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Imaging Mass Spectrometry for Visualization of Drug and Endogenous Metabolite Distribution: Toward In Situ Pharmacometabolomes

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Abstract

It is important to determine how a candidate drug is distributed and metabolized within the body in early phase of drug discovery. Recently, matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS; also referred to as mass spectrometry imaging) has attracted great interest for monitoring drug delivery and metabolism. Since this emerging technique enables simultaneous imaging of many types of metabolite molecules, MALDI-IMS can visualize and distinguish the parent drug and its metabolites. As another important advantage, changes in endogenous metabolites in response to drug administration can be mapped and evaluated in tissue sections. In this review, we discuss the capabilities of current IMS techniques for imaging metabolite molecules and summarize representative studies on imaging of both endogenous and exogenous metabolites. In addition, current limitations and problems with the technique are discussed, and reports of progress toward solving these problems are summarized. With this new tool, the pharmacological research community can begin to map the in situ pharmacometabolome.

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References

  • Ageta H, Asai S, Sugiura Y, Goto-Inoue N, Zaima N, Setou M (2008) Layer-specific sulfatide localization in rat hippocampus middle molecular layer is revealed by nanoparticle-assisted laser desorption/ionization imaging mass spectrometry. Med Mol Morphol 42:16–23

    Article  Google Scholar 

  • Altelaar AF, Klinkert I, Jalink K, de Lange RP, Adan RA, Heeren RM, Piersma SR (2006) Gold-enhanced biomolecular surface imaging of cells and tissue by SIMS and MALDI mass spectrometry. Anal Chem 78:734–742. doi:10.1021/ac0513111

    Article  CAS  PubMed  Google Scholar 

  • Annesley TM (2003) Ion suppression in mass spectrometry. Clin Chem 49:1041–1044. doi:10.1373/49.7.1041

    Article  CAS  PubMed  Google Scholar 

  • Astigarraga E, Barreda-Gomez G, Lombardero L, Fresnedo O, Castano F, Giralt MT, Ochoa B, Rodriguez-Puertas R, Fernandez JA (2008) Profiling and imaging of lipids on brain and liver tissue by matrix-assisted laser desorption/ionization mass spectrometry using 2-mercaptobenzothiazole as a matrix. Anal Chem 80:9105–9114

    Article  CAS  PubMed  Google Scholar 

  • 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 21:1271–1276. doi:10.1002/rcm.2952

    Article  CAS  PubMed  Google Scholar 

  • Caprioli RM, Farmer TB, Gile J (1997) Molecular imaging of biological samples: localization of peptides and proteins using MALDI-TOF MS. Anal Chem 69:4751–4760. doi:10.1021/ac970888i

    Article  CAS  PubMed  Google Scholar 

  • Cha S, Yeung ES (2007) Colloidal graphite-assisted laser desorption/ionization mass spectrometry and MSn of small molecules. 1. Imaging of cerebrosides directly from rat brain tissue. Anal Chem 79:2373–2385. doi:10.1021/ac062251h

    Article  CAS  PubMed  Google Scholar 

  • Chaurand P, Stoeckli M, Caprioli RM (1999) Direct profiling of proteins in biological tissue sections by MALDI mass spectrometry. Anal Chem 71:5263–5270. doi:10.1021/ac990781q

    Article  CAS  PubMed  Google Scholar 

  • Chaurand P, Norris JL, Cornett DS, Mobley JA, Caprioli RM (2006) New developments in profiling and imaging of proteins from tissue sections by MALDI mass spectrometry. J Proteome Res 5:2889–2900. doi:10.1021/pr060346u

    Article  CAS  PubMed  Google Scholar 

  • Chen Y, Allegood J, Liu Y, Wang E, Cachon-Gonzalez B, Cox TM, Merrill AH Jr, Sullards MC (2008) Imaging MALDI mass spectrometry using an oscillating capillary nebulizer matrix coating system and its application to analysis of lipids in brain from a mouse model of Tay-Sachs/Sandhoff disease. Anal Chem 80:2780–2788. doi:10.1021/ac702350g

    Article  CAS  PubMed  Google Scholar 

  • Colliver TL, Brummel CL, Pacholski ML, Swanek FD, Ewing AG, Winograd N (1997) Atomic and molecular imaging at the single-cell level with TOF-SIMS. Anal Chem 69:2225–2231. doi:10.1021/ac9701748

