Synthesis Of Self-fluorescent Mesoporous Silica Nanoparticles And Their Application As Multifunctional Drug Carriers

As novel biomedical materials, drug delivery systems have become one of the currently researching hotspots in the field of biomedical application because they can reduce the drug toxicity and side effect, improve the drug pharmacokinetics, and enhance the treatment efficiency. Among them, mesoporous silica nanoparticle has been extensively studied and considered as one of the most promising platform for drug delivery, due to its large surface area, biocompatibility, high drug loading ratio, etc. However, there are still some problems for mesoporous silica nanoparticle used in practical application, such as poor dispersion in water, toxic fluorescent label, competition between functional molecules, and the cooperation of different drugs. In view of these problems, we prepared a series of novel self-fluorescent mesoporous silica nanoparticles and investigated their potential application for drug delivery.A series of self-fluorescent mesoporous silica nanoparticles were developed. The preparation was monitored by thermogravimetric analysis(TGA) and Fourier transform infrared(FTIR) spectroscopy. The size and morphology of mesoporous silica nanoparticle before and after functionalization were observed by transmission electron microscope(TEM). N2 adsorption and desorption were employed to investigate the pore diameter and volume, surface area of the nanoparticles before and after functionalization. The fluorescence property of the nanoparticles was measured by fluorescent spectrophotometer, fluorescent microscopy, and laser scanning confocal microscopy. Cytotoxicity evaluation of the nanoparticles was determined by 3-[4, 5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide(MTT) assay. The stimuli-responsive drug release behaviors of the nanoparticle as drug delivery were performed. The detailed research works are as follows:1. pH-sensitive and self-fluorescent drug delivery systems were prepared based on the PAMAM dendrimer-modified mesoporous silica nanoparticles. After functionalization, there are lots of primary amine groups on the surface of the nanoparticles, which can further react with various functional molecules, such as targeting agents. The drug loading ratio can be increased after the nanoparticle functionalization with PAMAM dendrimers. The drug release can be controlled and the drug burst release can be prevented by the PAMAM dendrimers, which can alter its conformational structure and density at different pH value. More importantly, the fluorescent emission color and intensity were dependent on the cumulative release percentage and the drug loading ratio of curcumin molecules, making the nanoparticle potentially be employed in tracking or detecting applications. This newly described mesoporous silica nanoparticle used PAMAM dendrimers as both the pH-sensitive capping and self-fluorescent agents, avoiding the use of toxic fluorescent label.2. Multifunctional mesoporous silica nanoparticles were prepared via layer-by-layer assembly of PAMAM dendrimer and chondroitin sulfate. The assembly coating on the outer surface can effectively cap the pores of the nanoparticles. The release of DOX and CUR was slow and sustained at neutral pH, but fast at acidic environment. The dispersity of the nanoparticle can be improved by the assembly coating. Furthermore, the coating can enhance the blood biocompatibility of the nanoparticles by blocking the electrostatic interaction of silanol groups with the membrane of red blood cell. The fluorescent study showed the fluorescent imaging ability of the nanoparticles. More importantly, the targeting ability of chondroitin can help the nanoparticle enter cancer cells, increasing the toxicity of the nanoparticles to A549 cells.3. Self-fluorescent and stimuli-responsive drug delivery systems(LPCC-C-F127) were prepared by using fluorescent anticancer drug loaded micelles(CF127) as gating agents and fluorescent labels of mesoporous silica nanoparticles. In vitro drug release study showed that the micelles can effectively prevent the drug release under neutral condition, while achieve drug release at pH 5.5. The fluorescent intensity of CF127 micelles can be significantly increased after aggregation on the surface of mesoporous silica nanoparticles. Moreover, CF127 micelles exhibited good anti-photobleaching property, and the loaded drug curcumin in CF127 micelles could not release obviously in 24 h. These properties are benefiting for fluorescent imaging. More importantly, the prepared drug delivery systems comprising two kinds of nanocarriers can achieve not only the cooperation of two kinds of nanocarriers but also the cooperation of two kinds of drugs.4. Self-fluorescent mesoporous silica nanoparticles were prepared by using anticancer drug curcumin molecules as the gating agents and fluorescent labels. In vitro release of drug loaded in mesopores was studied. The drugs could be entrapped in the pores with nearly no leakage at neutral condition, and showed rapid release in the existence of glutathione(GSH) at pH 5.5 through the hydrolysis of β-thioesters. The fluorescent study showed that the nanoparticles possess the self-fluorescent property. And the PEG shell from F127 can improve the dispersity of the nanoparticles in water. In vitro cytotoxicity results revealed that LPCC-C-F127 has high cytotoxicity against A549 cells. These results demonstrated that the novel drug delivery systems would inspire the development of novel self-fluorescent drug delivery systems with imaging and therapeutic goals for cancer therapy.5. Multifunctional mesoporous silica nanoparticles were prepared by using curcumin polymer shell as the gating agents via one-pot method. In vitro drug release study showed that the curcumin polymer shell can retain the drugs in the pores and control the drug release at the existence of GSH and pH 5.5. The degradation study results confirm that curcumin polymer shell can be degraded by GSH, and the degradation rate is increased with the concentration of GSH. The fluorescent imaging can be achieved via the fluorescent curcumin. The dispersity of the nanoparticles can be improved by the curcumin polymer shell. Furthermore, the in vitro cytotoxicity results show that the nanoparticles coated with curcumin polymer shell can more effectively kill the A549 cells. These results reveal that the design strategy of multifunctional MSNs can contribute to further design promising drug delivery systems and broaden the application of curcumin in cancer treatment.