Centre for In Vivo Imaging Sciences - Brain Research Imaging ...

Date of submission: 31 October 2012
Project title: 12
Applicant: Val Brunton
2
Summary of proposed project (approximately 200 words):
Drug attrition rates in oncology are dismal (5%) and new approaches are required to optimise
the use of novel therapeutics. Drug delivery and retention within tumours is extremely
important when considering responses to therapy but is not routinely measured as traditional
imaging technologies require the use of bulky labels which frequently interfere with drug
function. Coherent Anti-stokes Raman Scattering (CARS) is a form of fast acquisition Raman
spectroscopy that allows label-free visualisation based on the vibration of particular chemical
species. However, problems with non-resonant background signals using CARS reduces its
applicability. Stimulated Raman Scattering (SRS), a new variant of CARS, provides more
sensitive optical imaging, and should also provide a quantitative measure of intra-tumoural
drug concentration 1,2 . Alkynes avoid many of the pitfalls of other labelling technologies: they
are small, unreactive in cellular environments, can be introduced using a range of
chemistries thus ensuring drug function is retained, and can be imaged at a wavelength that
falls in the Raman silent region of a cell. However, their potential as labels for both small
molecule drugs and antibody therapeutics for imaging purposes has yet to be exploited 3 .
This project will assess the ability of SRS (with or without alkyne labelling) to determine
intra-tumoural concentrations of HER2 targeted therapies (including the antibody
trastuzumab and small molecule kinase inhibitors) and establish its utility in monitoring drug
biodistribution in mouse models to address whether it will provide a new approach to
preclinical ‘pharmaco-kinetic’ drug analysis. This will be made possible by using optical
windows for intra-vital imaging that permits longitudinal imaging following drug treatment 4,5 .
Key references (up to five):
1. Mouras R, Rischitor G, Downes A, Salter D, Elfick A (2010) Nonlinear optical microscopy for drug
delivery monitoring and cancer tissue imaging. J Raman Spectrosc 41: 848-852
2. Saar BG, Freudiger CW, Reichman J, Stanley CM, Holtom GR, Xie XS (2010) Video-rate molecular
imaging in vivo with stimulated Raman scattering. Science 330: 1368-1370
3. Yamakoshi H, Dodo K, Okada M, Ando J, Palonpon A, Fujita K, Kawata S, Sodeoka M (2011)
Imaging of EdU, an Alkyne-Tagged Cell Proliferation Probe, by Raman Microscopy. J Am Chem Soc
133: 6102-6105
4. Canel M, Serrels A, Miller D, Timpson P, Serrels B, Frame MC, Brunton VG (2010) Quantitative in
vivo imaging of the effects of inhibiting integrin signalling via Src and FAK on cancer cell movement;
effects on E-cadherin dynamics. Cancer Res 70: 9413-22
5. Canel M, Serrels A, Anderson KI, Frame MC, Brunton VG (2010) Use of photoactivation and
photobleaching to monitor the dynamic regulation of E-cadherin at the plasma membrane. Cell Adh
Migr 4: 491-501
In what way does this PhD proposal meet the CIVIS criteria as described in the call for
proposals? (50 words)
This is a multi-disciplinary project and builds on an existing collaboration between Dr Brunton
and Dr Andy Downes (CSE). It now brings together cancer biologists chemists and engineers
to develop high speed Raman microscopy technologies, which we believe will have a
significant impact on preclinical drug development.
Please state which scheme your proposal should be considered for:
If you are unsure please discuss with named individual.
x UoE CMVM (Prof J Wardlaw, Prof I Marshall, Prof M Holmes, Prof E van Beek)
UoE CHSS PPLS Psychology (Prof R Logie)
UoE CSE Informatics DTC (Prof D Robertson)
HWU Engineering (Prof Rory Duncan)
Once completed, please return to
Mrs Moira Henderson – civis.enquiry@ed.ac.uk