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Imaging Chemistry and Biology (pre-2019)

Radiobiological assessment of radionuclide pairs used in theranostic (imaging and therapy) approaches

Project ID: 2017_214

Student: Alex Rigby

1st supervisor: Samantha Terry, King’s College London
2nd supervisor: Phil Blower, King’s College London

Molecular imaging with radionuclides can pinpoint disease locations and measure changes in metabolism and gene expression, and the same molecular targeting can deliver effective radionuclide therapy to cancers. The biological effects of the radionuclides, however, remain poorly understood. This project will investigate small and large scale biological effects of radionuclides used in imaging (diagnosis and monitoring therapy response) and therapy (killing cancer cells) to better understand how radionuclides kill cells, making radionuclide therapies more effective and imaging tracers safer. A range of important medical radionuclides will be tested for their intended and unintended effects on DNA and chromosomal damage, induction of DNA repair pathways and cell kill, in vitro and in vivo. This in turn will provide the ideal basis to determine whether current imaging modalities used in the clinic can be used more frequently and could enhance the way in which patients are treated with radiopharmaceuticals.

PET and SPECT imaging play a crucial part in personalised medicine as they aid the diagnosis of disease in patients and allow monitoring of therapy response. Recently, the success of the use of radionuclides for therapy as well as imaging has increased interest in theranostic approaches, i.e. the use of the same radionuclide, or pair of radioisotopes of the same element, for both imaging and therapy or the use of the same radiochemistry to easily attach either an imaging or therapeutic radionuclide to the same basic compound.

Despite the use of radionuclides for imaging and therapy becoming more commonplace, their biological effects are poorly understood. Although dosimetry can be carried out for both imaging and therapy, little to no dosimetric or radiobiological considerations are taken into account at the moment of radionuclide administration. Also the biological interpretation of dosimetry is currently still inaccurate as it is based on external beam radiation data with little input from subcellular localisation influences or non-targeted effects. The biological interpretation of the term “radiation absorbed dose” (Gy) is well-defined for external beam radiation; the same terminology and unit is used for dosimetry of radionuclides, but what exactly it means biologically for radionuclide imaging tracers or radiopharmaceuticals is unidentified and the detailed biological responses to radionuclides are unknown. Finally, the “linear-no-threshold” model is assumed for dosimetry of imaging radionuclides, implying that the long term biological damage caused by ionizing radiation is directly proportional to the dose. However, this is unproven and unlikely to be correct.

This means that we do not know if radiopharmaceuticals are being used to their maximum therapeutic potential; nor do we know the exact risks associated with multiple cycles of radionuclide imaging. It is possible patients can safely have more cycles of imaging than currently supposed and that patients are being undertreated with radionuclide therapeutics.

This project proposes an in depth, systematic approach to investigate the radiobiology of radionuclide imaging approaches and therapies.

Figure 1. The description is in the caption.

Figure 1. 40% of 111In is bound to prostate cancer cell lines DU145 and DU145-PSMA when attached to opine (left). The majority is located in the cytoplasm (right).

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