Preliminary Study Mesoporous Silica Core-Lipid Bilayer Shell Assembly Nanoparticles As A Novel Drug Carrier For Antitumor Drug

Mesoporous silica nanoparticles(MSN) were inorganic solid materials. They were growing used as drug carrier in drug delivery system(DDS) owing to their good biocompatibility and construction stability as well as high surface area and large pore volume. Also, they were easy to control in terms of the particle size and morphology. It was more important that they were more effectively endocytosed by the cells. However, some unsolved problems also exist about MSN and other traditional nanoparticles, such as uncontrolled release of drugs and drug leaking before reaching the target. At the same time, human cells can’t absorb enough MSN in order to maintain the effectiveness of durg, even MSN had the good biocompatibility.In this study, PTX as a model drug, to prepare mesoporous silica core-lipid bi-layer shell assembly nanoparticles as a novel drug carrier for antitumor drug. PTX-LMSN combined the advantages of MSN and liposomes. On one hand, MSN core as a support frame not only increased drug loading but also offered lipid layer with mechanical stability, controllable morphology and narrow size distribution. On the other hand, peripheral lipid membrane with good biocompatibility can enhance the cell uptake of drugs. Meanwhile, lipid membrane with a p H sensitive under normal physiological conditions(neutral environment) was stable, and under acid condition was easy to release. This was avail to play antitumor effect in acid environment of the tumor site, and solved the problem of drug carrier leaking before reach the tumor site.This paper mainly includes the following aspects:1. Pre-formulation study of PTX-LMSN preparation and establish the analytical method of PTX and its pharmaceutical products. Investigated the solubilization effect of different solvent and surfactant on PTX by HPLC. Preliminarily choose the suitable solvent medium and surfactant to provide a data support for the study of the in vitro release test and formulation.2. The synthesis technology research of MSN. Conducted single factor experiment investigation, set particle size and monodispersity as the main evaluation indexes. The optimal prescription for process as follows: temperature was 80℃, the concentration of CTAB and TEOS was 0.020 mol·L-1 and 0.224 mol·L-1, p H=10. Investigated the affection of different drugs/carrier ratio to drug loadings and the drug utilization, determined the best rate of drug/carrier was 1/5, drug loading was 3.21% and the maximum utilization ratio of drug was 16.05%. Characterize the MSN with SEM, TEM and Automatic determination of specific surface area and porosity. It shows that the MSN was a kind of mesoporous material with uniform size, good dispersion, inerratic channel structure. The aperture concentrated around 3.8 nm, PTX molecules can easily be loaded by mesoporous silica.3. The preparation technology research of MSN. To investigate the affection of the concentration of phospholipid, PTX-MSN, cholesterol and surfactant to particle size, potential and monodispersity of PTX-LMSN. The results show that factors-changing has great influence on the particle size and monodispersity. Determine the conditions for the preparation of PTX-LMSN with the concentration of phospholipid PTX-MSN, cholesterol and surfactant was 3%, 0.4%, 0.2% and 0.5% respectively. To make a primary stability investigation for PTX-LMSN prepared with the optimal conditions. The result showed that PTX-LMSN was unstable under high temperature and light conditions. It especially sensitive under the condition of high temperature, indicated that the appearance of color and shape was changed, the content of PTX droped more, so the PTX-LMSN should be stored under low temperature and away from light.4. The experimental result of in vitro release showed that PTX-LMSN was sensitive to p H and temperature, the release speed will accelerate while the decrease of the p H value as well as the temperature rise. It’s benefit for PTX-LMSN carried drug deliver to the tumor site effectively, and reduce the drug release in normal physiological conditions, which in turn reduce drug damage to normal tissue cells, side effects and increase the drug efficacy.5. In vitro anti-tumor cell toxicity experiment of PTX-LMSN with MTT method. The result showed that carrier material of MSN and LMSN had no cytotoxicity, PTX-LMSN had higher cell proliferation inhibition rate compared with PTX-MSN and PTX, Its lethality of A549 cells were 3.0 times and 2.8 times to free PTX and PTX-MSN, so it had a certain application prospect as a intelligent DDS for antitumor drugs.