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Qualitative and quantitative mass spectrometry imaging of drugs and metabolites in tissue at therapeutic levels

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Abstract

Mass spectrometry imaging (MSI) is a rapidly evolving technology that yields qualitative and quantitative distribution maps of small pharmaceutical-active molecules and their metabolites in tissue sections in situ. The simplicity, high sensitivity and ability to provide comprehensive spatial distribution maps of different classes of biomolecules make MSI a valuable tool to complement histopathology for diagnostics and biomarker discovery. In this review, qualitative and quantitative MSI of drugs and metabolites in tissue at therapeutic levels are discussed and the impact of this technique in drug discovery and clinical research is highlighted.

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Abbreviations

2D:

Two-dimensional

3D:

Three-dimensional

CASI:

Continuous accumulation of selected ions

CHCA:

α-Cyano-4-hydroxycinnamic acid

COC:

Cocaine

DHB:

2,5-Dihydroxybenzoic acid

FTICR:

Fourier transform ion cyclotron resonance

H&E:

Haematoxylin and eosin staining

LC:

Liquid chromatography

LC–MS/MS:

Liquid chromatography-tandem mass spectrometry

MALDI:

Matrix-assisted laser desorption/ionisation

MRM:

Multiple reaction monitoring

MS:

Mass spectrometry

MSI:

Mass spectrometry imaging

MS/MS:

Tandem mass spectrometry

MXF:

Moxifloxacin

PET:

Positron emission tomography

ROI:

Region of interest

SA:

Sinapinic acid

SRM:

Selected reaction monitoring

TOF:

Time-of-flight

References

  • Atkinson SJ, Loadman PM, Sutton C, Patterson LH, Clench MR (2007) Examination of the distribution of the bioreductive drug AQ4N and its active metabolite AQ4 in solid tumours by imaging matrix-assisted laser desorption/ionisation mass spectrometry. Rapid Commun Mass Spectrom 21(7):1271–1276. doi:10.1002/rcm.2952

    Article  PubMed  CAS  Google Scholar 

  • Balluff B, Rauser S, Ebert MP, Siveke JT, Hofler H, Walch A (2012) Direct molecular tissue analysis by MALDI imaging mass spectrometry in the field of gastrointestinal disease. Gastroenterology 143(3):544–549 e541–542. doi:10.1053/j.gastro.2012.07.022

    Google Scholar 

  • Castellino S, Groseclose MR, Wagner D (2011) MALDI imaging mass spectrometry: bridging biology and chemistry in drug development. Bioanalysis 3(21):2427–2441. doi:10.4155/bio.11.232

    Article  PubMed  CAS  Google Scholar 

  • Castellino S, Groseclose MR, Sigafoos J, Wagner D, de Serres M, Polli JW, Romach E, Myer J, Hamilton B (2013) Central nervous system disposition and metabolism of Fosdevirine (GSK2248761), a non-nucleoside reverse transcriptase inhibitor: an LC–MS and Matrix-assisted laser desorption/ionization imaging MS investigation into central nervous system toxicity. Chem Res Toxicol 26(2):241–251. doi:10.1021/tx3004196

    Article  PubMed  CAS  Google Scholar 

  • Chen J, Hsieh Y, Knemeyer I, Crossman L, Korfmacher WA (2008) Visualization of first-pass drug metabolism of terfenadine by MALDI-imaging mass spectrometry. Drug Metab Lett 2(1):1–4

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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 Methods 55(3):279–288. doi:10.1016/j.vascn.2006.11.004

    Article  PubMed  CAS  Google Scholar 

  • Goldshaid L, Rubinstein E, Brandis A, Segal D, Leshem N, Brenner O, Kalchenko V, Eren D, Yecheskel T, Salitra Y, Salomon Y, Scherz A (2010) Novel design principles enable specific targeting of imaging and therapeutic agents to necrotic domains in breast tumors. Breast Cancer Res 12(3):R29. doi:10.1186/bcr2579

    Article  PubMed  Google Scholar 

  • Goodwin RJ, Pitt AR (2010) Mass spectrometry imaging of pharmacological compounds in tissue sections. Bioanalysis 2(2):279–293. doi:10.4155/bio.09.180

    Article  PubMed  CAS  Google Scholar 

  • Goodwin RJ, Scullion P, Macintyre L, Watson DG, Pitt AR (2010) Use of a solvent-free dry matrix coating for quantitative matrix-assisted laser desorption ionization imaging of 4-bromophenyl-1,4-diazabicyclo(3.2.2)nonane-4-carboxylate in rat brain and quantitative analysis of the drug from laser microdissected tissue regions. Anal Chem 82(9):3868–3873. doi:10.1021/ac100398y

