Exploration of novel imaging agents and therapeutic targets for neurotrauma

[Truncated] The development of effective neuroprotective strategies to treat injury of the central nervous system (CNS) is an unresolved therapeutic challenge which requires innovative multidisciplinary research. Calcium dysregulation, mitochondrial dysfunction, and oxidative stress have been identified as key mediators which influence cellular death in CNS tissues and calcium influx through AMPA receptors is known to contribute to these processes. Regulation of calcium influx through the use of therapeutic drugs has not proven successful thus far, prompting further research into new treatment strategies to limit the contribution of calcium influx to cell death following neurotrauma.

Nanotechnology-based drug delivery is emerging as a potential CNS therapeutic strategy. Concurrently, the tracking of nanoparticle biodistribution is becoming increasingly important in nanotechnology research and in clinical trials, to ensure appropriate delivery of encapsulated or linked therapeutics and minimising off-target effects. To this end the development of advanced nanomaterials capable of supporting imaging through multiple platforms represents an important area of research. Upconversion nanoparticles are new potential candidates for biological imaging probes, possessing advantageous physical properties when compared with traditional fluorophores. However, in order to utilise such materials appropriately it is necessary to understand their fundamental imaging properties. This PhD program has focussed on two areas leading towards the development of novel therapeutic strategies to treat CNS injury. The first area is directed at better understanding the development of multimodal imaging platforms using upconversion nanomaterials. The second area is focussed around the search for a suitable target to limit calcium influx, with the eventual aim of designing a therapeutic nanoparticle system.

The emission properties of lanthanide doped, upconverting nanoparticles were analysed in the presence of superparamagnetic iron oxide nanoparticles in the solid state. In this work, two sizes of upconverting nanoparticles were investigated and it was found that in solid state mixtures, iron oxide not only imparts a quenching effect, but also a previously unreported laser-power dependent thermal effect, causing a reduction of the emissions of upconversion nanoparticles. The thermal effect on the upconversion nanoparticles, imparted by iron oxide was monitored via luminescent nano-thermometry through analysis of the upconversion nanoparticle emissions. The study highlighted that the thermal effects of mixed nanoparticle systems should be considered in the design of solid-state luminescent upconverting hybrid materials. Multimodal polymeric nanoparticles were synthesised via a non-spontaneous microemulsion, co-encapsulating superparamagnetic nanoparticles and upconversion nanoparticles, for tracking via MRI and near-infrared imaging respectively. The magnetic properties of these nanoparticles were analysed and their suitability as imaging probes was assessed in vitro in PC-12 cells. Cellular uptake of the polymeric nanoparticles was observed through intra-cellular upconversion emissions and these nanoparticles had no impact on cellular viability, even at very high concentrations. Polymeric constructs containing either 10 nm a-NaYF4:Yb,Er or 50 nm b-NaYF4:Yb,Er mixed with 6 nm magnetite nanoparticles were compared and it was found that the combination of 50 nm b- NaYF4:Yb,Er with 6 nm magnetite nanoparticles exhibited favourable, dual optical and magnetic properties. It was concluded that the size and the phase of the upconverting nanoparticles are important technical considerations when designing multimodal probes incorporating upconverting nanoparticles. These results suggest that upconverting magnetic nanoparticles may be useful as advanced nanoparticulate tracking agents in the CNS and other tissues.