Development of PET/PDT theranostics for High Grade Glioma
Primary Supervisor: Graeme Stasiuk, King’s College London
Secondary supervisor: Alexander MacRobert, UCL
Project
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 enable therapy, we will synthesise compounds known as 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 be highly effective for focal treatment of solid tumours with light delivered to the tumour site via fibre-optic light guides that can be implanted inside the tumour. PDT also raises an immune response against the tumour tissue, that may combat spread of the cancer. The target cancer for this project will be high-grade glioma (HGG), each year, in the UK, approximately 12,100 patients are diagnosed with a primary brain tumour of which around 4,500 cases are gliomas. Despite advanced treatments, HGG continues to have a poor prognosis with a median survival of 15 months and a 5-year survival of less than 5%. Although surgical excision remains first line of defence, novel adjuvant therapeutic tools are therefore needed to tackle HGG. Intraoperative PDT treatment of HGG guided by PET imaging could be applied to the tumour bed following surgical excision of the bulk of the tumour.
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 for HGG such as for EGRF/ uPAR which are known to be overexpressed in this cancer. 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 HGG cell lines (U87mg) 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 orthotopic preclinical models with laser light delivered using an implanted fibre-optic probe.
Candidate background
The project is suitable for a student with background in organic chemistry and a strong interest in life sciences, in particular oncology. The student will be able to gain new skills such as radiochemistry, cell culture, animal handling and preclinical imaging, and to acquire expert knowledge in basic science medical research.
Potential Research Placements
- Kerstin Sander, UCL Centre for Radiopharmaceutical Chemistry
- Alexander MacRobert, UCL Surgical Biotechnology
- Vijay Chudasama, UCL Department of Chemistry
References
- “Evaluation of a bispidine chelator for gallium-68 and of the porphyrin conjugate as PET/PDT theranostic agent”, T. W. Price, S. Y. Yap, R. Gillet, H. Savoie, L. J. Charbonnière, R. W. Boyle*, A.M. Nonat*, and G. J. Stasiuk*, Chem. Eur. J., 2020, 26, 7602 – 7608.
- “Selective radiolabelling under mild conditions, a route towards a PET/PDT theranostic agent”, S. Y. Yap, T. W. Price, H. Savoie, R. W. Boyle* and G. J. Stasiuk*, Chem. Commun., 2018, 54, 7952 – 7954
- “Site-selective multi-porphyrin attachment enables the formation of a next-generation antibody-based photodynamic therapeutic” A. Maruani, H.Savoie, F.Bryden, S. Caddick, R. Boyle and V. Chudasama Chem. Commun., 2015,51, 15304 – 15307
- “Photosensitizer Antibody-Drug Conjugates: Past, Present, and Future”, J. Sandland and R. Boyle, Bioconjugate Chem. 2019, 4, 975 – 993.