Abstract
Mass spectrometry (MS) imaging is a versatile method to analyze the spatial distribution of analytes in tissue sections. It provides unique features for the analysis of drug compounds in pharmacokinetic studies such as label-free detection and differentiation of compounds and metabolites. We have recently introduced a MS imaging method that combines high mass resolution and high spatial resolution in a single experiment, hence termed HR2 MS imaging. In the present study, we applied this method to analyze the spatial distribution of the anti-cancer drugs imatinib and ifosfamide in individual mouse organs. The whole kidney of an animal dosed with imatinib was measured at 35 μm spatial resolution. Imatinib showed a well-defined distribution in the outer stripe of the outer medulla. This area was analyzed in more detail at 10 μm step size, which constitutes a tenfold increase in effective spatial resolution compared to previous studies of drug compounds. In parallel, ion images of phospholipids and heme were used to characterize the histological features of the tissue section and showed excellent agreement with histological staining of the kidney after MS imaging. Ifosfamide was analyzed in mouse kidney at 20 μm step size and was found to be accumulated in the inner medulla region. The identity of imatinib and ifosfamide was confirmed by on-tissue MS/MS measurements. All measurements including mass spectra from 10 μm pixels featured accurate mass (≤2 ppm root mean square) and mass resolving power of R = 30,000. Selected ion images were generated with a bin size of ∆m/z = 0.01 ensuring highly specific information. The ability of the method to cover larger areas was demonstrated by imaging a compound in the intestinal tract of a rat whole-body tissue section at 200 μm step size. The described method represents a major improvement in terms of spatial resolution and specificity for the analysis of drug compounds in tissue sections.
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References
Chughtai K, Heeren RMA (2010) Mass spectrometric imaging for biomedical tissue analysis. Chem Rev 110(5):3237–3277
McDonnell LA, Heeren RMA (2007) Imaging mass spectrometry. Mass Spectrom Rev 26(4):606–643. doi:10.1002/mas.20124
Spengler B, Hubert M (2002) Scanning microprobe matrix-assisted laser desorption ionization (SMALDI) mass spectrometry: instrumentation for sub-micrometer resolved LDI and MALDI surface analysis. J Am Soc Mass Spectrom 13(6):735–748
Spengler B, Hubert M, Kaufmann R (1994) MALDI ion imaging and biological ion imaging with a new scanning UV-laser microprobe. In: Proceedings of the 42nd Annual Conference on Mass Spectrometry and Allied Topics, Chicago, Illinois, 29 May–3 June, p 1041
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):493–496
Jackson SN, Wang HYJ, Woods AS (2005) In situ structural characterization of phosphatidylcholines in brain tissue using MALDI-MS/MS. J Am Soc Mass Spectrom 16(12):2052–2056. doi:10.1016/j.jasms.2005.08.014
Chen RB, Jiang XY, Conaway MCP, Mohtashemi I, Hui LM, Viner R, Li LJ (2010) Mass spectral analysis of neuropeptide expression and distribution in the nervous system of the lobster Homarus americanus. J Proteome Res 9(2):818–832. doi:10.1021/pr900736t
Stoeckli M, Staab D, Staufenbiel M, Wiederhold KH, Signor L (2002) Molecular imaging of amyloid beta peptides in mouse brain sections using mass spectrometry. Anal Biochem 311(1):33–39
Reyzer ML, Caprioli RM (2007) MALDI-MS-based imaging of small molecules and proteins in tissues. Curr Opin Chem Biol 11(1):29–35. doi:10.1016/j.cbpa.2006.11.035
Reyzer ML, Hsieh YS, Ng K, Korfmacher WA, Caprioli RM (2003) Direct analysis of drug candidates in tissue by matrix-assisted laser desorption/ionization mass spectrometry. J Mass Spectrom 38(10):1081–1092. doi:10.1002/jms.525
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):195–202. doi:10.1016/j.ijms.2006.10.007
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):11–26. doi:10.1208/s12248-009-9158-4
Khatib-Shahidi S, Andersson M, Herman JL, Gillespie TA, Caprioli RM (2006) Direct molecular analysis of whole-body animal tissue sections by imaging MALDI mass spectrometry. Anal Chem 78(18):6448–6456. doi:10.1021/ac060788p
Cornett DS, Frappier SL, Caprioli RM (2008) MALDI-FTICR imaging mass spectrometry of drugs and metabolites in tissue. Anal Chem 80(14):5648–5653. doi:10.1021/ac800617s
Acquadro E, Cabella C, Ghiani S, Miragoli L, Bucci EM, Corpillo D (2009) Matrix-assisted laser desorption ionization imaging mass spectrometry detection of a magnetic resonance imaging contrast agent in mouse liver. Anal Chem 81(7):2779–2784. doi:10.1021/ac900038y
