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

Lead Research Organisation: University of Oxford
Department Name: Materials

Abstract

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.

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509711/1 01/10/2016 30/09/2021
1801634 Studentship EP/N509711/1 01/10/2016 31/03/2020 Amy Alexandra Sheader
 
Description C R Barber Trust
Amount £300 (GBP)
Organisation Institute of Physics (IOP) 
Sector Learned Society
Country United Kingdom
Start 09/2018 
End 09/2018
 
Description EMAG Travel Grant
Amount £300 (GBP)
Organisation Institute of Physics (IOP) 
Sector Learned Society
Country United Kingdom
Start 09/2018 
End 09/2018
 
Description EMS Scholarship
Amount £750 (GBP)
Organisation European Microscopy Society 
Sector Learned Society
Country Belgium
Start 09/2018 
End 09/2018
 
Description Travel Grant
Amount £300 (GBP)
Organisation Royal Microscopy Society 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 09/2018
 
Description Travel Grant
Amount £900 (GBP)
Organisation Armourers and Brasiers Gauntlet Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 09/2018
 
Description CUI 
Organisation King's College London
Department Centre for Ultrastructural Imaging
Country United Kingdom 
Sector Academic/University 
PI Contribution Optimising CUI JEM-F200 for spectroscopy and imaging of biological systems. Using Oxford ARM200F for EELS data collection.
Collaborator Contribution CUI provides access to electron microscopes (primarily the JEM-F200). Students/staff at the CUI also produce samples of chemotherapy- and vehicle-treated nerve tissue for use in this project, via access to high-pressure freezing equipment and cryoultramicrotomes.
Impact All outcomes are associated with this partnership.
Start Year 2016
 
Description School & College departmental visits 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Visits from school and college-aged students. Aimed at widening participation and/or encouraging students to think about the subject of Materials Science.
Year(s) Of Engagement Activity 2017,2018,2019