Synthesis and Evaluation of Eu(II/III) Systems for Imaging Transient Hypoxia

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The prolific nature of research into oxygen availability in the body is evident from the award of the Nobel Prize in Physiology or Medicine 2019. Hypoxia is where the body or a region of the body is oxygen deficient due to insufficient delivery of oxygen to living cells. It is significant because it is a major indicator of disease. Indeed, hypoxia is observed in various medical conditions such as Alzheimer's, cardiovascular diseases, kidney diseases, hepatic and neurological disorders, arthritis, metabolic diseases, diabetes, reproductive diseases, and cancer. In clinical medicine, there are currently no routine methods of detecting hypoxia, but clearly such technology, which essentially acts as a semi- universal indicator of disease, would be of significant benefit in improving healthcare.Medical imaging is the process of generating an image of the interior of the body and the aim of this project is to make and evaluate chemical compounds, so-called imaging agents, that when administered to the patient enable imaging of hypoxia. The project will focus on europium-containing imaging agents because europium can form stable compounds in two oxidation states i.e. with a different charge on the europium ion, which are both accessible under physiological conditions and exhibit dramatically different magnetic properties and different properties in their interaction with light. This project is based on the hypothesis that the Eu2+ state should be favoured under hypoxic conditions, and the Eu3+ state under non-hypoxic conditions, hence leading to contrast in the generated image, enabling hypoxic tissue to be identified.The ideal properties for a hypoxia sensing technique encompass excellent resolution in the image, non- invasiveness, no oxygen consumption, quantitative measurement of oxygen concentration, and negligible toxicity. Potential modes of imaging hypoxia include Magnetic Resonance Imaging (MRI) which is non-invasive and visualises morphological and functional anatomy with essentially unlimited depth penetration through use of strong magnetic fields and radiofrequency pulses. Utilising MRI would exploit the fact that one of the oxidation states of europium produces positive MRI contrast whereas the oxidation state does not. Another potential hypoxia imaging modality is optical imaging which is also non-invasive and is a powerful tool for visualising subcellular morphologies based on the use of molecules that absorb and emit light. Those that both absorb and emit light are so-called luminescent materials and are particularly useful for imaging as there are fewer chemical species in the body that exhibit luminescence than those that just absorb light, leading to a more defined image. Optical imaging with such europium-containing agents is also likely to produce good contrast because one of the oxidation states of europium displays longer lived luminescence than the other.This project will begin with synthesis of various europium-containing imaging agents and characterisation of their chemical and physical properties and stability, followed by in vitro testing of the agents for MRI and optical imaging of hypoxia and finally in vivo testing of such imaging modalities.This project falls within the EPSRC physical sciences and healthcare technologies research areas.