    Article  CAS  PubMed  Google Scholar 

  • Cornett DS, Frappier SL, Caprioli RM (2008) MALDI-FTICR imaging mass spectrometry of drugs and metabolites in tissue. Anal Chem 80:5648–5653. doi:10.1021/ac800617s

    Article  CAS  PubMed  Google Scholar 

  • Fuchser J, Cornett S, Becker M (2008) High resolution molecular imaging of pharmaceuticals at therapeutic levels. Application note # FTMS-37. Bruker Daltonics, Billerica

    Google Scholar 

  • Garrett TJ, Prieto-Conaway MC, Kovtoun V, Bui H, Izgarian N, Stafford G, Yost RA (2006) Imaging of small molecules in tissue sections with a new intermediate-pressure MALDI linear ion trap mass spectrometer. Int J Mass Spectrom 260:11

    Google Scholar 

  • Gharahdaghi F, Kirchner M, Fernandez J, Mische SM (1996) Peptide-mass profiles of polyvinylidene difluoride-bound proteins by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in the presence of nonionic detergents. Anal Biochem 233:94–99. doi:10.1006/abio.1996.0012

    Article  CAS  PubMed  Google Scholar 

  • Hayasaka T, Goto-Inoue N, Sugiura Y, Zaima N, Nakanishi H, Ohishi K, Nakanishi S, Naito T, Taguchi R, Setou M (2008) Matrix-assisted laser desorption/ionization quadrupole ion trap time-of-flight (MALDI-QIT-TOF)-based imaging mass spectrometry reveals a layered distribution of phospholipid molecular species in the mouse retina. Rapid Commun Mass Spectrom 22:3415–3426. doi:10.1002/rcm.3751

    Article  CAS  PubMed  Google Scholar 

  • Jackson SN, Wang HY, Woods AS (2005a) Direct profiling of lipid distribution in brain tissue using MALDI-TOFMS. Anal Chem 77:4523–4527. doi:10.1021/ac050276v

    Article  CAS  PubMed  Google Scholar 

  • Jackson SN, Wang HY, Woods AS (2005b) In situ structural characterization of phosphatidylcholines in brain tissue using MALDI-MS/MS. J Am Soc Mass Spectrom 16:2052–2056. doi:10.1016/j.jasms.2005.08.014

    Article  CAS  PubMed  Google Scholar 

  • Jackson SN, Ugarov M, Egan T, Post JD, Langlais D, Albert Schultz J, Woods AS (2007a) MALDI-ion mobility-TOFMS imaging of lipids in rat brain tissue. J Mass Spectrom 42:1093–1098. doi:10.1002/jms.1245

    Article  CAS  PubMed  Google Scholar 

  • Jackson SN, Wang HY, Woods AS (2007b) In situ structural characterization of glycerophospholipids and sulfatides in brain tissue using MALDI-MS/MS. J Am Soc Mass Spectrom 18:17–26. doi:10.1016/j.jasms.2006.08.015

    Article  CAS  PubMed  Google Scholar 

  • Jones JJ, Borgmann S, Wilkins CL, O’Brien RM (2006) Characterizing the phospholipid profiles in mammalian tissues by MALDI FTMS. Anal Chem 78:3062–3071. doi:10.1021/ac0600858

    Article  CAS  PubMed  Google Scholar 

  • Jungalwala FB, Hayssen V, Pasquini JM, McCluer RH (1979) Separation of molecular species of sphingomyelin by reversed-phase high-performance liquid chromatography. J Lipid Res 20:579–587

    CAS  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 78:6448–6456. doi:10.1021/ac060788p

    Article  CAS  PubMed  Google Scholar 

  • Kokaji T (2008) Applied biosystems’ IMS. In: Setou M (ed) Mass microscopy; imaging mass spectrometry protocol book. Springer, Tokyo

    Google Scholar 

  • Kotani M, Kawashima I, Ozawa H, Terashima T, Tai T (1993) Differential distribution of major gangliosides in rat central nervous system detected by specific monoclonal antibodies. Glycobiology 3:137–146. doi:10.1093/glycob/3.2.137

    Article  CAS  PubMed  Google Scholar 

  • Kowalski JM, Kowalski P, Holle A, Deininger SO, Khatib-Shahidi S, Caprioli RM (2007) MALDI tissue imaging of drugs with the ultraflex MALDI TOF/TOF. Application note # MT-87. Bruker Daltonics, Billerica

