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Smart Imaging Probes, Emerging Imaging

Imaging the cellular distribution of metals and radionuclides using novel elemental mapping techniques

Project ID: 2020_034

1st Supervisor: Phil Blower, King’s College London
2nd Supervisor: Sam Terry, King’s College London
Clinical Champions: Val Lewington, Lefteris Livieratos and Tamir Rashid, King’s College London

Aim of the PhD Project:

  • Novel methods to determine the distribution of metals and radionuclides within tissues at whole body (PET), cellular and sub-cellular level (including laser ablation and secondary ion mass spectrometry (LA-ICP-MS), XRF, EELS and microautoradiography)
  • Application to cellular radionuclide dosimetry in radionuclide imaging and therapy, and to Wilson’s disease diagnosis

Project Description / Background:

This project will suit a candidate with a first degree in chemistry and a particular interest in biological chemistry and analytical methods, as well as medical applications.

Metallomics is a rapidly growing field comprising the study of the role of trace metals, including essential and toxic metals and metallodrugs, in health and disease. Examples include changes in the trafficking of copper in brain in dementia, increased uptake of copper in prostate cancer (which has been used recently to detect prostate cancer metastases), changes in zinc trafficking in diabetes and breast cancer, copper disturbance in Wilson’s disease, and many others. This project will exploit the emerging techniques of metallomics to address a set of questions that relate to medical imaging in a number of ways:

  1. The techniques of metallomics1 themselves constitute a new panel of bioimaging techniques, and the project will develop their capability from their current early stage.
  2. Metallic radionuclides are important in nuclear medicine, and the way in which they distribute at the cell level, beyond resolution by PET and SPECT, provides important mechanistic information
  3. Targeted therapeutic radionuclides (alpha, beta, Auger electron emitters, each with their characteristic energy and range) will deliver a radiation dose whose toxicity depends acutely on their cellular and subcellular location (membrane vs cytoplasm vs nucleus, etc.). The relationship between biological effect and sub-cellular location (nucleus, cytoplasm, plasma membrane, mitochondria etc.), emission characteristics and radiation dose is very poorly understood at present
  4. The growing availability of radioisotopes of biologically essential metals – particularly at KCL where we now have access to positron emitting isotopes of copper, zinc, manganese, gallium (as an iron mimic), rubidium (as a potassium mimic) and others – offers a new means to study the trafficking of trace metals in relation to disease – for which we have coined the term “PET metallomics”2 and to use them to develop clinical diagnostic methods.

Metallomic methods, particularly LA-ICPMS and SIMS, coupled with microautoradiography, offer a way to obtain this information which is otherwise very difficult to access. The instrumentation is developing rapidly for these techniques and KCL is extremely well equipped at the LMF. In this project we will develop new methods to map elements and radionuclides at cell level, to complement the methods we already have (PET) to map them at whole body level, and apply them to a set of clinically relevant problems in molecular imaging and radionuclide therapy.

References:

  1. Stewart TJ. Across the spectrum: integrating multidimensional metal analytics for in situ metallomic imaging. Metallomics 2019;11:29-49.
  2. Bartnicka JJ, Blower PJ. Insights into trace metal metabolism in health and disease from PET: “PET metallomics.” J Nucl Med 2018;59:1355-1359
Figure 1: Exemplar use of elemental mapping and microautoradiography. Top left: schematic structure of thyroid follicle; Top right: SIMS image showing distribution of phosphorus (green) and iodine (red) in thyroid follicles. Iodine is confined to the colloid; Bottom left: fluorescence image of DAPI-stained thyroid tissue section and microautoradiograph, of thyroid tissue taken from a mouse injected with Tc-99m-pertechnetate; Bottom right: same section/autoradiograph showing silver grains enhanced (red) demonstrating radioactivity confined to the thyrocytes.

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