Applications of Mass Spectrometry Imaging for Safety Evaluation

  • David Bonnel
  • Jonathan StauberEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1641)


Mass spectrometry imaging (MSI) was first derived from techniques used in physics, which were then incorporated into chemistry followed by application in biology. Developed over 50 years ago, and with different principles to detect and map compounds on a sample surface, MSI supports modern biology questions by detecting biological compounds within tissue sections. MALDI (matrix-assisted laser desorption/ionization) imaging trend analysis in this field shows an important increase in the number of publications since 2005, especially with the development of the MALDI imaging technique and its applications in biomarker discovery and drug distribution. With recent improvements of statistical tools, absolute and relative quantification protocols, as well as quality and reproducibility evaluations, MALDI imaging has become one of the most reliable MSI techniques to support drug discovery and development phases. MSI allows to potentially address important questions in drug development such as “What is the localization of the drug and its metabolites in the tissues?”, “What is the pharmacological effect of the drug in this particular region of interest?”, or “Is the drug and its metabolites related to an atypical finding?” However, prior to addressing these questions using MSI techniques, expertise needs to be developed to become proficient at histological procedures (tissue preparation with frozen of fixed tissues), analytical chemistry, matrix application, instrumentation, informatics, and mathematics for data analysis and interpretation.

Key words

MALDI Mass spectrometry imaging (MSI) Label-free Staining Tissue distribution 



The authors would like to thank Juliette Masure for the technical support and Stefan Linehan for his comments that greatly improved the manuscript.


