI combine with MTNPs by the electrostatic interaction.The paclitaxel(PTX)was used as a model drug,and the the solvent adsorption equilibrium evaporation method was used to loading PTX.According to the results of XRD and DSC,it can be found that the drug exist in MTNPs in an amorphous state.The drug loading amount was 24.1%(w/w)by the TGA analysis.In vitro release experiments show that the carrier MTNPs can effectively improve the in vitro release rate of PTX.The cumulative drug release amount decreased by 86.3%to 3.2%at 3 h after modification of FA-PEI indicating that FA-PEI can effectively inhibit of the release of PTX.Following ultraviolet light(UV)radiation,the surface PEI molec?Les are cut off by free radicals(OH· and O2-)from TiO2 and then the drug loaded in the carrier is rapidly released into the cytoplasm.The rate of drug release showed UV irradiation time-dependent.Light control release of the FA-PEI-PTX-MTNPs was completed.The KB cells,which highly expressed FA receptor on surface of cell,was used as model of positive cells,and the A549 cells with low FA receptor expression on surface of cell was used as model of negative cells.According to the analysis of confocal laser scanning electron microscopy and flow cytometry,it can be found that the amount of FA-PEI-MTNPs-FITC taken up by KB cells was 5.3 times higher than that of FA-PEI-MTNPs-FITC taken up by A549 cells confirming that FA plays an important role in specific uptake and can effectively mediated cancer cell-specific endocytosis.We explored the cancer-cell killing effect of FA-PEI-PTX-MTNPs using MTT assay.For KB cells,after UV irradiation time of 5,10,and 15 min,the cell viability at the time point of 2 h was 45%,27%and 7%respectively,for A529 cells the cell viability at the time point of 2 h was 77%,71%and 65%respectively indicating that cell the killing effect showed significant UV irradiation time dependence,and the KB cell killing effect was stronger in A549 cells.The targeting and light-control anti-cancer effects can be accomplished by FA-PEI-PTX-MTNPs.