    Article  PubMed  CAS  Google Scholar 

  • Greer T, Sturm R, Li L (2011) Mass spectrometry imaging for drugs and metabolites. J Proteomics 74(12):2617–2631. doi:10.1016/j.jprot.2011.03.032

    Article  PubMed  CAS  Google Scholar 

  • Hamm G, Bonnel D, Legouffe R, Pamelard F, Delbos JM, Bouzom F, Stauber J (2012) Quantitative mass spectrometry imaging of propranolol and olanzapine using tissue extinction calculation as normalization factor. J Proteomics 75(16):4952–4961. doi:10.1016/j.jprot.2012.07.035

    Article  PubMed  CAS  Google Scholar 

  • Hankin JA, Barkley RM, Murphy RC (2007) Sublimation as a method of matrix application for mass spectrometric imaging. J Am Soc Mass Spectrom 18(9):1646–1652. doi:10.1016/j.jasms.2007.06.010

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Hsieh Y, Casale R, Fukuda E, Chen J, Knemeyer I, Wingate J, Morrison R, Korfmacher W (2006) Matrix-assisted laser desorption/ionization imaging mass spectrometry for direct measurement of clozapine in rat brain tissue. Rapid Commun Mass Spectrom 20(6):965–972. doi:10.1002/rcm.2397

    Article  PubMed  CAS  Google Scholar 

  • Hsieh Y, Chen J, Korfmacher WA (2007) Mapping pharmaceuticals in tissues using MALDI imaging mass spectrometry. J Pharmacol Toxicol Methods 55(2):193–200. doi:10.1016/j.vascn.2006.06.004

    Article  PubMed  CAS  Google Scholar 

  • Kallback P, Shariatgorji M, Nilsson A, Andren PE (2012) Novel mass spectrometry imaging software assisting labeled normalization and quantitation of drugs and neuropeptides directly in tissue sections. J Proteomics 75(16):4941–4951. doi:10.1016/j.jprot.2012.07.034

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Koeniger SL, Talaty N, Luo Y, Ready D, Voorbach M, Seifert T, Cepa S, Fagerland JA, Bouska J, Buck W, Johnson RW, Spanton S (2011) A quantitation method for mass spectrometry imaging. Rapid Commun Mass Spectrom 25(4):503–510. doi:10.1002/rcm.4891

    Article  PubMed  CAS  Google Scholar 

  • Krutchinsky AN, Chait BT (2002) On the nature of the chemical noise in MALDI mass spectra. J Am Soc Mass Spectrom 13(2):129–134

    Article  PubMed  CAS  Google Scholar 

  • Kuwayama K, Tsujikawa K, Miyaguchi H, Kanamori T, Iwata YT, Inoue H (2012) Distribution measurements of 3,4-methylenedioxymethamphetamine and its metabolites in organs by matrix-assisted laser desorption/ionization imaging mass spectrometry using an automatic matrix spraying system with an air brush and a turntable. Anal Bioanal Chem 404(6–7):1823–1830. doi:10.1007/s00216-012-6279-x

    Article  PubMed  CAS  Google Scholar 

  • Lanao JM, Fraile MA (2005) Drug tissue distribution: study methods and therapeutic implications. Curr Pharm Des 11(29):3829–3845

    Article  PubMed  CAS  Google Scholar 

  • Lietz CB, Gemperline E, Li L (2013) Qualitative and quantitative mass spectrometry imaging of drugs and metabolites. Adv Drug Deliv Rev. doi:10.1016/j.addr.2013.04.009

  • Liu X, Weaver EM, Hummon AB (2013) Evaluation of therapeutics in three-dimensional cell culture systems by MALDI imaging mass spectrometry. Anal Chem. doi:10.1021/ac400519c

  • Marko-Varga G, Fehniger TE, Rezeli M, Dome B, Laurell T, Vegvari A (2011) Drug localization in different lung cancer phenotypes by MALDI mass spectrometry imaging. J Proteomics 74(7):982–992. doi:10.1016/j.jprot.2011.03.019

