Preparation Of Silica-based Mesoporous Nanoparticles And Their Potential For Drug Delivery

Silica-based mesoporous nanoparticles for potential biomedical aplications have gained more and more attention due to their controllable particle size and pore diameter,high surface area and pore volume,biocompatibility and easy of surface functionalization.In recent years,silica-based mesoporous nanoparticles as carriers for drug/gene delivery have been widely studied in cancer therapy.In this dissertation,two types of silica-based mesoporous nanoparticles have been successfully synthesized.Based on both silica-based mesoporous nanoparticles,several drug delivery systems have been designed,and their magnetic hyperthermia capacity and drug delivery properties were investigated in detail.(1)Mesoporous silica nanoparticles(MSN)with small particle size and large pore size have been synthesized using hexadecyltrimethylammonium p-toluenesulfonate(CTAT)as structure-directing agent and tetraethylorthosilicate(TEOS)as silicon source.The effects of reaction time,TEOS amount and surfactant type to the particle size and morphology of MSN were systematically studied.The results showed that reaction time had negligible influence on the particle size and morphogy of MSN,but the particle size of MSN increased with the increase of TEOS amount.In addition,the mesoporous structure of MSN was influenced by mixing different surfactant.On the other hand,a potential cytosine-phosphate-guanosine oligodeoxynucleotides(CpG ODN)delivery system has been developed by binding of CpG ODN onto aminated MSN(MSN-NH2)for toll-like receptor 9(TLR9)-mediated induction of cytokines.Binding of CpG ODN onto MSN-NH2 to form the CpG/MSN-NH2 complexes enhanced the serum stability of CpG ODN,and the CpG/MSN-NH2 complexes signi?cantly enhanced the level of IL-6induction,stimulated by interaction between CpG ODN and TLR9 in endolysosomes.Therefore,MSN would be a promising carrier for enhancing the delivery ef?ciency of CpG ODN.(2)Magnetic mesoporous silica(MMS)nanoparticles with controllable magnetization have been prepared by encapsulating superparamagnetic Fe3O4 nanoparticles in a mesoporous silica matrix using a sol-gel technique.The magnetic heating capacity under different frequency and different magnetic strength were investigated.The result showed that MMS nanoparticles could controllably generateheat to reach the hyperthermia temperature within a short time upon exposure to an alternating magnetic ?eld due to the superparamagnetic behavior and controllable magnetization.Moreover,MMS nanoparticles had low cytotoxicity and can be effectively internalized into Hela cancer cells.Therefore,MMS nanoparticles could be used for potential hyperthermia therapy.(3)Based on MMS nanoparticles,three drug delivery systems have been developed.Firstly,a potential MMS-based CpG ODN delivery system was developed by binding of CpG ODN onto aminated MMS(MMS-NH2)nanoparticles to form CpG/MMS-NH2 complexes.When the CpG/MMS-NH2 complexes were delivered to Raw 264.7 cells,the CpG/MMS-NH2 complexes enhanced the serum stability of CpG ODN and could be localized in the endolysosomes after endocytosis by cells,and thereby significantly enhanced the TLR9-mediated IL-6 induction.Secondly,a potential MMS-based anticancer drug delivery system was developed.Doxorubicin hydrochloride(DOX),an anticancer drug,was used as a model drug to introduce into MMS nanoparticles.The in vitro release results showed that MMS nanoparticles exhibited a sustained drug release in the medium of pH 5.0,but a very slow release in the medium of pH 7.4,which would be beneficial for chemotherapy.Thirdly,we proposed a strategy to construct DNA-capped MMS nanoparticles for potential temperature controlled drug release.MMS nanoparticles were functionalized with 15-mer single-stranded DNA(ss DNA).After loading of DOX,ss DNA-functionalized MMS nanoparticles were capped with 33-mer complementary DNA(cDNA)through the formation of double-stranded DNA(ds DNA)for capping the mesopores.DOX release could be controlled by the temperature-triggered denaturization of dsDNA capping agent.The results showed that the DNA-capped MMS nanoparticles could release DOX fast at 50 oC,but very slow at 37 oC.Furthermore,DNA-capped MMS nanoparticles could be effectively taken up by murine breast cancer 4T1 cells,and negligible cytotoxicity of the MMS-NH2-dsDNA complexes has been observed.Therefore,DNA-capped MMS nanoparticles had potential for cancer therapy with temperature controlled drug release.Generally,a series of silica-based mesoporous nanoparticles were successfully fabricated,among which MMS and MSN with small particle size and large pore size exhibited excellent behavior to deliver CpG ODN and could enhance the delivery ef?ciency of CpG ODN.MMS nanoparticles not only showed outstanding hyperthemiabehavior,but also could be applied to pH-or temperature-triggered drug release system,which provided siginificant data support for hyperthermia therapy or chemotherapy for cancer.