In the recent years, nanoporous silica materials have been regarded as promising nano-carriers to deliver various therapeutic agents, due to their high pore volume and surface area, ease of surface functionalization and excellent biocompatibility. Although numerous porous silica nanoparticles have been developed for therapeutic delivery, more efforts are still needed in the synthesis of nanoporous silica nanoparticles simultaneously possessing good dispersity, high uniformity, small particle size (< 200 nm) for efficient cellular uptake and sufficient pore size to encapsulate desired therapeutic agents with large molecular sizes.
This thesis focuses on synthesizing self assembled porous silica nanoparticles for high performance of biomedical applications. Three types of porous silica nanoparticles, including silica vesicles, SBA-15 rods and mesoporous organosilica nanoparticles will be synthesized. The self assembly based formation mechanism will be discussed, which is believed as a key to design porous silica nanoparticles with superior and more controllable structures and properties. In addition, their drug/protein loading capacity and release profile, biocompatibility, cellular uptake performance, and therapeutic efficacy will be evaluated in vitro.
The first part of the experimental chapters focuses on the synthesis of silica vesicles (SVs) with a diameter of 30 nm and reduced aggregation using mixed triblock copolymer surfactants as the structure-directing agents, tetraethyl orthosilicate (TEOS) and tetrapropyl orthosilicate (TPOS) as mixed silica sources. The reduced aggregation is attributed to the incompletely hydrolysed hydrophobic –OCH2CH2CH3 groups of TPOS on the surface of SVs, thus preventing the inter-particle aggregation. The drug delivery performance of SVs is evaluated using a photosensitizer ─ silicon phthalocyanine dichloride (SiPC) as a model drug. The cell viability results show the significantly enhanced cell inhibition of SiPC-SV (~61.5%) compared to pure drug (~35.5%). The efficient cellular uptake of SiPC-SV is also visualized by confocal image. Those results strongly suggest the potential application of the SVs as nanocarriers for efficient cancer therapy.
In the second part of the experimental chapters, porous silica nanoparticles with rod like morphology are prepared. The sized of SBA-15 rods can be controlled from ~100 nm to ~1 μm by finely tuning the synthesis pH in a narrow range of 3.40–3.88. The smallest SBA-15 rod obtained at pH 3.88 (SR-3.88) is 80-200 nm in length, 18±8 nm in width with a pore size of 8.3 nm. Compared to traditional SBA-15 with larger particle sizes and MCM-41 with smaller pore sizes, we demonstrate their improved adsorption capacity towards large protein molecules such as bovine serum albumin (438 mg g-1) and lysozyme (417 mg g-1). The cellular uptake of SR-3.40, SR-3.88 and MCM-41 in human osteosarcoma cancer cells is visualized using confocal image and quantified using ICP technique, revealing the significantly enhance cellular uptake efficiency of SR-3.88 (7.4 pg/cell) compared to SR-3.40 (2.0 pg/cell) and MCM-41 (6.1 pg/cell). Hence, the SBA-15 rods with small particle sizes, large pores as well as excellent biocompatibility are believed as a promising delivery system for cellular delivery of large molecular weight therapeutic agents with improved efficacy.
Lastly, we tuned the composition of porous silica nanoparticles by incorporating benzene groups in the silica framework to synthesize large pore well dispersed mesoporous organosilica nanoparticles (MOSNs) by using a biphase synthesis approach. The role of the biphase system has been demonstrated essential to enlarge pore size and facilitate the surfanctant/organosilica precursor assembly. The obtained MOSNs with pore size of 7.6 nm show enhanced protein loading capacity at 144.5 μg mg-1 and sustained release profile over 72 hours. In order to investigate the potential in biomedical application, the efficient cell uptake is firstly visualized using confocal image and the low cytotoxicity of nanopaticles (<25% cell death) were confirmed using MTT assay at 24 h, 48 h and 72 h at different concentrations. Furthermore, the protein loaded MOSNs shows significantly enhanced cell inhibition of ~64% at 72h, while pure protein show only negligible cytotoxicity at the same condition. These results clearly suggested the promising potential of large pore MOSNs for efficient intracellular protein delivery applications.