Hachani, Roxanne; (2018) Development of novel magnetic nanoparticles to track stem cells in tissue-engineered organs. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This overall aim of this thesis was to develop and optimise the synthesis of superparamagnetic iron oxide nanoparticles (IONPs) as potential magnetic resonance imaging (MRI) contrast agents. Indeed, these nanoparticles offer the possibility of multimodality, surface biofunctionalisation, and can offer better MRI sensitivity than conventional molecular-based contrast agents as long as their magnetic properties are adequate and that they are administered in a sufficient and safe dose. In the initial phases of this project, IONPs were synthesised by the polyol method in various experimental conditions: under inert atmosphere using a Schlenk line, using a microwave reactor and in high pressure high temperature conditions. The impact of these synthetic methods and the reaction variables on the physical and chemical properties of nanoparticles were studied. Iron oxide nanoparticles with low polydispersity were obtained through the polyol synthesis in high pressure high temperature conditions. Iron oxide NPs with a diameter of ca. 8 nm could be obtained in a reproducible manner and with good crystallinity as evidenced by X-ray diffraction analysis and high saturation magnetisation value (84.5 emu/g). However, poor results were obtained for their stability in aqueous solution. To overcome this, alternative surface functionalisation was investigated, using a variety of ligands in order to improve their stability. The surface of the IONPs could be modified post synthesis with the ligand 3,4-dihydroxyhydrocinnamic acid (DHCA) which provided functionality and long term stability in water and phosphate buffer saline (PBS). Their potential as MRI contrast agents was confirmed as they had an improved r2/r1 ratio by a factor of more than 3 in comparison to FDA-approved nanoparticles for MRI Resovist® and Endorem®, with relaxivity values of r1 = 7.95 mM-1 s-1 and r2 = 185.58 mM-1 s-1 measured at 1.4 T. To assess their biocompatibility, multiparametric high-content imaging analysis was carried out with human mesenchymal stem cells (hMSCs) to evaluate cell viability, formation of reactive oxygen species, mitochondrial health, as well as cell morphology. Results demonstrated that hMSCs were minimally affected after labelling with IONP-DHCA. Their cellular uptake was confirmed by transmission electron microscope (TEM) and iron specific Prussian Blue staining and quantified using a colourimetric method. In vivo, IONPs were detected as hypointense regions in the liver by 9.4 T MRI up to two weeks after intravenous administration into six Swiss female mice. These results demonstrate the successful development of novel iron oxide nanoparticles, their biocompatibility with hMSCs, and their potential as MRI contrast agents.

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