| Summary: | <p>Secondary brain cancer (brain metastasis) is a leading cause of cancer morbidity and mortality. As treatments for primary tumours and systemic metastatic disease improve, the significance of brain metastasis as a cause of death increases. The poor survival of patients with brain metastasis is partly attributed to the unique microenvironment of the brain, includes the blood-brain barrier (BBB), which limits penetration of systemics cancer therapies and imaging contrast agents, and partly to the late stage of diagnosis. Current diagnosis relies on breakdown of the BBB, which only occurs at later stages of metastasis progression and, thus, delaying the introduction of potential treatments. To address this critical issue, development of novel molecular magnetic resonance imaging (MRI) contrast agents for the detection of brain metastasis at the early stages of formation was the overall focus of this thesis.</p>
<p>Inflammation is a hallmark of many neurological disorders, and expression of cell adhesion molecules on blood vessels is a key component of this process. Brain endothelial activation can readily be targeted by iron oxide particles in vivo and unmasked using routine MRI acquisition methods. A number of different types of iron oxide particles, MRI sequences and magnetic field strengths have been used previously for visualising this endothelial activation. Hence, in this thesis, the initial aim was to optimise each of these parameters to further improve molecular MRI in mouse brain. </p>
<p>Endothelial activation is also an early event in the development of brain metastasis. Two adhesion molecules, activated leukocyte cell adhesion molecule (ALCAM) and E selectin, were assessed in brain metastasis models from three primary tumours (breast, melanoma and lung) as potential biomarkers for detection of brain micrometastases in the preclinical models. Iron oxide based microparticles against these surrogate biomarkers of brain metastases were developed, validated and applied in vivo.</p>
<p>The results of this work demonstrated that targeting both ALCAM and E selectin can reveal brain metastases at the microscopic level, and before conventional imaging methods. The advances in our ability to detect early brain metastatic stages using molecular MRI, and the presented contrast agents in this body of work is likely to yield substantial improvements in patient survival. </p>
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