Quantitative Nanoscale Imaging of Trace Elements in Biological Systems
Lead Research Organisation:
University of Manchester
Department Name: Chem Eng and Analytical Science
Abstract
The project we propose involves research into novel chemical imaging methodology for 2D and 3D visualisation of trace elements in cells and tissues with greatly improved sensitivity, easy of reliability and magnification over current approaches. The technology includes powerful lasers for the uniform and highly sensitive detection of atoms and small molecules ejected from biological specimens under bombardment from high energy particles. The result is a multi-element chemical map of the specimen showing detail on the sub-cellular length scale. We shall demonstrate the power of this approach in the detection and localisation of cancer drugs in cells and model tissues. However, the methodology we will develop will be more widely applicable in a number of important biological problems involving trace element transport, storage and distribution. This includes but is not limited to drug development, disease diagnosis and fundamental cell biology.
Technical Summary
Analytical techniques including those able to identify and quantify trace elements in cells and tissues have contributed to a greater molecular level understanding of biology. However many important questions remain unanswered, for example concerning the cellular structures involved in processes associated with drug uptake and disease progression. To complement the range of analytical tools currently available there is a clear need for the quantitative determination of elemental species, in particular metals, at the sub-cellular level and in the context of the physiological environment. In this project we seek to demonstrate the huge advantages that the method of laser sputtered neutral mass spectrometry (L-SNMS), which has been highly successful in other disciplines, can bring to biology. The approach involves scanning a focused (50 nm) ion beam across the sample surface ejecting atomic and molecular fragments highly characteristic of the surface chemistry. A pulsed laser beam is then used to ionise all the species within a defined region above the sample, and the resultant ions are subjected to mass spectrometric detection. The result is a pixel-by-pixel series of mass spectra that can be manipulated to display chemical images, in 2D or 3D. The laser can be tuned (resonant) or detuned (non-resonant) to ionise selective atoms or all atoms within the laser focus with 100% efficiency. The focus of this project is the enahanced detection and imaging of metallo-drugs in cells and tissue models. Cell cultures and multicellular spheroids will be exposed to drug e.g. cisplatin and analysed using L-SNMS. We seek to demonstrate very significant (in excess of x10) sensitivity increases and more uniform limits of detection over the related technique of secondary ion mass spectrometry (SIMS).
Planned Impact
The project proposed will demonstrate the full capability of our technology applied to quantitative elemental imaging in biological systems, and reveal unique potential for its development. If successful, this development will be very significant and provide an enormously powerful new tool for imaging cells and tissues to help understand cellular and metabolic processes, which could impact on research across disciplines from fundamental cell biology, through to healthcare, medicinal screening and diagnostics. Whilst these are high risk areas of research the scientific expertise and state-of-the-art instrumentation is very likely to provide exciting lines for development and provide opportunities for broader impact. The immediate beneficiaries include academic groups involved in developing related bioanalytical technologies. In the longer term this research has the potential to impact much more widely. Greater understanding at the cellular level of the role of metals in health, dietary metabolism, disease and therapeutic intervention will have widespread implications across a number of sectors. For example, private sector pharmaceutical manufacturers will gain new scientific insights to inform the design, development and commercialisation of new drugs and drug targets. This would foster economic competitiveness. Policy makers and charitable organisation will in turn have new evidence on which to base strategic decisions regarding public health, including the allocation of funding for clinical trials. This in turn would impact on the nation's health and wealth, improving quality of life.
Organisations
Publications
Alnajeebi AM
(2016)
Matrix effects in biological SIMS using cluster ion beams of different chemical composition.
in Biointerphases
Karras G
(2014)
Quantitative surface analysis of a binary drug mixture--suppression effects in the detection of sputtered ions and post-ionized neutrals.
in Journal of the American Society for Mass Spectrometry
Description | We have explored the use of laser post-ionisation (LPI) methods in the detection of various drug molecule from solid samples. In doing so we have compared the results in terms of sensitivity to a more established method (secondary ion mass spectrometry, SIMS) to assess the optimum approach in imaging drig distributions in biological samples including cells and tissue. The LPI approach has enable upto 100-fold increase in sensitivity in the detection of the drug cisplatin. We have established calibration data using drugs diltuted into a biological mimic (gelatin), demonstrating that the limit of detection reaches levels matching the concentrations of these drugs in clinical use. This suggests the LPI method is appropriate in imaging drug distrubutions in real samples from patients undergoing drug therapy. This has important implications for the monitoring of therapy and the development of new drugs which target specific cells. We have further demonstrated this capability by imaging a boron-based drug in a brain tumour biopsy taken from a patient given a therapeutic drug dose. |
Exploitation Route | At the present stage of development more academic research is needed into the LPI process and its application in the biosciences. We have further demonstrated signficiant advantages in specific analytes, but it remains to be seen how these advantages can be gained in the majority of drugs and small biomolecules. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | EPSRC DTA |
Amount | £50,000 (GBP) |
Organisation | University of Manchester |
Sector | Academic/University |
Country | United Kingdom |
Start | 01/2013 |
End | 06/2016 |
Description | International exchange scheme |
Amount | £3,000 (GBP) |
Funding ID | IE140362 |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 07/2014 |
End | 09/2014 |
Description | Schools Openday |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | The Manchester Institute of Biotechnology Schools Openday welcomed 175 AS/A-level students from 8 different schools into MIB for lab tours, talks and demonstrations highlighting our interdisciplinary research work and promoting science education/careers. |
Year(s) Of Engagement Activity | 2017 |