Designed synthesis of mono-dispersed silica-based nanostructures and their applications in drug/gene delivery

Yu, Meihua (2014). Designed synthesis of mono-dispersed silica-based nanostructures and their applications in drug/gene delivery PhD Thesis, Australian Institute for Bioengineering & Nanotechnology, The University of Queensland. doi:10.14264/uql.2014.398

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Author Yu, Meihua
Thesis Title Designed synthesis of mono-dispersed silica-based nanostructures and their applications in drug/gene delivery
School, Centre or Institute Australian Institute for Bioengineering & Nanotechnology
Institution The University of Queensland
DOI 10.14264/uql.2014.398
Publication date 2014-10-30
Thesis type PhD Thesis
Open Access Status Other
Supervisor Chengzhong (Michael) Yu
Peter Thorn
Wenyi Gu
Total pages 196
Language eng
Subjects 1007 Nanotechnology
0903 Biomedical Engineering
Formatted abstract
Over the last two decades, silica based nanoparticles (SiNPs) have been extensively investigated as promising nano-carriers to deliver various therapeutic/diagnostic agents into living systems, due to their unique properties of tunable pore structure and particle size, easy surface modification and low cost. In particular, SiNPs with small sizes (less than 100 nm) and high monodispersity, SiNPs possess great advantages in cell endocytosis process, which is vital to achieve high efficiency in biomedical applications. Although there have been tremendous studies in the synthesis of monodisperse nanometer-sized SiNPs, more efforts are still needed to develop facile, economic and environmentally friendly synthesis approaches for fabricating novel monodisperse SiNPs with desired particle size, nano-structure and functionality. The as-designed novel SiNPs are expected to expand their capacity in various biomedical applications, such as enhanced bio-imaging performance in three dimensional spheroid models, improved cellular drug/gene delivery efficiency.

The aim of this project is to develop novel and facile approaches to prepare highly mono-dispersed SiNPs with finely controlled structures for drug/gene delivery and gain insight into the roles of particle size, surface functionality on cell penetration performance and drug/gene delivery efficiency. The main achievements obtained in this thesis are listed below.

In the first part, a new and facile approach has been developed to prepare monodisperse mesoporous silica nanospheres (MMSNs) with controlled particle sizes (50-100 nm) and pore diameters (2.8-4.0 nm). In this approach, MMSNs were synthesized simply in a sodium acetate solution without adding any other alkali or alcohol additives. By further investigations on formation process, we proposed a spherical micelle templating mechanism to explain the formation of MMSNs in our system, which is different from that of traditional highly ordered mesoporous silica nanoparticles (MCM-41). MMSNs developed in this part are expected to have potential applications in drug/gene delivery and cell imaging.

In the second part, even smaller mono-dispersed SiNPs (ultra-small hybrid silica spheres, UHSS) with a diameter of only about 10 nm were developed by a facile strategy under phosphate-citrate buffer solution (pH = 4.6) at room temperature without addition of toxic additives. Compared to traditional MCM-41 nanomaterials, the designed novel UHSS showed enhanced penetration ability in three dimensional glioma spheroids.

Following the second part, epoxysilane functionalized UHSS (Epoxy-UHSS) with a diameter of about 10 nm were designed under similar synthesis conditions, which can be easily covalently conjugated with cationic polyethyleneimine (PEI) (PEI-UHSS). This designed positively charged PEI-UHSS demonstrated excellent delivery efficiency of a functional siRNA against polo-like kinase 1 (PLK1-siRNA) in osteosarcoma cancer cells (KHOS) and survivin-siRNA in human colon cancer cells (HCT-116) inducing a significant cell inhibition, which is comparable to commercial agents. These results indicated that suitable functionality of SiNPs is significant to achieve efficient gene delivery.

In the fourth part, we further investigated the influence of surface functionality of SiNPs on drug delivery efficiency. Hyaluronic acid (HA) modified mesoporous silica nanoparticles (MSNs) were developed, which possess specific affinity to CD44 over expressed on the surface of a specific cancer cell line, HCT-116 (human colon cancer cells). Compared with bare MSNs, HA-MSNs exhibited a higher cellular uptake via HA receptor mediated endocytosis. An anticancer drug, doxorubicin hydrochloride (Dox), were loaded into MSNs and HA-MSNs. Dox loaded HA-MSNs showed greater cytotoxicity to HCT-116 cells than free Dox and Dox-MSNs due to the enhanced cell internalization behavior of HA-MSNs. This work indicated that the desired surface functionality is also crucial to improve drug delivery efficiency.

Apart from surface functionality, the particle size of SiNPs is expected to have significant effect on gene delivery efficiency. In the last part, amine modified monodisperse Stöber spheres (NH2-SS) with various diameters of 125, 230, 330, 440 and 570 nm were synthesized. The in vitro transfection efficiencies of NH2-SS were studied in HEK293T cells by delivering plasmid DNA encoding green fluorescent protein (GFP) (pcDNA3-EGFP, abbreviated as pcDNA, 6.1kbp). It was found that an optimized particle size of 330 nm exhibited the highest expression of GFP. Our mechanistic study showed that the binding affinity of pcDNA/NH2-SS complexes decreased while the cellular uptake ability increased with NH2-SS size increasing from 125 to 570 nm. The opposite effects lead to an optimal NH2-SS size of 330 nm that provides the maximum gene delivery efficiency. A similar size-dependent gene delivery relationship was further demonstrated in another plasmid DNA with a bigger size of 8.9 kbp. This work for the first time demonstrates the significant role of particle size of cationic silica nano-carriers on gene delivery efficiency. The knowledge obtained from this work is crucial for the rational design of synthetic gene delivery systems with improved efficiency for gene therapy.
Keyword Monodisperse silica nanoparticles
Surface modification
Drug delivery
Gene delivery
Plasmid DNA
Cellular uptake

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Created: Tue, 28 Oct 2014, 12:02:44 EST by Meihua Yu on behalf of Scholarly Communication and Digitisation Service