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Type: Thesis
Title: Mesoporous Silica Nanocomposites for Drug and Gene Delivery
Author: Xiong, Lin
Issue Date: 2016
School/Discipline: School of Chemical Engineering
Abstract: A drug delivery system is an essential tool for improving drug therapies by overcoming the limitations of ‘free’ drug delivery including low solubility in water, poor stability in biological systems, short residence time, unspecific toxicity and side effects. Nowadays, nanomaterials have become ideal vehicles for drug delivery owing to their very small size and high surface-to-volume ratio. Their small size ensures access to different biological tissues, efficient cellular uptake and facilitates intracellular delivery of therapeutics. Their high surface area allows for high drug loading and the attachment of various functional groups. Among various nanomaterials, mesoporous silica nanoparticles show great potential for delivery application due to their good biocompatibility, well-developed mesoporosity, and versatile surface functionalization. However, to construct an efficient delivery system, the primary silica nanoparticles still need to be optimized in structure to load large biomolecules and modified in surface chemistry to achieve efficient targeting and release control. With this aim, this Ph.D thesis has demonstrated the design and fabrication of a serial of novel mesoporous silica based nanocomposites as drug and gene delivery carriers. These researches include: (1) We firstly studied the controllable synthesis of stellate mesoporous silica nanoparticles with radial pore morphology. By using triethanolamine as the base catalyst and adjusting the surfactant composition, reaction temperature and time, and reagent ratio, we demonstrated that the particle size of these nanomaterials could be tailored continuously from 50 to 140 nm and the pore size could be tuned from 2 to 20 nm, respectively. After further functionalization with low molecular weight poly(ethyleneimine), these nanocomposites demonstrated good capability for intracellular delivery of the anticancer drug doxorubicin. (2) Then, we developed a cancer cell-specific nuclear-targeted delivery system based on mesoporous silica nanoparticles. Mesoporous silica nanoparticles with 40 nm particle size were modified with dual targeting ligands, i.e., folic acid for cancer cell targeting and dexamethasone for nuclear targeting. The resulting nanocarriers could not only enhance the inhibition efficacy of doxorubicin on cancerous Hela cells through active nucleus accumulation but also reduce toxic side effects on normal cells though receptor-mediated selective cellular uptake. (3) Next, we studied magnetic core–shell silica nanoparticles with large radial mesopores for small interfering RNA (siRNA) delivery. These nanoparticles possess both high loading capacity of siRNA and strong magnetic response under an external magnetic field. Furthermore, an acid-liable coating composed of tannic acid was applied to further protect the siRNA loaded in the large pores. The coating also increased the dispersion stability of the siRNA-loaded carrier and served as a pH-responsive releasing switch. Using these nanocarriers, enhanced delivery of functional siRNA into human osteosarcoma cancer cells was achieved with the aid of the external magnetic field. (4) Finally, we prepared bowl-like mesoporous organosilica nanoparticles for DNA delivery. The nanoparticles were prepared by a simple “hard templating followed by hydrothermal etching” method. After amine functionalization, these nano-bowls showed significantly higher loading capacity for plasmid DNA than traditional structured (hollow, dendric, MCM41 type) silica-based nanocarriers thanks to their large accessible center cavity. Furthermore, after co-loading with an endosomolytic reagent in the mesopores, enhanced transfection efficiency comparable to the polymer standard was achieved for in vitro plasmid DNA transfection. In summary, these findings have demonstrated the design and fabrication of several novel silica nanocomposties for drug and gene delivery, provided a deeper understanding of the relationship between the physicochemical properties of silica nanocomposties and their bioactivity, and may pave a way of the further development of silica-based delivery system.
Advisor: Qiao, Shizhang
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Chemical Engineering, 2017
Keywords: Mesoporous silica
drug delivery
gene delivery
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