The focus of this thesis is the development of two molecularly targeted imaging methods, in both cases based on contrast agents encompassing micron-sized microparticles of iron oxide (MPIO). MPIO are obligate intravascular agents and as presented in this thesis the half-life in the blood circulation is < 1min. In the first approach described in the thesis, the overall goal was to detect metastasis in mouse lungs, very early in metastatic development, by targeting vascular cell adhesion molecule 1 (VCAM-1) using conjugates of an anti-VCAM-1 antibody and 1 μm MPIO (VCAM-MPIO). In Chapter 3, I demonstrate specific retention of VCAM-MPIO in the vasculature of a lung metastasis model, and also the very short blood half-life of the contrast agent; both of which suggest the potential for in vivo detection. In Chapter 4, I show that whilst the bound VCAM-MPIO do not sufficiently dephase the signal obtained with the bright lung MRI approaches used (hyperpolarized <sup>3</sup>He/<sup>129</sup>Xe or <sup>19</sup>F MRI), it is possible to sensitively detect the presence of lung metastases in vivo using radiolabelled VCAM-MPIO (<sup>89</sup>Zr-DFO-VCAM-MPIO) in combination with PET imaging. The overall goal of the second approach described, was to detect and characterize tumour angiogenesis by targeting α<sub>v</sub>β<sub>3</sub>-expressing endothelium in vivo, using a conjugate of cyclic penta-peptides c(RGDyK) and 2.8 μm MPIO [c(RGDyK)-MPIO]. To this end, I demonstrate in Chapter 5 that c(RGDyK)-MPIO specifically binds to α<sub>v</sub>β<sub>3</sub>-expressing endothelium in subcutaneous tumours and yields quantifiable contrast effects on T<sub>2</sub>*-weighted MRI. Furthermore, I have implemented in this approach gadolinium DCE imaging, providing dynamic vascular information. To date there is no reported detection method for pulmonary metastasis at the micrometastastic stage, as presented in this thesis. Translation of this method into clinic could allow for earlier therapeutic intervention and, thus, more effective treatment. The angiogenesis characterization imaging method presented here may provide a sensitive approach for the characterization of heterogeneity in tumour angiogenesis/vascularity and monitoring of anti-angiogenic therapies.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:658452 |
| Date | January 2014 |
| Creators | Melemenidis, Stavros |
| Contributors | Sibson, Nicola; Muschel, Ruth |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:2b107d9b-0e16-48af-9fc8-d42d67c3d4e0 |
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