Synthesis of porous nanoparticles as carriers in therapeutic delivery

Budi Hartono, Sandy (2013). Synthesis of porous nanoparticles as carriers in therapeutic delivery PhD Thesis, AIBN, The University of Queensland.

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Author Budi Hartono, Sandy
Thesis Title Synthesis of porous nanoparticles as carriers in therapeutic delivery
School, Centre or Institute AIBN
Institution The University of Queensland
Publication date 2013
Thesis type PhD Thesis
Supervisor Michael Yu
Shizhang Qiao
Max Lu
Total pages 118
Total colour pages 33
Total black and white pages 85
Language eng
Subjects 1007 Nanotechnology
Formatted abstract
In the last decade, considerable efforts have been spent in the development of functionalized mesoporous silica nanoparticles as carrier for gene delivery by researcher around the world. Non-porous and small pore size (<3nm) silica based materials have been used for nucleic acid-based biopharmaceutical (siRNA/DNA) delivery. The materials with small pore sizes (<3 nm) face some drawbacks such as poor diffusion of guest molecules within the pores and restricted adsorption towards large molecules. They are also susceptible to pore blocking. This study seeks to overcome the limitations of small pore size silica materials. Large pore mesoporous silica nanoparticles (LPMSN) with cubic mesostructure have been synthesised with the expectations that the material can improve gene or drug efficacy into target cells.

Poly-L-lysine (PLL) functionalized LPMSN (LP-MSN-P) were designed as a new carrier for gene delivery. The LPMSN have a particle size of ~ 200 nm and a large pore size. The cavity pore size of LPMSN is 28 nm while the entrance pore size is 13 nm. Various instruments were used to confirm the successful attachment of PLL onto LPMSN, such as: X-ray photoelectron spectroscopy, solid state 13C magic-angle spinning nuclear magnetic resonance, fourier transformed infrared and thermogravimetric analysis. The system showed some advantages, such as high binding capacity, strong ability to deliver oligo DNA (a model of siRNA) and low cytotoxicity. The system was tested to deliver functional siRNA against minibrain-related kinase and polo-like kinase 1 in osteosarcoma cancer cells. It was demonstrated that LP-MSN-P caused a reasonable reduction of cellular viability of the oncogenes.

Secondly, large pore mesoporous silica nanoparticles (LPMSN) were loaded with iron oxide and covalently modified by polyethyleneimine (PEI-Fe-LPMSN). The large pore size is essential for the formation of large iron oxide nanoparticles to increase the magnetic properties and the adsorption capacity of siRNA molecules. PEI-Fe-LPMSN enables enhanced cellular uptake on exposure to magnetic field. The PEI-Fe-LPMSN delivered siRNA-PLK1 effectively into osteosarcoma cancer cells, leading to cell viability inhibition of 80%, higher compared to 50% reduction when the same dose of siRNA was delivered by a commercial product, oligofectamine. The composite materials can be very useful not only for gene delivery but also for imaging applications.

Finally, a novel composite of poly(2-dimethylaminoethyl acrylate) (PDMAEA)-LPMSN has been developed. A ”self-catalyzed degradation” PDMAEA was grafted onto the surface of LPMSN. The unique property of PDMAEA-LPMSN has endowed this system with multi-functions, such as time-dependant release and co-delivery of gene and drug molecules. The cationic polymer unit binds to genetic molecules and undergoes a self-catalyzed hydrolysis in water to form a non-toxic anionic polymer poly(acrylic acid), allowing controlled release of siRNA in a time-dependent manner. The nanopores of LPMSN provides a reservoir for storage and release of chloroquine to facilitate endosome escape. Their siRNA delivery performance was tested in a KHOS cell line, showing promising potential as nano-carriers for the co-delivery of genes and drug.These results showed that modified LPMSN demonstrated great potential for efficient gene transfer.
Poly-L-lysine (PLL)
Polyethyleneimine (PEI)
Poly(2-dimethylaminoethyl acrylate) (PDMAEA)
Magnetic property
Gene Delivery
Small interfering RNA (siRNA)

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Created: Tue, 17 Dec 2013, 19:15:10 EST by Mr Sandy Budi Hartono on behalf of University of Queensland Graduate School