Breast cancer remains the most commonly diagnosed cancer among women over the age of 20, as recently reported by the Canadian Cancer Society. Studies have shown a strong correlation between early detection and increased survival rates thus it is important to have a means to adequately screen and detect breast cancer. Currently, tests are limited to traditional imaging methods such as ultrasound (US), magnetic resonance imaging (MRI) and standard mammography. There remains a need for a molecular imaging probe that is capable of providing further prognostic information particularly with respect to assessing tumour aggressiveness and the likelihood of a cancer to metastasize.
Overexpression of the insulin receptor (IR) has been detailed in patients with breast cancer but there is currently no means of non-invasive and quantifiable detection of the receptor. The goal of the work described here was to prepare an insulin derived nuclear imaging probe via direct coupling of a prosthetic group bearing a radionuclide to the B29 lysine (B29-Lys) residue of the hormone. Benzoic acid bearing halogens were chosen as model compounds. The lead candidate N-[4-fluorobenzoyl]-(B29-Lys) insulin (4) was prepared in 60% overall yield and showed affinity for the IR similar to that of native insulin (IC50=3.6 nM). The 18F analogue (9) was successfully synthesized and showed high stability (up to 4 hours) post formulation in both saline and phosphate buffered solution (PBS). The product represents a promising new probe for assessing the role of the IR in cancer growth and metastasis.
A complementary strategy for imaging markers of tumour aggressiveness was investigated through the development of a novel ultrasound probe. A pretargeting approach involving urokinase plasminogen activator receptor (uPAR), which is known to play a role in cancer metastasis, was used to develop the agent of interest. Here an in vivo reaction between tetrazine tagged microbubbles (MBs) and anti-uPAR antibodies conjugated to trans-cyclooctene (TCO) was employed. Following preparation of the antibody conjugate and tetrazine functionalized MBs, preliminary in vitro testing in a flow cell system was conducted. Results showed the ability of the uPAR expressing cells to exclusively capture the tetrazine MBs after they have been previously incubated with the TCO anti-uPAR antibody. No capture was observed when the target and/or the antibody were absent. The contrast agent developed represents the first MB targeted against uPAR and has the potential to impact current diagnostic paradigms particularly given the widespread use of ultrasound in cancer patient management. / Thesis / Master of Science (MSc)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/16037 |
| Date | 11 1900 |
| Creators | ElGamal, Mahmoud |
| Contributors | Valliant, John F., Chemical Biology |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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