    Google Scholar 

  • Krause E, Wenschuh H, Jungblut PR (1999) The dominance of arginine-containing peptides in MALDI-derived tryptic mass fingerprints of proteins. Anal Chem 71:4160–4165. doi:10.1021/ac990298f

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Shrestha B, Vertes A (2007) Atmospheric pressure molecular imaging by infrared MALDI mass spectrometry. Anal Chem 79:523–532. doi:10.1021/ac061577n

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Shrestha B, Vertes A (2008) Atmospheric pressure infrared MALDI imaging mass spectrometry for plant metabolomics. Anal Chem 80:407–420. doi:10.1021/ac701703f

    Article  CAS  PubMed  Google Scholar 

  • Liu Q, Guo Z, He L (2007) Mass spectrometry imaging of small molecules using desorption/ionization on silicon. Anal Chem 79:3535–3541. doi:10.1021/ac0611465

    Article  CAS  PubMed  Google Scholar 

  • Liu Q, Xiao Y, Pagan-Miranda C, Chiu YM, He L (2008) Metabolite imaging using matrix-enhanced surface-assisted laser desorption/ionization mass spectrometry (ME-SALDI-MS). J Am Soc Mass Spectrom 20:80–88

    Article  PubMed  Google Scholar 

  • Mansson JE, Vanier MT, Svennerholm L (1978) Changes in the fatty acid and sphingosine composition of the major gangliosides of human brain with age. J Neurochem 30:273–275. doi:10.1111/j.1471-4159.1978.tb07064.x

    Article  CAS  PubMed  Google Scholar 

  • Mazel V, Richardin P, Debois D, Touboul D, Cotte M, Brunelle A, Walter P, Laprevote O (2007) Identification of ritual blood in African artifacts using TOF-SIMS and synchrotron radiation microspectroscopies. Anal Chem 79:9253–9260. doi:10.1021/ac070993k

    Article  CAS  PubMed  Google Scholar 

  • McLean JA, Ridenour WB, Caprioli RM (2007) Profiling and imaging of tissues by imaging ion mobility–mass spectrometry. J Mass Spectrom 42:1099–1105. doi:10.1002/jms.1254

    Article  CAS  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 127:12152–12153. doi:10.1021/ja051223y

    Article  CAS  PubMed  Google Scholar 

  • Murakami M, Nakatani Y, Atsumi G, Inoue K, Kudo I (1997) Regulatory functions of phospholipase A2. Crit Rev Immunol 17:225–283

    CAS  PubMed  Google Scholar 

  • Northen TR, Yanes O, Northen MT, Marrinucci D, Uritboonthai W, Apon J, Golledge SL, Nordstrom A, Siuzdak G (2007) Clathrate nanostructures for mass spectrometry. Nature 449:1033–1036. doi:10.1038/nature06195

    Article  CAS  PubMed  Google Scholar 

  • Ostrowski SG, Van Bell CT, Winograd N, Ewing AG (2004) Mass spectrometric imaging of highly curved membranes during Tetrahymena mating. Science 305:71–73. doi:10.1126/science.1099791

    Article  CAS  PubMed  Google Scholar 

  • Palestini P, Masserini M, Sonnino S, Giuliani A, Tettamanti G (1990) Changes in the ceramide composition of rat forebrain gangliosides with age. J Neurochem 54:230–235. doi:10.1111/j.1471-4159.1990.tb13305.x

    Article  CAS  PubMed  Google Scholar 

  • Palestini P, Sonnino S, Tettamanti G (1991) Lack of the ganglioside molecular species containing the C20-long-chain bases in human, rat, mouse, rabbit, cat, dog, and chicken brains during prenatal life. J Neurochem 56:2048–2050. doi:10.1111/j.1471-4159.1991.tb03465.x

    Article  CAS  PubMed  Google Scholar 

  • Piomelli D, Astarita G, Rapaka R (2007) A neuroscientist’s guide to lipidomics. Nat Rev Neurosci 8:743–754. doi:10.1038/nrn2233

    Article  CAS  PubMed  Google Scholar 

  • Prideaux B, Atkinson SJ, Carolan VA, Morton J, Clench MR (2007) Sample preparation and data interpretation procedures for the examination of xenobiotic compounds in skin by indirect imaging MALDI-MS. Int J Mass Spectrom 260:243–251

    Article  CAS  Google Scholar 

  • Pulfer M, Murphy RC (2003) Electrospray mass spectrometry of phospholipids. Mass Spectrom Rev 22:332–364. doi:10.1002/mas.10061

