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Title: The assessment of a number of different mesoporous silica nanoparticles for delivery of chemotherapeutics and siRNAs
Author: Huang, Xinyue
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2015
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Mesoporous silica nanoparticles (MSNPs) are of interest as effective drug carriers because of their controllable physical properties and biomedical compatibilities. A number of different MSNPs have been assessed for their suitability as intracellular nano-scale carriers of chemotherapeutics and siRNAs. Four morphologically different MSNPs were synthesised after optimisation of existing protocols. The MSNPs were characterised with regards to size, porosity, surface area, surface charge, cytotoxicity and biodegradability. Their suitability as drug carrier in vivo was examined in terms of cargo loading, ability to be endocytosed by cells and take ad-vantage of the Enhanced Permeability and Retention effect. The loading and unloading profiles of two model compounds and a potential chemotherapeutic agent LY294002 were investigated. The release behaviours of the cargoes were altered by modifying the particle surface with polymeric capping agents. In addition, the particles were capped with pH-sensitive molecules, and the release behaviour in low pH was assessed since tumours are known to have an acidic microenvironment. The physiological function of LY294002 on selected cancer cell lines was also studied. LY294002 was shown to affect the proliferation, survival, and metabolism of selected cells under different oxidative conditions. The effect differed when cells were under oxi-dative stress and/or glucose stress. Cell viability was also compromised after treatment with LY294002 loaded MSNPs. The sensitivity to each LY294002 loaded MSNP differed between cell lines. Engulfment and cell motility 1 (ELMO1) - targeted siRNA was also delivered using MSNPs to two distinct rhabdomyosarcoma lines. Significant knock-down of the ELMO1 gene was shown, illustrating that MSNPs could be efficient transfection agents for siRNA. In particular, the two MSNP candidates were shown to be significantly better than a current commercial product. A co-delivery system for LY294002 and ELMO1-targeted siRNA was established. Cell viability and ELMO1 expression were both suppressed after treatment with the co-delivery system.
Supervisor: Townley, Helen ; Thompson, Ian P. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available