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.
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
Sheader AA
(2018)
Observation of metal nanoparticles at atomic resolution in Pt-based cancer chemotherapeutics.
in Journal of microscopy
Sheader A
(2019)
Microscopy on Drugs: Characterization and Quantification of Pt-based Pharmaceuticals using the STEM.
in Microscopy and Microanalysis
Sheader A
(2019)
Intracellular Elemental Mapping using Simultaneous EELS and EDS: A Combined Approach to Quantifying Na, K and Ca
in Microscopy and Microanalysis
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
EP/N509711/1 | 30/09/2016 | 29/09/2021 | |||
1801634 | Studentship | EP/N509711/1 | 30/09/2016 | 14/09/2020 | Amy Sheader |
Description | C R Barber Trust |
Amount | £300 (GBP) |
Organisation | Institute of Physics (IOP) |
Sector | Learned Society |
Country | United Kingdom |
Start | 08/2018 |
End | 09/2018 |
Description | EMAG Travel Grant |
Amount | £300 (GBP) |
Organisation | Institute of Physics (IOP) |
Sector | Learned Society |
Country | United Kingdom |
Start | 08/2018 |
End | 09/2018 |
Description | EMS Scholarship |
Amount | £750 (GBP) |
Organisation | European Microscopy Society |
Sector | Learned Society |
Country | Belgium |
Start | 08/2018 |
End | 09/2018 |
Description | Travel Grant |
Amount | £900 (GBP) |
Organisation | Armourers and Brasiers Gauntlet Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2018 |
End | 09/2018 |
Description | Travel Grant |
Amount | £300 (GBP) |
Organisation | Royal Microscopy Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 08/2018 |
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 |