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Download PhD position A targeted imaging agent for detecting tumour cell death
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Supervisors: Finian Leeper (Department of Chemistry) and Kevin Brindle (Cancer Research UK Cambridge Institute) Project title: A targeted imaging agent for detecting tumour cell death As part of the CRUK and EPSRC Cancer Imaging Centre in Cambridge and Manchester, Finian Leeper and Kevin Brindle look for a joint PhD student to work on production and studies of targeted imaging agents for detecting tumour cell death. This project extends the continuing successful collaboration between the Leeper and Brindle labs [Wainman et al. 2013, Neves et al. 2013 and 2011, Stöckmann et al. 2011a and b]. Previously we have shown that a small protein, the C2A domain of synaptotagmin I, binds to the phosphatidylserine (PS) that is exposed by dying cells [Krishnan 2008, Alam et al. 2010]. We aim to exploit this to develop a clinically usable method to image a tumour's response to chemotherapy as soon as possible after the treatment begins. Methods: the C2A domain has been mutated to introduce a single, solvent-‐exposed cysteine residue (C2Am) [Alam et al. 2010]. This cysteine will be used as the point of attachment of a highly strained trans-‐cyclooctene moiety (TCO). trans-‐Cyclooctenes react in an extremely fast manner with tetrazines [Wainman et al. 2013, Stöckmann et al. 2011a], thus we will make tetrazines that have attached radioisotopes such as 18-‐F for PET imaging or 111-‐In for SPECT imaging. Tumour-‐bearing animals will be injected with a anti-‐ cancer drug (or with nothing for the control animals) and then subsequently with C2Am-‐TCO. Once the C2Am-‐TCO has had time to bind to the dying cells or be cleared from the blood stream, the radiolabelled tetrazine will be injected and specific accumulation of the radioisotope in the tumour, observed by PET or SPECT imaging, will indicate the effect of the drug on the tumour. To apply, please send your academic CV and a covering letter as attachments to Marion Karniely: [email protected] Eligibility: No nationality restrictions apply to these studentships. Applications are invited from recent graduates or final year undergraduates who hold or expect to gain a first/upper second class degree (or equivalent) in a relevant subject from any recognised university worldwide. Experience of organic synthesis as well as of work in a biological lab would be a distinct advantage. Stipend: These studentships include full funding for University and College fees and a stipend of GBP 19,000 per annum. References 1. Wainman et al. (2013) Dual-‐sugar imaging using isonitrile and azido-‐based click chemistries, Org. Biomol. Chem., 2013, 11 (42), 7297-‐7300. 2. Neves et al. (2013) Imaging cell surface glycosylation in vivo using ‘double click’ chemistry, Bioconjugate Chem., 2013, 24 (6), 934–941. 3. Stöckmann et al. (2011a) (E,E)-‐1,5-‐cyclooctadiene: A small and fast click-‐chemistry multitalent, Chem. Comm., 2011, 47 (25), 7203-‐7205. 4. Stöckmann et al. (2011b) Development and evaluation of new cyclooctynes for cell surface glycan imaging in cancer cells, Chem. Sci., 2011, 2, 932-‐936. 5. Neves et al. (2011) Imaging sialylated glycans in a murine tumor in vivo, FASEB J., 2011, 25 (8), 2528-‐2537. 6. Krishnan et al. (2008) Detection of cell death in tumors using MRI and a gadolinium-‐based targeted contrast agent. Radiology 2008, 246 (3), 854-‐862. 7. Alam et al. (2010) Comparison of the C2A Domain of Synaptotagmin-‐I and Annexin-‐V as probes for detecting cell death. Bioconjug. Chem., 2010, 21, 884-‐891.
