This fellowship will pioneer a unique approach to magnetic resonance imaging (MRI) contrast agent design, providing a solution to the safety and environmental concerns associated with current agents.
MRI is an essential tool for medical diagnosis. Contrast agents play a crucial role in improving the images obtained, and hence patient outcomes. Most clinical MRI contrast agents are based on gadolinium, due to its electronic structure. However, there is growing evidence of gadolinium deposition in the bones, skin, brain, and internal organs of patients following exposure to these contrast agents. This is particularly concerning for patients that require repeated administration of contrast agents and for children. For patients with kidney problems, there is also a clear link with a potentially fatal condition called nephrogenic systemic fibrosis. Furthermore, the use of gadolinium-based contrast agents is now a recognised source of environmental contamination of water sources.
There is a clear need to develop gadolinium-free MRI contrast agents. New MRI contrast agents would need to be as efficient or better (requiring lower doses) than current agents, be as stable and display no toxicity. The potential for "smart" targeted agents provides an exciting opportunity to improve medical diagnosis.
This fellowship will develop a completely new solution to MRI contrast agent design, and trial these in preclinical studies. We design brand new proteins from the simple building blocks of human life: amino acids. Many proteins in the human body use a metal and our new proteins can be designed to give a metal ion specific properties. In this case, we can tune the properties of a copper ion to behave as a contrast agent. And one that is more "efficient", better, than current agents. This was previously thought to be impossible!
Using a biologically essential metal ion (essential for correct biological function), such as copper, is exciting as our bodies already know how to process and remove trace amounts of these metals if needed. Unlike gadolinium which will accumulate in the body over time.
This fellowship will explore the full range of essential metal ions (e.g., copper, manganese, iron, nickel, cobalt etc.) bound to these new proteins and screen their performance as MRI contrast agents. The most promising combinations will be optimised, taking advantage of computers to rapidly screen and improve thousands of designs. Lead designs will then be prepared and their performance validated experimentally, in terms of their "efficiency" as MRI contrast agents, their stability and ultimately their toxicity. One work package takes advantage of the protein, to develop a "plug and play" strategy to access "smart" targeted MRI contrast agents. The overall lead, top-performing MRI contrast agent candidate, will be progressed to preclinical studies.
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