Characterisation of targeted imaging and theranostic agents for cancer and fibrosis

Thompson, James Andrew

Medicine
September 2018

Thesis or dissertation


Rights
© 2018 James Andrew Thompson. All rights reserved. No part of this publication may be reproduced without the written permission of the copyright holder.
Abstract

Positron emission tomography (PET) imaging is a non-invasive modality that permits the characterisation of biological processes at the molecular level. Integrin αvβ6 and the chemokine receptor CXCR4 are important receptors in the pathogenesis of various cancers as well other diseases such as idiopathic pulmonary fibrosis (IPF) that may be exploited for the diagnosis, prognosis and assessment of therapeutic response. The gold-standard method for diagnosis of various cancers, such as breast, is immunohistochemistry (IHC), which suffers from a lack of a well-defined and reproducible cut-off value for tumour-positive or benign classification.

The integrin αvβ6 is involved in various signalling pathways and it’s expression is generally very low in healthy tissues, and is greatly upregulated in various pathologies such as cancer and IPF, being linked to worse prognosis in pancreatic, head and neck, breast and ovarian cancers. Upregulation of αvβ6 during fibrosis or in tumours makes it an attractive target for a non-invasive imaging agent for the early detection of αvβ6 in cancer or IPF, monitoring of disease progression and the assessment of therapeutic response to existing or novel therapies. This thesis has evaluated αvβ6-targeted peptides for use as non-invasive PET imaging agents. [⁶⁸Ga]Ga-DO3A-JD2-RGD1 was selected as the lead peptide and demonstrated high affinity binding and high specificity for αvβ6 in competitive enzyme-linked immunosorbent assays, surface plasmon resonance and cellular binding assays in vitro as well as imaging and biodistribution studies in vivo using αvβ6+ cancer models, indicating its suitability for the detection of αvβ6 in cancer. Preliminary studies of [natLu]Lu-DO3A-JD2-RGD1 showed that chelation of lutetium-177 did not affect peptide binding to αvβ6, making it a promising potential peptide-receptor radionuclide therapy (PRRT) agent for αvβ6+ cancer.

The chemokine receptor CXCR4 and its cognate ligand CXCL12 play a pivotal role in normal physiological processes. CXCR4 overexpression has been associated with over twenty types of human cancer with aggressive, invasive phenotypes, presenting a requirement for a non-invasive imaging agent for the detection of malignant sites including metastatic lesions. This thesis has evaluated the CXCR4-binding characteristics of novel tetraazamacrocycles [natCu]CuCB-bicyclam and [natCu]Cu2CB-bicyclam, synthesised by Archibald and colleagues, by surface plasmon resonance in a comparison study with the clinically used AMD3100. Both novel inhibitors were able to bind to CXCR4 with greater affinity than AMD3100, indicating their suitability for further validation as both PET imaging agents in CXCR4+ cancer detection and therapeutic agents in cancer and IPF.

Publisher
Hull York Medical School, The University of Hull and The University of York
Supervisor
Hart, Simon P.; Cawthorne, Chris; Archibald, Stephen J.
Qualification level
Doctoral
Qualification name
PhD
Language
English
Extent
4 MB
Identifier
hull:17287
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