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

In1992, Beck in Mobil U.S. firstly reported the synthesis of MCM-41mesoporous molecule sieves. After that, mesoporous silica material has attracted more and more attention because of its ordered pore network, high specific surface area and pore volume, and abundant silanol for further modification. After Vallet-Regi etc. applied mesoporous silica in the research of drug delivery systems in2001, mesoporous silica has been a shining star in biomedical area, especially as vehicles of drug. However, as the vehicles of drug, many research was focused on convential constant, not controlled release of drugs at target sites. In contrast, environmental responsive organic/inorganic composite micro-spheres containing mesoporous structure can release drugs in a controlled manner at the stimulation of the outer environment. Generally speaking, the mesopore in the composite microspheres can hold the drug in the process of delivery, and the outer environmental responsive organic material can work as a ’door’, which would open and release the drug after stimulating while close and keep the drug without stimulation. Based on the research background, this thesis has foused on the preparation of multifunctional microsphere, such as magnetic-, pH-, heat-and reduction-responsive composite microspheres, which were used in drug loading and controlled drug releasing under different environment. Details were stated as follows:(1) Core/shell structured magnetic-and pH-responsive composite micro-spheres were synthesized by distillation precipitation polymerization. The composite microspheres involved Fe304inner cores, mesoporous silica as sandwiched layer, and cross-linked poly(methacrylic acid)(PMAA) shell as outer layer. When the cross-linking density of the composite microspheres were set as5%,10%, and15%, the pKa was5.3,6.4, and8.9, respectively, showing their response to pH, and its adjustable pKa which could be controlled by the cross-linking density of the outer PMAA shell. High drug loading efficiency and entrapment efficiency were obtained when using DOX as the model drug. The composite microsphere whose cross-linking density was10%(pKa=6.4), was proved to be pH-reponsive as the24h drug releasing percentage at pH=5.5was2.5times higher than that at pH=7.4. (2) Core/shell structured magnetic-and heat-responsive composite micro-spheres were synthesized by seeded precipitation polymerization. The outer heat-sensitive polymer shell was based on cross-linked poly(N-isopropylacryl-amide)(PNIPAM), whose volume phase transition temperature (VPTT) was adjusted by co-polymerization with N-hydroxymethyl acrylamide (NHMA). When using DOX as model drug, high drug loading efficiency and entrapment efficiency were obtained. Regarding to the composite microspheres whose VPTT was38.0℃,24h drug releasing rate at40℃was1.8times higher than that at35℃, showing its heat-responsive property.(3) In this section, we modified disulfide bond on the APS-modified mesoporous silica nanoparticles (MSNs) by Michael addition reaction. After that, BAC was used as cross-linker to synthesize heat-and reduction-responsive polymer microspheres and magnetic-, heat-, and reduction-responsive composite microspheres. The decrease cross-linking density of two microspheres resulted from the disulfide bond destory in100mM glutathione (GSH) accelerated DOX releasing speed. Otherwise, the24h DOX releasing percentage of two microspheres was significantly affacted by temperature and the existance of GSH, showing the heat-and reduction-response of two microspheres.