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Proceedings Paper

Application of stimulated Raman scattering for measurement of intracellular drug distribution (Conference Presentation)
Author(s): Valerie Brunton; William Tipping; Kristel Sepp; Martin Lee; Alison Hulme

Paper Abstract

Oncology drug development is costly and ineffective with a 5% success rate from first-in-man studies to new drug registration. A task force set up to address issues in anticancer therapy development highlighted the necessity to demonstrate proof of mechanism and obtain information on key pharmacokinetic aspects of drug behaviour in both preclinical and early clinical trials. Spectroscopically bioorthogonal Raman detection in the “cellular-silent’ region presents an optimal region for drug imaging, as there is minimal contribution from endogenous cellular biomolecules thus improving detection sensitivity. This offer the potential to transform our understanding of intracellular drug distribution and mechanism of action. We demonstrate the utility of stimulated Raman scattering (SRS) in mapping intracellular concentrations of the tyrosine kinase inhibitor ponatinib used in the treatment of chronic myeloid leukemia and link this to resistance mechanisms associated with ponatinib treatment. As few drugs have inherent Raman active groups (5% of FDA approved drugs) further adoption and widespread use of SRS will require addition of bioorthogonal tags in the majority of cases. We have established an effective workflow for the design and use of Raman-labels for intracellular imaging. An iterative strategy of Raman-label design and validation identified minimally perturbative bis(alkyne) labels with approximately 60-fold increase in Raman scattering activity, compared to the mono-alkynes previously used. Combining SRS microscopy with this biorthogonal Raman labelling approach enabled direct visualisation of drug uptake to be correlated with markers of cell cycle status, and mapped across intracellular structures using multi-modal imaging platforms.

Paper Details

Date Published: 4 March 2019
Proc. SPIE 10859, Visualizing and Quantifying Drug Distribution in Tissue III, 108590E (4 March 2019); doi: 10.1117/12.2511244
Show Author Affiliations
Valerie Brunton, The Univ. of Edinburgh (United Kingdom)
William Tipping, The Univ. of Edinburgh (United Kingdom)
Kristel Sepp, The Univ. of Edinburgh (United Kingdom)
Martin Lee, The Univ. of Edinburgh (United Kingdom)
Alison Hulme, The Univ. of Edinburgh (United Kingdom)

Published in SPIE Proceedings Vol. 10859:
Visualizing and Quantifying Drug Distribution in Tissue III
Kin Foong Chan; Conor L. Evans, Editor(s)

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