  1. 1.
    Caprioli R, Farmer T, Gile J (1997) Molecular imaging of biological samples: localization of peptides and proteins using MALDI-TOF MS. Anal Chem 69(23):4751–4760CrossRefPubMedGoogle Scholar
  2. 2.
    Stoeckli M, Chaurand P, Hallahan DE, Caprioli RM (2001) Imaging mass spectrometry: a new technology for the analysis of protein expression in mammalian tissues. Nat Med 7(4):493–496CrossRefPubMedGoogle Scholar
  3. 3.
    Chaurand P, Schwartz SA, Caprioli RM (2002) Imaging mass spectrometry: a new tool to investigate the spatial organization of peptides and proteins in mammalian tissue sections. Curr Opin Chem Biol 6(5):676–681CrossRefPubMedGoogle Scholar
  4. 4.
    Chaurand P, Cornett DS, Caprioli RM (2006) Molecular imaging of thin mammalian tissue sections by mass spectrometry. Curr Opin Biotechnol 17(4):431–436CrossRefPubMedGoogle Scholar
  5. 5.
    Lemaire R, Menguellet SA, Stauber J, Marchaudon V, Lucot JP, Collinet P, Farine MO, Vinatier D, Day R, Ducoroy P, Salzet M, Fournier I (2007) Specific MALDI imaging and profiling for biomarker hunting and validation: fragment of the 11S proteasome activator complex, Reg alpha fragment, is a new potential ovary cancer biomarker. J Proteome Res 6(11):4127–4134CrossRefPubMedGoogle Scholar
  6. 6.
    Stoeckli M, Staab D, Schweitzer A (2007) Compound and metabolite distribution measured by MALDI mass spectrometric imaging in whole-body tissue sections. Int J Mass Spectrom 260(2–3):195–202CrossRefGoogle Scholar
  7. 7.
    Cornett D, Frappier S, Caprioli R (2008) MALDI-FTICR imaging mass spectrometry of drugs and metabolites in tissue. Anal Chem 80(14):5648–5653CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Groseclose MR, Massion PP, Chaurand P, Caprioli RM (2008) High-throughput proteomic analysis of formalin-fixed paraffin-embedded tissue microarrays using MALDI imaging mass spectrometry. Proteomics 8(18):3715–3724CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Franck J, Arafah K, Elayed M, Bonnel D, Vergara D, Jacquet A, Vinatier D, Wisztorski M, Day R, Fournier I, Salzet M (2009) MALDI imaging mass spectrometry: state of the art technology in clinical proteomics. Mol Cell Proteomics 8(9):2023–2033CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Grey AC, Chaurand P, Caprioli RM, Schey KL (2009) MALDI imaging mass spectrometry of integral membrane proteins from ocular lens and retinal tissue. J Proteome Res 8(7):3278–3283CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Solon EG, Schweitzer A, Stoeckli M, Prideaux B (2010) Autoradiography, MALDI-MS, and SIMS-MS imaging in pharmaceutical discovery and development. AAPS J 12(1):11–26CrossRefPubMedGoogle Scholar
  12. 12.
    Bonnel D, Legouffe R, Willand N, Baulard A, Hamm G, Deprez B, Stauber J (2011) MALDI imaging techniques dedicated to drug-distribution studies. Bioanalysis 3(12):1399–1406CrossRefPubMedGoogle Scholar
  13. 13.
    Bonnel D, Longuespee R, Franck J, Roudbaraki M, Gosset P, Day R, Salzet M, Fournier I (2011) Multivariate analyses for biomarkers hunting and validation through on-tissue bottom-up or in-source decay in MALDI-MSI: application to prostate cancer. Anal Bioanal Chem 401(1):149–165CrossRefPubMedGoogle Scholar
  14. 14.
    Seeley EH, Caprioli RM (2011) MALDI imaging mass spectrometry of human tissue: method challenges and clinical perspectives. Trends Biotechnol 29(3):136–143CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Brignole-Baudouin F, Desbenoit N, Hamm G, Liang H, Both J-P, Brunelle A, Fournier I, Guerineau V, Legouffe R, Stauber J, Touboul D, Wisztorski M, Salzet M, Laprevote O, Baudouin C (2012) A new safety concern for glaucoma treatment demonstrated by mass spectrometry imaging of benzalkonium chloride distribution in the eye, an Experimental Study in Rabbits. PLoS One 7(11):e50180CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kreye F, Hamm G, Karrout Y, Legouffe R, Bonnel D, Siepmann F, Siepmann J (2012) MALDI-TOF MS imaging of controlled release implants. J Control Release 161(1):98–108CrossRefPubMedGoogle Scholar
  17. 17.
    Prideaux B, Stoeckli M (2012) Mass spectrometry imaging for drug distribution studies. J Proteome 75(16):4999–5013CrossRefGoogle Scholar
  18. 18.
    Navis AC, Niclou SP, Fack F, Stieber D, van Lith S, Verrijp K, Wright A, Stauber J, Tops B, Otte-Holler I, Wevers RA, van Rooij A, Pusch S, von Deimling A, Tigchelaar W, van Noorden CJ, Wesseling P, Leenders WP (2013) Increased mitochondrial activity in a novel IDH1-R132H mutant human oligodendroglioma xenograft model: in situ detection of 2-HG and alpha-KG. Acta Neuropathol Commun 1:18CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Anderson DG, Ablonczy Z, Koutalos Y, Spraggins J, Crouch R, Caprioli R, Schey K (2014) High resolution MALDI imaging mass spectrometry of retinal tissue lipids. J Am Soc Mass Spectrom 25(8):1394–1403CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Miyamoto S, Hsu C-C, Hamm G, Darshi M, Diamond-Stanic M, Declèves A-E, Slater L, Pennathur S, Stauber J, Dorrestein PC, Sharma K (2016) Mass spectrometry imaging reveals elevated glomerular ATP/AMP in diabetes/obesity and identifies sphingomyelin as a possible mediator. EBioMedicine 7:121–134CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Sun N, Fernandez IE, Wei M, Wu Y, Aichler M, Eickelberg O, Walch A (2016) Pharmacokinetic and pharmacometabolomic study of pirfenidone in normal mouse tissues using high mass resolution MALDI-FTICR-mass spectrometry imaging. Histochem Cell Biol 145(2):201–211CrossRefPubMedGoogle Scholar
  22. 22.
    Groseclose MR, Laffan SB, Frazier KS, Hughes-Earle A, Castellino S (2015) Imaging MS in toxicology: an investigation of juvenile rat nephrotoxicity associated with dabrafenib administration. J Am Soc Mass Spectrom 26:887–898CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hamm G, Bonnel D, Legouffe R, Pamelard F, Delbos J-M, Bouzom F, Stauber J (2012) Quantitative mass spectrometry imaging of propranolol and olanzapine using tissue extinction calculation as normalization factor. J Proteome 75(16):4952–4961CrossRefGoogle Scholar
  24. 24.
    Pirman DA, Reich RF, Kiss A, Heeren RMA, Yost RA (2012) Quantitative MALDI tandem mass spectrometric imaging of cocaine from brain tissue with a deuterated internal standard. Anal Chem 85(2):1081–1089CrossRefPubMedGoogle Scholar
  25. 25.
    Groseclose MR, Castellino S (2013) A mimetic tissue model for the quantification of drug distributions by MALDI imaging mass spectrometry. Anal Chem 85(21):10099–10106CrossRefPubMedGoogle Scholar
  26. 26.
    Chumbley CW, Reyzer ML, Allen JL, Marriner GA, Via LE, Barry CE 3rd, Caprioli RM (2016) Absolute quantitative MALDI imaging mass spectrometry: a case of rifampicin in liver tissues. Anal Chem 88(4):2392–2398CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Stauber J (2013) Quantitation by MS imaging: needs and challenges in pharmaceuticals. Bioanalysis 4(17):2095–2098CrossRefGoogle Scholar
  28. 28.
    Lemaire R, Desmons A, Tabet JC, Day R, Salzet M, Fournier I (2007) Direct analysis and MALDI imaging of formalin-fixed, paraffin-embedded tissue sections. J Proteome Res 6(4):1295–1305CrossRefPubMedGoogle Scholar
  29. 29.
    Stauber J, Lemaire R, Franck J, Bonnel D, Croix D, Day R, Wisztorski M, Fournier I, Salzet M (2008) MALDI imaging of formalin-fixed paraffin-embedded tissues: application to model animals of Parkinson disease for biomarker hunting. J Proteome Res 7(3):969–978CrossRefPubMedGoogle Scholar
  30. 30.
    Goodwin RJA, Iverson SL, Andren PE (2012) The significance of ambient-temperature on pharmaceutical and endogenous compound abundance and distribution in tissues sections when analyzed by matrix-assisted laser desorption/ionization mass spectrometry imaging. Rapid Commun Mass Spec 26(5):494–498CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media LLC 2017

Authors and Affiliations

  1. 1.ImaBiotechParc EurasantéLoosFrance

Personalised recommendations