AbstractThis thesis focuses on the development of novel nanomaterials for biomedical imaging using both iron oxide nanoparticles and cadmium based quantum dots, and two different coating methods. The first approach involved a coating ligand consisting of the stealth molecule polyethylene glycol, and a bisphosphonate enabling strong binding to the nanoparticle surface. This polymer conjugate was chosen in order to reduce undesirable reticuloendothelial system uptake, and hence increase blood circulation times allowing for efficient delivery of
particles to specific in vivo vascular targets. The second route employed a naturally occurring amphiphilic protein, hydrophobin, as an encapsulation agent according water solubility of nanomaterials and potential for bioconjugation.
The first part of the study involved the synthesis of novel iron oxide nanomaterials of small size distribution and a near-zero surface charge resulting in dispersions that were stable in solution for several months. Both longitudinal (r 1) and transverse (r 2) relaxivity measurements were performed at a clinically relevant magnetic field of 3 T, revealing a low r 2/r 1 ratio of 2.97 showing the particles to have optimal properties for efficient T1 -weighted magnetic
resonance imaging. The strong T1 effect was validated in vivo, revealing a long blood circulation time and a 6-fold enhancement of its signal, allowing for high resolution visualisation of vessels and vascularised organs. The low reticuloendothelial system uptake observed was confirmed by radiolabelling the particles, hence according dual-modality contrast, and performing in vivo single photon emission computed tomography. From this study, the blood
half-life was calculated to be 2.97 h. In vitro targeting studies using three different cardiovascular/ cancer biomarkers (VCAM-1, PSMA, and p32) were conducted, showing specific uptake of the targeted particles to relevant cell lines.
The second section examines the potential for applying the polyethylene glycol-bisphosphonate coating to other inorganic nanomaterials. CdZnSeS alloyed quantum dots were successfully synthesised, with the resulting particles exhibiting red emission (_604.0 nm) and no significant shift after phase transfer into aqueous solution. Preliminary in vitro cell studies revealed particle emission at the expected wavelength.
Finally, the synthesised nanoparticles were successfully coated with the amphiphilic protein (hydrophobin). The resulting nanoparticles exhibited no change in core size or morphology as determined by transmission electron microscopy, as well as no shift in emission (~627.0nm). In vitro studies were performed allowing for visualisation of the quantum dots in a biological environment after incubation at physiological temperature. In addition, particles
were injected intratumourly into a live mouse model, with emission detected up to 24 h post injection. Lastly, radiolabelling with iodine-131 was achieved; confirming the possibility of utilising exposed residues on the protein to further functionalise the surface.
In conclusion, the described methods and nanoparticles synthesised represent a promising platform for the development of targeted agents for multimodal medical imaging and other bio-applications.
|Date of Award||2015|
|Supervisor||Mark Green (Supervisor) & Rafael T. M. de Rosales (Supervisor)|