Exploring ammonium salt doping to enhance ion abundance for quantitative mass spectrometry imaging

Increasing ion abundance in mass spectrometry is essential for enhancing detection, quantification, and understanding of biomolecules involved in key cellular processes. Infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI), MALDI, and nano-DESI have shown improved ion abundance when integrating specific concentrations of ammonium fluoride into the sample preparation and/or ionization steps. Herein, the importance of electronegativity and atomic size for the proposed mechanism of increased ion abundance is evaluated by testing a variety of ammonium halide salts. Ammonium fluoride was confirmed to result in the largest increase in ion abundance and was subsequently used to perform quantitative mass spectrometry imaging (qMSI) of glutathione (GSH) in healthy mouse liver tissue. Using ~70 µM NH₄F as an ESI dopant, up to a ~ two-fold increase in ion abundance was observed for these biomolecules, as well as an improvement in the limit of detection, detection frequency, and quantification of endogenous GSH in tissue.