Causal mechanisms of chemotherapy-induced neurotoxicity by mapping local chemistry in the electron microscope

Up to 60% of patients receiving standard chemotherapy for various cancers will develop neurotoxicity as a consequence of their treatment resulting in ongoing pain, numbness, tingling and cold/mechanical hypersensitivities in their hands and feet. Chemotherapy-induced neurotoxicity (CIN) is a substantial clinical problem which limits anti-cancer benefits and impacts on patient quality of life and survival. Currently there are no treatments to prevent CIN or effectively treat it once it emerges. Greater understanding of the causal mechanisms of CIN will aid development of novel therapies for this debilitating disorder. In this project the latest cutting-edge spectroscopic techniques in the high-resolution electron microscope will be used to map changes in concentration of key elemental species in the neuronal mitochondria to study the mitochondrial disorder which results from the neurotoxicity.

The key aim of the project is to use state-of-the-art technologies developed for materials science and to extend their application into an area to which they have not yet been applied and with the potential for significant impact in healthcare. These include the use of atomic-resolution Z-contrast imaging, energy-dispersive X-ray (EDX) spectroscopy and ptychography in the scanning transmission electron microscope. All of these have benefitted from recent developments in technology and methods for application to materials science problems, but they all have potential for the study of chemotherapy-induced neurotoxicity. For example, Z-contrast imaging can be used to study the locations in dosed tissue of the heavy metals found in chemotherapy drugs. Composition measurements using EDX will be used to monitor changes in elemental distribution within cells and ptychography used to simultaneous measure the local tissue structure.

The EPSRC theme supported by this work in Healthcare technologies, in particular the Development of Future Therapies challenge. The main research area is analytical science. The aim is to use the new analytical capabilities to guide the development of new chemotherapy candidates that can mitigate the clinical problem of CIN.