Bio-inspired virus-mimicking nanoparticles for efficient cellular delivery

Niu, Yuting (2015). Bio-inspired virus-mimicking nanoparticles for efficient cellular delivery PhD Thesis, Australian Institute for Bioengineering and Nanotechnology (AIBN), The University of Queensland. doi:10.14264/uql.2016.10

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Author Niu, Yuting
Thesis Title Bio-inspired virus-mimicking nanoparticles for efficient cellular delivery
School, Centre or Institute Australian Institute for Bioengineering and Nanotechnology (AIBN)
Institution The University of Queensland
DOI 10.14264/uql.2016.10
Publication date 2015-12-18
Thesis type PhD Thesis
Supervisor Chengzhong Yu
Total pages 166
Language eng
Subjects 0304 Medicinal and Biomolecular Chemistry
0601 Biochemistry and Cell Biology
Formatted abstract
Delivery of various drugs and biomolecules into cells is crucial in modern medicine, providing promising potential in the treatment of incurable diseases. Most naked therapeutic biomolecules, for example, proteins, siRNAs and some free drugs can hardly penetrate into cells, thus various natural particulates and synthetic vectors have been used as cellular delivery vehicles. The understanding of structure–function relationships of natural particulates provides a useful guide for the design of new nanocarriers with better safety and higher delivery efficiency. Currently, many research attempts have focused on the synthesis of new drug delivery systems by mimicking the advantages of enveloped viruses, which have evolved sophisticated mechanisms that make use of or shield off cellular signalling and transport pathways to traffic within host cells and deliver cargos into appropriate subcellular compartments. However, there are still some parameters of enveloped viruses requiring intensive study, for example, the contribution of viral surface topography (rough surface) to intracellular delivery of cargo molecules.

This thesis focuses on the development of a novel drug delivery system with high performance based on the preparation of silica nanoparticles with virus-mimicking rough morphology and gains insight into the roles of surface roughness variation and surface functionality (e.g. polyethylenimine and octadecyl-group) in biomolecule (e.g. siRNAs and therapeutic proteins) delivery performance. The main achievements obtained in this thesis are listed below.

In the first part, a new and facile approach has been developed to prepare the virus-mimicking silica nanoparticle (VMSN) with a rough surface. We show that increases in nanoscale surface roughness promote both binding of biomolecules (e.g., genetic molecules) and cellular uptake; thus, the cargo delivery efficiency is significantly increased, regardless of surface functionality and cell types. Finally, gene delivery efficiency was tested, where the biomimetic nanoparticles shows a better cell growth inhibition performance than the smooth silica nanoparticle and a commercial delivery reagent.

In the second part, the novel and facile approach for systematically controlling surface roughness of silica nanoparticles has been developed. Based on our "neck-enhancing" approach, rough silica nanoparticles (RSNs) with a fixed core particle (211 nm in diameter) and varied shell particles are obtained. The increase of shell particle sizes from ̴ 13 to ̴ 98 nm enlarges interspacing distance between neighbouring shell particles from ̴ 7 to ̴ 38 nm, where protein molecules will favourably absorb onto one of RSNs without impacting protein binding ability. Moreover, hydrophobically modified RSN having the optimized interspacing distance of ̴ 38 nm successfully complexes with therapeutic anti-pAkt antibody, and it shows enhanced intracellular delivery efficiency in human breast cancer (MCF-7) cells, leading to significant cell growth inhibition by blocking pAkt and the downstream anti-apoptotic protein of Bcl-2.

In the third part, we quantitatively demonstrate both the individual and combined contributions of surface roughness and hydrophobic modification for the improvement of protein therapeutics. Both surface roughening and hydrophobic modification enhance the protein adsorption capacity, while the contribution from surface roughness is more effective. For sustained protein release, hydrophobic modification has a stronger effect compared to rough surface. Both structural parameters improve cellular uptake performance; however the contribution difference is cell type-dependent. It is clear that surface roughness has little contribution to endo/lysosomal escape. Only surface chemistry, i.e., hydrophobic modification, facilitates the release of nanoparticle/cargo molecules from endosome/ lysosome entrapment. Collectively, octadecyl-functionalized rough silica nanoparticle (C18-RSN) shows the best performance in therapeutic protein (RNase A) delivery, causing significant cell viability inhibition in MCF-7 and SCC-25 cell lines compared to RSN and smooth silica nanoparticle with (C18-SSN) and without (SSN) C18-modification.
Keyword Bio-inspired
Silica nanoparticle
Intracellular delivery
Gene therapy
Protein therapeutics
Surface functionalization
Surface roughness

Document type: Thesis
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Created: Fri, 11 Dec 2015, 13:00:51 EST by Yuting Niu on behalf of Learning and Research Services (UQ Library)