    Article  PubMed  CAS  Google Scholar 

  • Marko-Varga G, Vegvari A, Rezeli M, Prikk K, Ross P, Dahlback M, Edula G, Sepper R, Fehniger TE (2012) Understanding drug uptake and binding within targeted disease micro-environments in patients: a new tool for translational medicine. Clin Transl Med 1(1):8. doi:10.1186/2001-1326-1-8

    Article  PubMed  Google Scholar 

  • Monroe EB, Jurchen JC, Lee J, Rubakhin SS, Sweedler JV (2005) Vitamin E imaging and localization in the neuronal membrane. J Am Chem Soc 127(35):12152–12153. doi:10.1021/ja051223y

    Article  PubMed  CAS  Google Scholar 

  • Mouton JW, Theuretzbacher U, Craig WA, Tulkens PM, Derendorf H, Cars O (2008) Tissue concentrations: do we ever learn? J Antimicrob Chemother 61(2):235–237. doi:10.1093/jac/dkm476

    Article  PubMed  CAS  Google Scholar 

  • Neubert P, Walch A (2013) Current frontiers in clinical research application of MALDI imaging mass spectrometry. Expert Rev Proteomics 10(3):259–273. doi:10.1586/epr.13.19

    Article  PubMed  CAS  Google Scholar 

  • Nilsson A, Fehniger TE, Gustavsson L, Andersson M, Kenne K, Marko-Varga G, Andren PE (2010) Fine mapping the spatial distribution and concentration of unlabeled drugs within tissue micro-compartments using imaging mass spectrometry. PLoS ONE 5(7):e11411. doi:10.1371/journal.pone.0011411

    Article  PubMed  Google Scholar 

  • Nilsson A, Forngren B, Bjurstrom S, Goodwin RJ, Basmaci E, Gustafsson I, Annas A, Hellgren D, Svanhagen A, Andren PE, Lindberg J (2012) In situ mass spectrometry imaging and ex vivo characterization of renal crystalline deposits induced in multiple preclinical drug toxicology studies. PLoS ONE 7(10):e47353. doi:10.1371/journal.pone.0047353

    Article  PubMed  CAS  Google Scholar 

  • Pellegatti M, Pagliarusco S (2011) Drug and metabolite concentrations in tissues in relationship to tissue adverse findings: a review. Expert Opin Drug Metab Toxicol 7(2):137–146. doi:10.1517/17425255.2011.545053

    Article  PubMed  Google Scholar 

  • Pirman DA, Reich RF, Kiss A, Heeren RM, Yost RA (2013) Quantitative MALDI tandem mass spectrometric imaging of cocaine from brain tissue with a deuterated internal standard. Anal Chem 85(2):1081–1089. doi:10.1021/ac302960j

    Article  PubMed  CAS  Google Scholar 

  • Pislyagin EA, Dmitrenok PS, Gorpenchenko TY, Avilov SA, Silchenko AS, Aminin DL (2013) Determination of cucumarioside A-2 in mouse spleen by radiospectroscopy, MALDI-MS and MALDI-IMS. Eur J Pharm Sci. doi:10.1016/j.ejps.2013.05.017

  • Prideaux B, Stoeckli M (2012) Mass spectrometry imaging for drug distribution studies. J Proteomics 75(16):4999–5013. doi:10.1016/j.jprot.2012.07.028

    Article  PubMed  CAS  Google Scholar 

  • Prideaux B, Dartois V, Staab D, Weiner DM, Goh A, Via LE, Barry CE 3rd, Stoeckli M (2011) High-sensitivity MALDI-MRM-MS imaging of moxifloxacin distribution in tuberculosis-infected rabbit lungs and granulomatous lesions. Anal Chem 83(6):2112–2118. doi:10.1021/ac1029049

    Article  PubMed  CAS  Google Scholar 

  • Puolitaival SM, Burnum KE, Cornett DS, Caprioli RM (2008) Solvent-free matrix dry-coating for MALDI imaging of phospholipids. J Am Soc Mass Spectrom 19(6):882–886. doi:10.1016/j.jasms.2008.02.013

    Article  PubMed  CAS  Google Scholar 

  • Reich RF, Cudzilo K, Levisky JA, Yost RA (2010) Quantitative MALDI-MS(n) analysis of cocaine in the autopsied brain of a human cocaine user employing a wide isolation window and internal standards. J Am Soc Mass Spectrom 21(4):564–571. doi:10.1016/j.jasms.2009.12.014

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Reyzer ML, Hsieh Y, 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

