Enhanced Sensitivity Using MALDI Imaging Coupled with Laser Postionization (MALDI-2) for Pharmaceutical Research

Visualizing the distributions of drugs and their metabolites is
one of the key emerging application areas of matrix-assisted laser
desorption/ionization–mass spectrometry imaging (MALDI-MSI)
within pharmaceutical research. The success of a given MALDI-MSI experiment
is ultimately determined by the ionization efficiency of the compounds
of interest, which in many cases are too low to enable detection at
relevant concentrations. In this work we have taken steps to address
this challenge via the first application of laser-postionisation coupled
with MALDI (so-called MALDI-2) to the analysis and imaging of pharmaceutical
compounds. We demonstrate that MALDI-2 increased the signal intensities
for 7 out of the 10 drug compounds analyzed by up to 2 orders of magnitude
compared to conventional MALDI analysis. This gain in sensitivity
enabled the distributions of drug compounds in both human cartilage
and dog liver tissue to be visualized using MALDI-2, whereas little-to-no
signal from tissue was obtained using conventional MALDI. This work
demonstrates the vast potential of MALDI-2-MSI in pharmaceutical research
and drug development and provides a valuable tool to broaden the application
areas of MSI. Finally, in an effort to understand the ionization mechanism,
we provide the first evidence that the preferential formation of [M
+ H]+ ions with MALDI-2 has no obvious correlation with
the gas-phase proton affinity values of the analyte molecules, suggesting,
as with MALDI, the occurrence of complex and yet to be elucidated
ionization phenomena.