Development of PET/PDT theranostics for Leukaemia/Lymphoma
Primary Supervisor: Dr Graeme Stasiuk, School of Biomedical Engineering and Imaging Science, King’s College London
Secondary Supervisor: Dr Kerstin Sander, Centre for Radiopharmaceutical Chemistry, University College London
Current clinical care of cancers typically relies on imaging of the tumour for diagnosis and therapeutic interventions (surgery, chemotherapy, radiotherapy) to be performed separately, sometimes several weeks apart. Critically, during this time, the tumour has the opportunity to grow and spread. In this project, we seek to combine both imaging and therapy into a single molecule. This has the potential to inhibit tumour growth directly following diagnosis, by using the same intervention, i.e. the molecule used for imaging. The chosen imaging modality, positron emission tomography (PET), is regarded as the technique of choice for identifying and staging tumours due to its high sensitivity. To allow for therapy, we will synthesise compounds known as a photosensitizers, which generate highly toxic reactive oxygen species when irradiated with high intensity visible light. The technique, known as photodynamic therapy (PDT), has been shown to significantly inhibit tumour growth. PDT also raises an immune response against the tumour tissue, thus, although PDT is unlikely to cure the tumour, it may prevent it from growing in the period between imaging and conventional therapy, and may recruit the immune system to combat spread of the cancer.
This multidisciplinary project will involve chemical synthesis of the photosensitiser, conjugation to the chelator for the radiometal gallium-68 and bioconjugation to targeting peptide/antibody (antibody fragment such as Mylotarg) for leukaemia and lymphoma (Non-Hodgkin lymphoma). This will be followed by radiolabelling experiments with gallium-68 to show specific uptake into the chelator, radiochemical yield and specific activity. Once the PET/PDT agent has been made it will be validated in leukaemia/lymphoma cell lines along with other tumour cell lines to show toxicity under irradiated light and specific uptake in tumour cells. This will be followed by in vivo experiments to show the efficacy of the image guided therapeutic in preclinical models.
Potential research placements
1. UCL – Centre for Radiopharmaceutical Chemistry: organic radiochemistry and in vivo PET imaging, Dr Kerstin Sander.
2. UCL – Surgical Biotechnology: In vivo PDT, Professor Alexander MacRobert
3. UCL – Department of Chemistry: bioconjugation techniques to antibodies and proteins, Professor Vijay Chudasama.
The funding for this studentship covers students with home tuition fee status only. For more information on home tuition fee status please visit the UKCISA website. Please note that we will only be able to offer studentships to candidates that have home tuition fee status or provide evidence that they can fund the international portion of the tuition fee from external sources (i.e. not self-funded).
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2. Yap, S.W. et al., Selective radiolabelling under mild conditions, a route towards a PET/PDT theranostic agent. Chem. Commun., 54, 7952-7954 doi: 10.1039/c8cc03897j. (2018)
3. Maruani, A. et al., Site-selective multi-porphyrin attachment enables the formation of a next-generation antibody-based photodynamic therapeutic. Chem. Commun.,51, 15304-15307 doi: 10.1039/c5cc06985h. (2015)
4. Sandland, J. and Boyle, R. Photosensitizer Antibody-Drug Conjugates: Past, Present, and Future , Bioconjugate Chem. 4, 975-993. doi: 10.1021/acs.bioconjchem.9b00055. (2019)
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