Towards early Alzheimer's disease diagnosis: development of amyloid-targeted magnetic nanoparticles for use as MRI/MPI tracers

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Copyright: Ulanova, Marina
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Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease characterised by the development of amyloid-beta (Aβ) plaques, neurofibrillary tau tangles and neurodegeneration. Currently, a definitive diagnosis is only possible with positron emission tomography imaging of amyloid-beta or the analysis of cerebrospinal fluid for AD biomarkers. Both approaches have limitations, namely they are expensive, not widely available and having limited repeatability. Magnetic resonance imaging (MRI) using magnetic nanoparticle contrast agents has opened the potential for less invasive and costly diagnosis. Moreover, magnetic particle imaging (MPI) is a novel tracer-based technology, which derives signal from magnetic nanoparticles to produce images with high sensitivity. While this technology is in the preclinical stages, its high spatial resolution and rapid image acquisition renders it a powerful new tool for neuroimaging research and diagnosis of AD. This thesis seeks to develop biocompatible Aβ-targeted magnetic nanoparticle for use as -MRI contrast agent and MPI tracer as tools for early AD diagnosis. Investigations were undertaken to examine the in vitro biocompatibility and imaging efficacy of Aβ-targeted spherical and cube nanoparticles stabilised with a dimercaptosuccinic acid (DMSA) coating and Aβ targeted spherical iron oxide nanoparticles coated with poly(maleic anhydride-alt-1-octadecene) (PMAO). Results indicated superior stability and MRI contrast enhancement of the PMAO-coated nanoparticles, and thus we employed these in subsequent in vivo analyses. Having established the efficiency of PMAO-coated nanoparticles, we sought to determine their in vivo biocompatibility and biodistribution, and evaluate the efficacy of the targeted nanoparticles as a dual-mode MRI and MPI tracer for AD diagnosis using a mouse model of AD. Critically, this study demonstrated that administration of Aβ-targeted PMAO-coated nanoparticles results in hypointensities in the MRI image and signal in MPI scans, which colocalise with Aβ plaques on histology. Furthermore, MPI is demonstrated as an effective and efficient tool for determining and quantifying nanoparticle biodistribution, establishing it as a powerful tool for research and diagnosis. The present work provides compelling preliminary investigation and evaluation of an Aβ-targeted MRI contrast agent which could facilitate more widespread availability early AD diagnosis, opening the window for more effective treatment and prevention of AD.
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Publication Year
2022
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Thesis
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PhD Doctorate
UNSW Faculty