    Article  CAS  PubMed  Google Scholar 

  • Rujoi M, Estrada R, Yappert MC (2004) In situ MALDI-TOF MS regional analysis of neutral phospholipids in lens tissue. Anal Chem 76:1657–1663. doi:10.1021/ac0349680

    Article  CAS  PubMed  Google Scholar 

  • Sambasivarao K, McCluer RH (1964) Lipid components of gangliosides. J Lipid Res 15:103–108

    CAS  PubMed  Google Scholar 

  • Schwarz HP, Kostyk I, Marmolejo A, Sarappa C (1967) Long-chain bases of brain and spinal cord of rabbits. J Neurochem 14:91–97. doi:10.1111/j.1471-4159.1967.tb09497.x

    Article  CAS  PubMed  Google Scholar 

  • Shimma S, Setou M (2007) Mass microscopy to reveal distinct localization of heme B (m/z 616) in colon cancer liver metastasis. J Mass Spectrom Soc Jpn 55:145–148

    CAS  Google Scholar 

  • Shimma S, Sugiura Y, Hayasaka T, Zaima N, Matsumoto M, Setou M (2008) Mass imaging and identification of biomolecules with MALDI-QIT-TOF-based system. Anal Chem 80:878–885

    Article  CAS  PubMed  Google Scholar 

  • Sonnino S, Chigorno V (2000) Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures. Biochim Biophys Acta 1469:63–77

    CAS  PubMed  Google Scholar 

  • 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 7:493–496. doi:10.1038/86573

    Article  CAS  PubMed  Google Scholar 

  • 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 311:33–39. doi:10.1016/S0003-2697(02)00386-X

    Article  CAS  PubMed  Google Scholar 

  • Stoeckli M, Staab D, Schweitzer A (2006) Compound and metabolite distribution measured by MALDI mass spectrometric imaging in whole-body tissue sections. Int J Mass Spectrom 260:195–202

    Google Scholar 

  • Sugiura Y, Shimma S, Konishi Y, Yamada MK, Setou M (2008) Imaging mass spectrometry technology and application on ganglioside study; visualization of age-dependent accumulation of C20-ganglioside molecular species in the mouse hippocampus. PLoS One 3:e3232. doi:10.1371/journal.pone.0003232

    Article  PubMed  Google Scholar 

  • Sugiura Y, Konishi Y, Zaima N, Kajihara S, Nakanishi H, Taguchi R, Setou M (2009) Visualization of the cell-selective distribution of PUFA-containing phosphatidylcholines in mouse brain by imaging mass spectrometry. J Lipid Res (in press)

  • Taira S, Sugiura Y, Moritake S, Shimma S, Ichiyanagi Y, Setou M (2008) Nanoparticle-assisted laser desorption/ionization based mass imaging with cellular resolution. Anal Chem 80:4761–4766. doi:10.1021/ac800081z

    Article  CAS  PubMed  Google Scholar 

  • Touboul D, Brunelle A, Halgand F, De La Porte S, Laprevote O (2005) Lipid imaging by gold cluster time-of-flight secondary ion mass spectrometry: application to Duchenne muscular dystrophy. J Lipid Res 46:1388–1395. doi:10.1194/jlr.M500058-JLR200

    Article  CAS  PubMed  Google Scholar 

  • 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 80:8628–8634

    Article  CAS  PubMed  Google Scholar 

  • van Echten G, Sandhoff K (1993) Ganglioside metabolism. Enzymology, topology, and regulation. J Biol Chem 268:5341–5344

    PubMed  Google Scholar 

  • Wang HY, Jackson SN, Woods AS (2007) Direct MALDI-MS analysis of cardiolipin from rat organs sections. J Am Soc Mass Spectrom 18:567–577. doi:10.1016/j.jasms.2006.10.023

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Cha S, Yeung ES (2007) Colloidal graphite-assisted laser desorption/ionization MS and MS(n) of small molecules. 2. Direct profiling and MS imaging of small metabolites from fruits. Anal Chem 79:6575–6584. doi:10.1021/ac0706170

    Article  CAS  PubMed  Google Scholar 

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Sugiura, Y., Setou, M. Imaging Mass Spectrometry for Visualization of Drug and Endogenous Metabolite Distribution: Toward In Situ Pharmacometabolomes. J Neuroimmune Pharmacol 5, 31–43 (2010). https://doi.org/10.1007/s11481-009-9162-6

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  • DOI: https://doi.org/10.1007/s11481-009-9162-6

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