Preparation Of Stimuli-responsive Composite Nanoparticles Based On Mesoporous Silica And Its Application In Drug Delivery

In recent years, the preparation of inorganic/organic composite nanoparticles has gained much interest for its unique properties combined the robust properties from polymers and special characters from inorganic nanoparticles. Nanoparticles used as drug delivery system have unique advantages. Nanoparticles can easily reach specific sites, or even cross blood-brain barrier. For environment responsive nanoparticles, their physicochemical and colloidal properties could be changed with external environment (such as temperature and pH), so they have promising future to utilize as controlled release drug delivery system. Based on such research background, we proposed systematic study on the preparation of environment sensitive composite nanoparticles, containg mesoporous channels applied as anti-cancer drug delivery system. Based on "storehouse" mesoporous channels, high loading capacity could be achieved. Environment stimuli acted as a trigger, controlling the release of anticancer drugs in physiological condition. In addition, we researched the killing effect of the environment responsive composite nanoparticles on tumor cells, exploring potential nanoparticles used as anticancer drug delivery system. The results of each part are listed as follows:(1) First, a kind of mesoporous silica nanoparticles was prepared through sol-gel approach with CTAB as template. Then, pH-responsive polymer shell chitosan/poly (methacrylic acid)(CS-PMAA) was coated on mesoporous silica nanoparticles (MSN) through the facile in situ polymerization method. The resultant composite microspheres showed a flexible control over shell thickness, surface charges and hydrodynamic size by adjusting the feeding amount of MSN and the molar ratio of [-NH2]/MAA. The MSN/CS-PMAA composite microspheres were stable in the pH range of5to8as well as in the physiological saline (0.15M NaCl). Doxorubicin hydrochloride (DOX) was applied as a model drug to investigate the drug storage and release behavior. The results demonstrated that DOX could be effectively loaded into the composite microspheres. The cumulative release of DOX-loaded composite microspheres was pH dependent and the release rate was much faster at low pH (5.5) than that of pH7.4.(2) First, we synthesized CTAB stabilized gold nanorods by seed growth approach and encapsulated a layer of mesoporous silica structure around gold nanorods through improved stober method. Then we developed poly(N-isopropylacrylamide-co-N-hydroxymethyl acrylamide)(P(NIPAM-co-NHMA)) shell coated gold nanorod@mesoporous silica (GNR@mSiO2) via precipitation polymerization. The composite nanoparticles presented a temperature sensitivity and the volume phase transition temperature could be precisely regulated by the content of NHMA. It showed that the thermally induced collapse of the polymer shell lead to an increase of the absorbance intensity, which was fully reversible. Doxorubicin hydrochloride (DOX) was applied as a model drug to investigate the drug storage and release behavior. The results demonstrated that DOX could be effectively loaded into the composite nanoparticles with20.5%±0.6%loading capacity and87.4%±3.0%encapsulation efficiency. The cumulative release of DOX-loaded composite nanoparticles was temperature dependent and the release rate was much faster at high temperature.(3) The cytotoxicity test by MTT assay showed that the blank carrier MSN/CS-PMAA and GNR@mSiO2/P(NIPAM-co-NHMA) composite nanoparticles were biocompitable and suitable as drug carriers. The cellular uptake of MSN/CS-PMAA composite microspheres was investigated by confocal laser scanning microscopy (CLSM), which indicated that MSN/CS-PMAA could deliver the drugs into HeLa cell and release drugs in the cells. For the GNR@mSiO2/P(NIPAM-co-NHMA) composite nanoparticles, due to the enough loading space provided by the mesoporous silica layer and excellent photothermal therapy effect provided by the gold nanorods, beneficial synergies were achieved with short NIR laser exposure time, which rendered the composite nanoparticles a potential application in drug delivery and chemo-photothermal therapy. With relatively low composite concentration and short laser irradiation time to achieve excellent chemo-photothermal therapy effect, potential side effect to the normal tissues should be avioded. Overall, the simple and efficient nature of the approach, coupled with the capability to achieve good therapeutic efficacy, make the prepared environment sensitive polymer-coated composite nanoparticles a promising site specific anticancer drug delivery carrier.