A Novel Anticancer Drug Carrier System Based On Silica Nanoparticles

Cancer therapy can alleviate the suffering, improve quality of life and reduce mortality of patients.Traditional chemotherapy exists side effects and cause greatly physical and psychological damage to the patients. Recently, nanotechnology constantly influence antitumor drugs delivery field and triggered a profound revolution. Silica nanoparticles, as one of the important inorganic nanomaterials, display several features of straightforward synthesis, good stability, excellent biocompatibility and easily modification, which make them be widely applied in biomedicine. Aiming at the important aspect of anticancer drug delivery, this thesis mainly focuses on development of a novel anticancer drug carrier system based on silica nanoparticles. The three parts of the thesis are as follows.1. Study on a novel drug carrier system based on phosphonate-terminated silica nanoparticles.Pingyangmycin (PYM) doped phosphonate-terminated silica nanoparticles (PO4-PYM-SiNP) were prepared via the synchronous modification of functional group in the water-in-oil microemulsion. The effect of 3-trihydroxysilylpropyl methylphosphonate (THPMP) on the PO4-PYM-SiNP has been investigated. The results showed that the zeta potential of PO4-PYM-SiNP decreased obviously, and the release rate of PYM from the PO4-PYM-SiNP accelerated with increase of added THPMP. However, the quantum of THPMP had no impact on the size of PO4-PYM-SiNP. A PO4-PYM-SiNP with good stability and long acting release has been prepared using optimal quantum THPMP, at which the drug can release steadily and slowly. The prepared PO4-PYM-SiNP presented drug loading and entrapment efficiency of 7.2% and 37.81%, respectively. The PO4-PYM-SiNP could make the survival rate of CNE-2 cells fell gradually, and PO4-SiNP itself was nontoxic. The research work expands the applications of silica nanoparticles in the field of drug carrier.2. Study on NaF-Catalyzed Synthesis of Doxorubicin Doped Silica NanoparticlesWe used sodium fluoride (NaF) catalyzed hydrolysis of silane precursors in the reverse microemulsion to encapsulate doxorubicin (DOX) in the SiNPs. We investigated the effect of the concentration of DOX on fluorescence intensity of DOX-SiNP. Then, amino-terminated DOX-SiNP (NH2-DOX-SiNP), poly(ethylene glycol)(PEG)-terminated DOX-SiNP (PEG-DOX-SiNP), phosphonate-terminated DOX-SiNP (PO4-DOX-SiNP) and carboxyl-terminated DOX-SiNP (COOH-DOX-SiNP) were then prepared by NaF as a catalyst via the synchronous modification of functional group in the water-in-oil microemulsion. We thus determined the release behavior of DOX from different functional groups modified DOX-SiNP and selected carboxylic acid modified SiNP as the drug carrier in our research. Because carboxylic acid groups on the SiNP surface are potential modified and covalent linked to the functional biomolecules. The results showed that the anticancer drug DOX which is unstable in alkaline and strong acid condition could be encapsulated into the SiNP by using NaF as a catalyst. The different silylating reagent modified functional groups linked DOX-SiNP all show long-term sustained release curves. By optimization of the DOX concentration and the best quantum of TSEA, the prepared DOX-SiNP present uniform size, regular shape, good dispersion, high stability, long sustained release and drug loading, and entrapment efficiency of 4.2% and 21.98%, respectively. This proposed NaF-catalyzed method will be promising for envelopment molecular which is unstable in alkaline and strong acid condition.3. The Aptamer Functionalized DOX-SiNP Application in Tumor Targeted TherapyWe covalently conjugated the Sgc8c aptamer to the carboxyl-terminated Dox-SiNPs (COOH-DOX-SiNP) to form Sgc8c-Dox-SiNPs by EDC/NHS activation chemistry. The Sgc8c aptamer has high binding affinity toward CCRF-CEM cells (human acute leukemia T cells) cells. On this basis, cell toxicity test and propidium iodide (PI)-stained nuclei was selected to test the cytotoxic effect of NaF catalyzed pure carboxyl-terminated SiNPs (COOH-SiNP), Sgc8c unmodified carboxyl-terminated DOX-doped SiNP (COOH-DOX-SiNP) and Sgc8c-DOX-SiNP to tumor cells. The results showed that COOH-SiNP carrier itself is not toxic in a certain range of concentration. While the COOH-DOX-SiNP had a significant toxicity in CCRF-CEM cells and Ramos cells, and had unselective toxicity to the CCRF-CEM cells and Ramos cells. As to CCRF-CEM cells, the inhibition concentration (IC50) of COOH-DOX-SiNP show a 5.46-fold increase in toxicity to that of free DOX. After modification of the target molecule, Sgc8c-DOX-SiNP could selectively kill the target CCRF-CEM cells, while the cytotoxicity of Sgc8c-DOX-SiNP was negligible to non-target Ramos cells. The reason for this is that the aptamer modified drug carrier can specifically recognize their target cells. The results were further confirmed by flow cytometry and confocal laser scanning microscopy through the fluorescence of DOX itself. Accordingly, we report here the first aptamer-conjugated DOX-SiNP for potential anticancer drug targeted delivery and therapy.