Student: George Keeling
1st supervisor: Rafael T.M. de Rosales, King’s College London
2nd supervisor: Samantha Terry, King’s College London
Additional supervisors: Phil Blower, Michelle Ma, Nick Long
Industrial supervisor: Jeevan Virk, Theragnostics
The trishydroxypyridinone (THP) chelator developed at King’s College London has received considerable attention as it allows simple chelation of Ga-68, the first PET radionuclide available from a GMP-certified generator. This enables efficient radiolabeling of targeting vectors (e.g. small molecules, peptides) that can be used for the diagnosis of disease using PET imaging. Preliminary data shows that THP can be used for targeted radionuclide therapy, which traditionally uses beta-emitting radionuclides such as Lu-177 (medium energy, medium range) that may result in healthy tissue toxicity, which may be avoided by chelating alpha particle and Auger electron emitters.
In this project we will develop new bifunctional conjugates of the excellent chelator THP. The ultimate aim is to create the best possible theranostic compounds, where, with the same simple radiochemistry, a radionuclide is attached for either imaging or therapy (Figure 1a). Here, THP-folate and THP-bisphosphonate will be used for in vivo imaging (using Ga-68) of a range of cancer types, both primary site and metastases, as well as cells located near the tumour such as macrophages, and vascular calcification. The student will also use the THP-conjugates to chelate therapeutic radionuclides (Ga-67, Auger electron emitter; Bi-213, alpha particle-emitter). The mechanism behind how these radionuclides work has not yet been determined and this study will be amongst the first to figure out how they cause damage to the DNA (Figure 1b) and ultimately kill the cells to which they have been targeted. This project will also allow in vivo imaging to monitor therapy response of tumours and/or their metastases in preclinical models treated with these radiopharmaceuticals.
This interdisciplinary PhD studentship will cover both chemistry and biology basic research. The student will be involved in the chemistry/radiochemistry of imaging/radionuclide therapy agents, (radio)biology, and therapeutic evaluation and eventually commercial development of the products.
Figure 1. (a) Schematic representation of the THP-conjugates that will be studied (b) Fluorescence micrograph showing DNA damage (green spots) in the nuclei of irradiated cells (in blue). This type of method (immunofluorescence for yH2AX) will be used to determine the biological effects of imaging and therapeutic radionuclides in cells.