    Article  PubMed  CAS  Google Scholar 

  • Reyzer ML, Chaurand P, Angel PM, Caprioli RM (2010) Direct molecular analysis of whole-body animal tissue sections by MALDI imaging mass spectrometry. Methods Mol Biol 656:285–301. doi:10.1007/978-1-60761-746-4_17

    Article  PubMed  CAS  Google Scholar 

  • Riemann B, Schafers KP, Schober O, Schafers M (2008) Small animal PET in preclinical studies: opportunities and challenges. Q J Nucl Med Mol Imaging 52(3):215–221

    PubMed  CAS  Google Scholar 

  • Rohner TC, Staab D, Stoeckli M (2005) MALDI mass spectrometric imaging of biological tissue sections. Mech Ageing Dev 126(1):177–185. doi:10.1016/j.mad.2004.09.032

    Article  PubMed  CAS  Google Scholar 

  • Römpp A, Spengler B (2013) Mass spectrometry imaging with high resolution in mass and space. Histochem Cell Biol 139(6):759–783. doi:10.1007/s00418-013-1097-6

    Article  PubMed  Google Scholar 

  • Römpp A, Guenther S, Takats Z, Spengler B (2011) Mass spectrometry imaging with high resolution in mass and space (HR(2) MSI) for reliable investigation of drug compound distributions on the cellular level. Anal Bioanal Chem 401(1):65–73. doi:10.1007/s00216-011-4990-7

    Article  PubMed  Google Scholar 

  • Shahidi-Latham SK, Dutta SM, Prieto Conaway MC, Rudewicz PJ (2012) Evaluation of an accurate mass approach for the simultaneous detection of drug and metabolite distributions via whole-body mass spectrometric imaging. Anal Chem 84(16):7158–7165. doi:10.1021/ac3015142

    Article  PubMed  CAS  Google Scholar 

  • Shanta SR, Kim TY, Hong JH, Lee JH, Shin CY, Kim KH, Kim YH, Kim SK, Kim KP (2012) A new combination MALDI matrix for small molecule analysis: application to imaging mass spectrometry for drugs and metabolites. Analyst 137(24):5757–5762. doi:10.1039/c2an35782h

    Article  PubMed  CAS  Google Scholar 

  • Signor L, Varesio E, Staack RF, Starke V, Richter WF, Hopfgartner G (2007) Analysis of erlotinib and its metabolites in rat tissue sections by MALDI quadrupole time-of-flight mass spectrometry. J Mass Spectrom 42(7):900–909. doi:10.1002/jms.1225

    Article  PubMed  CAS  Google Scholar 

  • Sleno L, Volmer DA (2006) Assessing the properties of internal standards for quantitative matrix-assisted laser desorption/ionization mass spectrometry of small molecules. Rapid Commun Mass Spectrom 20(10):1517–1524. doi:10.1002/rcm.2498

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    CAS  Google Scholar 

  • Sugiura Y, Setou M (2010) Imaging mass spectrometry for visualization of drug and endogenous metabolite distribution: toward in situ pharmacometabolomes. J Neuroimmune Pharmacol 5(1):31–43. doi:10.1007/s11481-009-9162-6

    Article  PubMed  Google Scholar 

  • Takai N, Tanaka Y, Inazawa K, Saji H (2012) Quantitative analysis of pharmaceutical drug distribution in multiple organs by imaging mass spectrometry. Rapid Commun Mass Spectrom 26(13):1549–1556. doi:10.1002/rcm.6256

    Article  PubMed  CAS  Google Scholar 

  • Takai N, Tanaka Y, Watanabe A, Saji H (2013) Quantitative imaging of a therapeutic peptide in biological tissue sections by MALDI MS. Bioanalysis 5(5):603–612. doi:10.4155/bio.13.13

    Article  PubMed  CAS  Google Scholar 

  • Wang HY, Jackson SN, McEuen J, Woods AS (2005) Localization and analyses of small drug molecules in rat brain tissue sections. Anal Chem 77(20):6682–6686. doi:10.1021/ac050868d

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors gratefully acknowledge the financial support of the BMBF (No. 0315508A and No. 01IB10004E) and the Deutsche Forschungsgemeinschaft (SFB 824 TP B1, SFB 824 TP Z2 and WA 1656/3-1).

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Correspondence to Axel Walch.

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Sun, N., Walch, A. Qualitative and quantitative mass spectrometry imaging of drugs and metabolites in tissue at therapeutic levels. Histochem Cell Biol 140, 93–104 (2013). https://doi.org/10.1007/s00418-013-1127-4

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