Mesoporous Carbon Carriers For The Evaluation Of Improving Oral Absorption And Targeted Delivery Of Paclitaxel

Due to convenience,safety and good compliance,oral administration has become the first choice of the best routes of drug administration.However,for the Bio-pharmaceutic classification system,the BCS ?? drugs with low solubility and low permeability take with a low oral bioavailability as a result of slow dissolution rate in the gastrointestinal tract and poor transmembrane transport of the released drug molecules.Paclitaxel(PTX)is a typical BCS IV drug with a lower water solubility(4.93 ?g·mL-1),poor transmembrane transport,substrate of P-glycoprotein(P-gp)and strong first-pass elimination effect makes the oral bioavailability of PTX is only 4.56%,greatly limiting the oral application of PTX.Therefore,improving dissolution rate and increasing the transmembrane transport of the BCS ? drugs to improve the oral bioavailability has been a hot and difficult research topic in the field of pharmacy.Aiming at these problems,because of the advantages of mesoporous carbon nanoparticles in drug delivery,uniform mesoporous carbon spheres(UMCS)were prepared in this study.The skeleton structure of mesoporous carbon nanoparticles could realize effective drug dispersion and efficient loading at the same time,controlling the state of agents in the mesopores,improving the dissolution rate,enhancing the bioavailability of drugs.On the basis,we need to increase the transmembrane transport of drugs and promote oral absorption of BCS class ? drug and verify the drug carrier system does not improve the efficacy of drugs,but also reduce the side effects.And whether the folate-polyethylenimine(FA-PEI)modification could improve the oral absorption of BCS class ? drug and ralize targeted drug delivery still need to be vertified.And the mechanism of the drug loaded system to promote the oral absorption and targeted drug delivery was studied at cytological level.In the present study,UMCS nanoparticles were fabticated by the furfuryl alcohol as the carbon precursor and silica as the template,with a size of about 350 nm.Surface area analysis shows a specific surface area of 979 m2·g-1,with a pore diameter of 3.6 nm,pore volume is 0.762 cm3·g-1.The high specific surface area,pore volume and the strong adsorption of carbon material make UMCS nanoparticles an ideal drug loading reservoir of insoluble drug paclitaxel.The drug loading is up to 50%.FA-PEI complex is modified onto mesoporous carbon nanoparticles surface through simple,low electrostatic attraction.The functionalized FA-PEI comples does not only control the release of drug molecules,increase the stability of the carrier,but also enhance the ability of carrier for targeted delivery.In this study,Caco-2 cells were used as a in-vitro cell model to study the impact of multifunctional nanoparticles carrier in cell proliferation using MTT assay.Even if the FA-PEI@UMCS nanoparticle concentrations was up to 100 ?g·mL-1,the survival rate of Caco-2 cells was still more than 80%.Flow cytometry and confocal microscopy were used for qualitative and quantitative research of Caco-2 cells intaking FA-PEI@UMCS nanoparticles.The results indicate that folic acid modification can indeed promote the endocytosis of UMCS nanoparticles by Caco-2 cells.The results of paclitaxel across Caco-2 cell monolayer membrane show that drug encapsulated in FA functionalized nanoparticles retained the best permeability,increasing the transport by 5.7 fold compared with the commercial Taxol(?).Pharmacokinetic studies showed that the constructed PTX-FA-PEI@UMCS nanoparticles significantly increases the oral absorption of paclitaxel,the oral bioavailability was up to 30.86%,6.8 times as Taxol(?).In order to verify the targeted drug delivery to tumor of the established drug delivery system FA-PEI@UMCS,KB cell and A549 were used in-vitro.KB cells with folate receptors overexpressing were used as positive cell model and normal folate receptor expression of human lung cancer A549 cells were used as negative cell model.Confocal microscopy and flow cytometry analysis showed that the KB cells internalized five times more FA-PEI-FITC@UMCS nanoparticles than A549 cells,indicating that the modified folate ligand can effectively enhance the endocytosis of UMCS by folate receptor overexpressing cancer cells.The results of in vitro cell survival of PTX-FA-PEI@UMCS nanoparticles in the KB,H22 and A549 cells group showed IC50 values were 0.062 ?g·mL-1,1.27 ?g·mL-1 and 134.65 ?g·mL-1,indicating that FA-PEI@UMCS nanoparticles can not only improve the targeting antitumor effect of PTX,but also reduce the toxicity to normal organization of PTX.In Kunming mice bearing an H22 transplanted tumor,FA-PEI-FITC-UMCS nanoparticles also demonstrated an in-vivo tumor targeting.The in vivo antitumor effects of these three paclitaxel formulations including Taxol(?),PTX-PEI@UMCS and PTX-FA-PEI@UMCS were examined in Kunming mice bearing an H22 transplanted tumor.PTX-FA-PEI@UMCS showed an optimal antitumor effect,the inhibition rate was 86.53%,2.6 times as the commercial Taxol(?).