Understanding the distribution of a dosed drug within the body is a key part of the drug development process, both in terms of drug efficacy (does the drug reach the target area and at sufficient concentration to have a pharmacological effect?) and potential side effects (where else does the drug go and what does it do there?). As many current drug targets are intracellular the ability to visualise unlabelled compounds inside the cell at physiological dosages can offer valuable insight into the compound behaviour both on and off-target. Understanding the effect a compound has on the underlying biology and the reasons why cellular responses vary is vital to successful drug discovery.
This talk will discuss our work using mass spectrometry to image the distribution of dosed molecules in cells and their effect on endogenous molecules. Examples will include the use of use Secondary Ion Mass Spectrometry (SIMS) to image the 3-dimensional spatial distribution of unlabelled drugs and identify endogenous metabolites at cellular resolutions. Our use of the LiveCell MS technology, originally developed by Professor Masujima, using a semi-automated methodology that allows the collection of intracellular content with a modified CQ1 imaging system developed by Yokowaga will also be discussed. In this work, we show the applicability of the LiveCell MS technology to drug discovery and its ability to identify drug related material and endogenous metabolites when incubated in a mammalian cell at a therapeutic dose. We will also discuss the dynamic range of single cell analysis by direct comparison with data from a metabolomics assay using bulk samples.