Trim PJ, Henson CM, Avery JL, McEwen A, Snel MF, Claude E, Marshall PS, West A, Princivalle AP, Clench MR (2008) Matrix-assisted laser desorption/ionization-ion mobility separation-mass spectrometry imaging of Vinblastine in whole body tissue sections. Anal Chem 80(22):8628–8634. doi:10.1021/ac8015467
Hopfgartner G, Varesio E, Stoeckli M (2009) Matrix-assisted laser desorption/ionization mass spectrometric imaging of complete rat sections using a triple quadrupole linear ion trap. Rapid Commun Mass Spectrom 23(6):733–736. doi:10.1002/rcm.3934
Drexler DM, Garrett TJ, Cantone JL, Diters RW, Mitroka JG, Prieto Conaway MC, Adams SP, Yost RA, Sanders M (2007) Utility of imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization (MALDI) on an ion trap mass spectrometer in the analysis of drugs and metabolites in biological tissues. J Pharmacol Toxicol Meth 55(3):279–288. doi:10.1016/j.vascn.2006.11.004
Marshall AG, Hendrickson CL (2002) Fourier transform ion cyclotron resonance detection: principles and experimental configurations. Int J Mass Spectrom 215(1–3):59–75
Römpp A, Taban IM, Mihalca R, Duursma MC, Mize TH, McDonnell LA, Heeren RMA (2005) Examples of Fourier transform ion cyclotron resonance mass spectrometry developments: from ion physics to remote access biochemical mass spectrometry. Eur J Mass Spectrom 11(5):443–456
Scigelova M, Makarov A (2006) Orbitrap mass analyzer—overview and applications in proteomics. Proteomics 6(1):16–21. doi:10.1002/pmic.200600528
Landgraf RR, Conaway MCP, Garrett TJ, Stacpoole PW, Yost RA (2009) Imaging of lipids in spinal cord using intermediate pressure matrix-assisted laser desorption-linear ion trap/Orbitrap MS. Anal Chem 81(20):8488–8495. doi:10.1021/ac901387u
Römpp A, Guenther S, Schober Y, Schulz O, Takats Z, Kummer W, Spengler B (2010) Histology by mass spectrometry: label-free tissue characterization obtained from high-accuracy bioanalytical imaging. Angew Chem Int Ed 49(22):3834–3838
Guenther S, Römpp A, Kummer W, Spengler B (2011) AP-MALDI imaging of neuropeptides in mouse pituitary gland with 5 μm spatial resolution and high mass accuracy. Int J Mass Spectrom. doi:10.1016/j.ijms.2010.11.011
Bouschen W, Schulz O, Eikel D, Spengler B (2010) Matrix vapor deposition/recrystallization and dedicated spray preparation for high-resolution scanning microprobe matrix-assisted laser desorption/ionization imaging mass spectrometry (SMALDI-MS) of tissue and single cells. Rapid Commun Mass Spectrom 24(3):355–364
Koestler M, Kirsch D, Hester A, Leisner A, Guenther S, Spengler B (2008) A high-resolution scanning microprobe matrix-assisted laser desorption/ionization ion source for imaging analysis on an ion trap/Fourier transform ion cyclotron resonance mass spectrometer. Rapid Commun Mass Spectrom 22(20):3275–3285. doi:10.1002/rcm.3733
Guenther S, Koestler M, Schulz O, Spengler B (2010) Laser spot size and laser power dependence of ion formation in high resolution MALDI imaging. Int J Mass Spectrom 294(1):7–15. doi:10.1016/j.ijms.2010.03.014
Weinman EJ, Lakkis J, Akom M, Wali RK, Drachenberg CB, Coleman RA, Wade JB (2002) Expression of NHERF-1, NHERF-2, PDGFR-alpha, and PDGFR-beta in normal human kidneys and in renal transplant rejection. Pathobiology 70(6):314–323. doi:10.1159/000071271
Acknowledgements
Financial support by the State of Hesse (LOEWE Research Focus “Ambiprobe”), by the European Research Council Starting Grant 2008 (Z. T.), and by the European Union (STREP project LSHG-CT-2005-518194) is gratefully acknowledged. We thank Lilli Walz for H&E staining of mouse kidney sections. We also thank Julia Kokesch for help with data analysis. This publication represents a component of the doctoral (Dr. rer. nat.) thesis of S.G. at the Faculty of Biology and Chemistry, Justus Liebig University Giessen, Germany.
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Andreas Römpp and Sabine Guenther equally contributed to this paper.
Published in the special issue MALDI Imaging with Guest Editor Olivier Laprévote.
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Römpp, A., Guenther, S., Takats, Z. et al. Mass spectrometry imaging with high resolution in mass and space (HR2 MSI) for reliable investigation of drug compound distributions on the cellular level. Anal Bioanal Chem 401, 65–73 (2011). https://doi.org/10.1007/s00216-011-4990-7
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DOI: https://doi.org/10.1007/s00216-011-4990-7