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Title: Molecular magnetic resonance imaging of vascular inflammation using microparticles of iron oxide
Author: Akhtar, Asim
ISNI:       0000 0004 2706 9331
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2010
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One approach that has demonstrated success in the field of molecular imaging utilizes microparticles of iron oxide (MPIO) conjugated to specific antibodies and/or peptides to provide contrast effects on MRI in relation to the molecular expression of a specified target. The experimental aims of this thesis were 1) to investigate the ability of VCAM-1 and P-selectin targeted MPIO to detect the expression of VCAM-1 and P-selectin on the activated endothelium in-vitro and in-vivo in mouse models of renal and cerebral ischemia reperfusion injury, and 2) develop a novel contrast agent for imaging αvβ3-integrin expression in angiogenesis using RGD peptide conjugated MPIO (RGD-MPIO) in-vitro. MPIO (1.0 µm) were conjugated to monoclonal antibodies against VCAM-1 (VCAM-MPIO) or P-selectin (PSEL-MPIO). In vitro, MPIO bound in a dose-dependent manner to tumor necrosis factor (TNF)-alpha stimulated sEND-1 endothelial cells when conjugated to VCAM-1 (R² = 0.88, P<0.01) and P-selectin antibodies (R² = 0.93, P<0.01), reflecting molecular VCAM-1 and P-selectin mRNA and protein expression. Mice subjected to unilateral, transient (30 minutes) renal ischemia and subsequent reperfusion received intravenous VCAM-MPIO and PSEL-MPIO (4.5 mg iron/kg body weight). In ischemic kidneys, MR related contrast effects of VCAM-MPIO were 4-fold higher than unclamped kidneys (P<0.01) and 1.5-fold higher than clamped kidneys of PSEL-MPIO injected mice (P<0.05). VCAM-MPIO binding was less evident in IRI kidneys pre-treated with VCAM-1 antibody (P<0.001). VCAM-1 mRNA expression and VCAM-MPIO contrast volume were highly correlated (R² = 0.901, P<0.01), indicating that quantification of contrast volume reflected renal VCAM-1 transcription. In mice subjected to cerebral ischemia, contrast volume was 11-fold greater in animals injected with VCAM-MPIO versus control IgG-MPIO (P<0.05). Finally, S-nitroso-N-acetylpenicillamine (SNAP) stimulated HUVEC-C cells, which express αvβ3-integrin, showed 44-fold greater RGD-MPIO binding than unstimulated cells (P<0.001) and 4-fold greater RGD-MPIO binding than SNAP stimulated cells blocked with soluble RGD peptide (P<0.001) in-vitro. This thesis demonstrated that targeted MPIO exhibited contrast effects that defined and quantified the molecular expression of specific targets through the use of high-resolution MRI in in-vitro and in-vivo models of vascular inflammation.
Supervisor: Choudhury, Robin Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Medical Sciences ; Cardiovascular disease ; Disease prevention ; Stroke ; Radiology ; Vascular research ; Advanced materials ; molecular imaging ; vascular inflammation ; contrast agents ; microparticles ; iron oxide