Paper AS+BI-MoA4
Study of Drug Uptake and Action on Metabolic Processes at the Single-Cell Level using the 3D OrbiSIMS

Monday, October 30, 2017, 2:40 pm, Room 13

A major quest for the pharmaceutical industry is the reduction of late-stage drug failure. Measurements that can identify future failure at the early stages of drug development are therefore of great importance. This requires label-free imaging of the distribution of pharmaceutical compounds and metabolites with subcellular resolution. We have previously shown [1] that ToF-SIMS can provide useful sub-cellular resolution images but analysis is limited by insufficient mass accuracy, mass resolving power for accurate identification of metabolites and sensitivity.

We have recently led the development of a powerful new hybrid instrument, the 3D OrbiSIMS [2], combining an Orbitrap^TM-based Thermo Scientific^TM Q Exactive^TM HF instrument and a dedicated ToF-SIMS 5. The instrument is equipped with high-resolution ion beams including a new micrometre resolution argon cluster ion beam for biomolecular imaging and 3D analysis of organics and an ultra-high resolution Bi cluster focussed ion beam with < 200 nm resolution.

In this study, we demonstrate the unparalleled ability for 2D and 3D metabolite imaging with sub-cellular resolution. We show significant variability of drug uptake at the single cell level and demonstrate direct evidence of up regulation of metabolites. This can only be revealed with a single-cell study. Furthermore, we demonstrate a new method for in situ matrix deposition for 3D imaging that significantly increases sensitivity. This is especially important for current drug candidates with Log P values ≤ 3 (Lipinski rule of five), which are known to have low molecular secondary ion yields. [3]

[1] M.K. Passarelli et al, Analytical chemistry 87 (13), 2015, 6696

[2] M.K. Passarelli et al, submitted, 2017

[3] J.L. Vorng et al, Analytical Chemistry 88 (22), 2016, 11028