Preparation Of Multi-responsive Mesoporous Microspheres And Its Application In Controlled Drug Release

Nanoparticles used as drug carriers exhibit several unique advantages,and nanoparticles with proper modification circulate for a long time in vivo,reach all part of the body easily,even can penetrate the blood-brain barrier,which have broad applications in therapy of brain diseases and malignant tumour.Active target drug system can be desigend because the physical and chemical properties of the malignant tumour is quite different from the moral tumour.With the first discovery of MCM-41 materials by Mobil Corporation scientists in 1992,synthesis and applications of mesoporous silica microshperes have attracted great interests due to their outstanding properties,e.g.ordered pore network,high specific pore volume and surface area.Up to date,it has been well established that mesoporous silica materials(MCM-41) are applied as vehicles in the drug delivery-release systems.However,most research work is focusing on conventional constant,not controlled release of drugs at target sites.Based on the research background,this thesis has focused on the preparation of multifunctional microspheres which were used in drug loading and controlled drug releasing under different releasing environment.The results of each part are listed as follows:(1) First,a kind of mesoporous silica nanoparticles was prepared through sol-gel technology with oleic acid stabilized Fe₃O₄ as core,CTAB as template which had a pore diameter of 3.1 nm.Then,the mesoporous silica nanoparticles were modified with different functional groups,e.g.phosphonate group and carboxylic acid group with negative charge,amine group with positive charge.Finally,the multifunctional composite microspheres which were magnetic and pH responsive were used as drug carriers in loading drugs with different charges.Negative charged micropheres were used to load positive charged drugs(DOX) and positive charged microspheres were used to load negative charged drugs(ZnPcS₄).The releasing results showed that the microspheres with different functional groups presented different releasing behaviors. (2) We reported a novel strategy to prepare core/shell structured magnetic mesoporous silica microspheres combining three advantages into one single entity, which involved Fe₃O₄ magnetic nanoparticle as core,mesoporous silica as sandwiched layer,and cross-linked thermosensitive P(NIPAM-co-NHMA) copolymer as outer shell.Such well-designed core/shell composite microspheres are promising to payload and temperature-triggered release of target objects,and could be guided by the applied magnetic field and realize the release of therapeutic agents in tissue-specific sites.To control the release temperature,copolymerization ratio of N-hydroxymethyl acrylamide(NHMA) with NIPAM was adjusted to give different crosslinked copolymer shells with different volume phase-transition temperatures (VPTT).Zn(â…¡) phthalocyanine tetrasulfonic acid(ZnPcS₄),a well-known photodynamic therapy(PDT) drug,was used as a model drug to assess the loading and controlled-releasing behavior of this novel kind of core/shell composite microsphere.Compared to other reported systems,the current composite microspheres give a ZnPcS₄ storage capacity of 26%,which is almost four times higher than the previous results.Meanwhile,the composition of copolymer shell was expecetd to affect the release behavior of drug molecules due to a control of volume-phase transition temperature from 38℃to 44℃.The release behavior of the drug was dependent on the temperature and the rapid drug release behaviors above the VPTT of the composite microspheres indicated a potential application in therapy of malignant tumors.(3) On the basis of previous work,trimethylbenzene was used in the synthesis process of a novel kind of magnetic mesoporous silca nanoparticles with large pore diameter.Then carboxylic acid groups were modified to the nanoparticles to endow pH sensitives.After that P(NIPAM-co-NHMA) copolymer was modified to the magnetic mesoporous silica nanoparticles to prepare a kind of multi-responsive mesoporous silica microspheres,through chain transfer reaction.DOX was used as a model drug to measure the drug loading and controlled drug releasing properties.The result indicated that the multi-responsive microspheres exhibited an excellent drug loading capacity of 48.5%and drug entrapment capacity of 94.3%.The controlled drug releasing could be obtained by changing the temperature and pH values and the results indicated that a fast releasing rate could be obtained under high temperature and low pH values.