MALDI imaging mass spectrometry: bridging biology and chemistry in drug development.

Our understanding of drug tissue distribution impacts a number of areas in drug development, including: pharmacology, pharmacokinetics, safety, drug-drug interactions, transport and metabolism. Despite their extensive use, autoradiography and tissue homogenate LC-MS analysis have limitations in providing a comprehensive assessment of tissue distributions. In the case of autoradiography, it is the inability to distinguish between parent drug and drug metabolites. In LC-MS analysis of tissue homogenate, all tissue localization information is lost. The emerging technique of MALDI imaging mass spectrometry has the capability to distinguish between parent and metabolites while maintaining spatial distribution in tissues. In this article, we will review the MALDI imaging MS methodology as applied to drug development and provide examples highlighting the impact of this important technique in drug development.

[1]  L. Zhigilei,et al.  Molecular dynamics simulations of MALDI: laser fluence and pulse width dependence of plume characteristics and consequences for matrix and analyte ionization. , 2010, Journal of mass spectrometry : JMS.

[2]  R. Caprioli,et al.  Profiling and imaging of tissues by imaging ion mobility-mass spectrometry. , 2007, Journal of mass spectrometry : JMS.

[3]  W. Stumpf.  Drug localization and targeting with receptor microscopic autoradiography. , 2005, Journal of pharmacological and toxicological methods.

[4]  Tyler Greer,et al.  Mass spectrometry imaging for drugs and metabolites. , 2011, Journal of proteomics.

[5]  A. Bristow.  Accurate mass measurement for the determination of elemental formula--a tutorial. , 2006, Mass spectrometry reviews.

[6]  R. Caprioli,et al.  MALDI Imaging Mass Spectrometry – Painting Molecular Pictures , 2010, Molecular oncology.

[7]  P. Chaurand,et al.  From Whole-body Sections Down to Cellular Level, Multiscale Imaging of Phospholipids by MALDI Mass Spectrometry* , 2010, Molecular & Cellular Proteomics.

[8]  Richard M Caprioli,et al.  Instrument design and characterization for high resolution MALDI-MS imaging of tissue sections. , 2007, Journal of mass spectrometry : JMS.

[9]  R. Knochenmuss.  Photoionization pathways and free electrons in UV-MALDI. , 2004, Analytical chemistry.

[10]  Walter A. Korfmacher,et al.  Direct analysis of drug candidates in tissue by matrix-assisted laser desorption/ionization mass spectrometry. , 2003, Journal of mass spectrometry : JMS.

[11]  U. Kubitscheck,et al.  Localization of analyte molecules in MALDI preparations by confocal laser scanning microscopy. , 2001, Analytical chemistry.

[12]  J. Vickerman.  Molecular imaging and depth profiling by mass spectrometry--SIMS, MALDI or DESI? , 2011, The Analyst.

[13]  Alain Schweitzer,et al.  Autoradiography, MALDI-MS, and SIMS-MS Imaging in Pharmaceutical Discovery and Development , 2010, The AAPS Journal.

[14]  A. Monro.  Interspecies comparisons in toxicology: the utility and futility of plasma concentrations of the test substance. , 1990, Regulatory toxicology and pharmacology : RTP.

[15]  A. Marshall,et al.  Fourier transform ion cyclotron resonance mass spectrometry: a primer. , 1998, Mass spectrometry reviews.

[16]  R. Caprioli,et al.  Direct molecular analysis of whole-body animal tissue sections by imaging MALDI mass spectrometry. , 2006, Analytical chemistry.

[17]  R. Heeren,et al.  A concise review of mass spectrometry imaging. , 2010, Journal of chromatography. A.

[18]  B. Döme,et al.  Drug localization in different lung cancer phenotypes by MALDI mass spectrometry imaging. , 2011, Journal of proteomics.

[19]  A. Baulard,et al.  MALDI imaging techniques dedicated to drug-distribution studies. , 2011, Bioanalysis.

[20]  Jonathan Stauber,et al.  Imaging mass spectrometry: Hype or hope? , 2009, Journal of the American Society for Mass Spectrometry.

[21]  A. Pitt,et al.  Mass spectrometry imaging of pharmacological compounds in tissue sections. , 2010, Bioanalysis.

[22]  S. Rauser,et al.  Normalization in MALDI-TOF imaging datasets of proteins: practical considerations , 2011, Analytical and bioanalytical chemistry.

[23]  Zoltan Takats,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 , 2011, Analytical and bioanalytical chemistry.

[24]  Brendan Prideaux,et al.  High-sensitivity MALDI-MRM-MS imaging of moxifloxacin distribution in tuberculosis-infected rabbit lungs and granulomatous lesions. , 2011, Analytical chemistry.

[25]  R Zenobi,et al.  MALDI ionization: the role of in-plume processes. , 2003, Chemical reviews.

[26]  Nari Talaty,et al.  A quantitation method for mass spectrometry imaging. , 2011, Rapid communications in mass spectrometry : RCM.

[27]  Richard M Caprioli,et al.  Automated acoustic matrix deposition for MALDI sample preparation. , 2006, Analytical chemistry.

[28]  Martin Strohalm,et al.  Molecular mass spectrometry imaging in biomedical and life science research , 2010, Histochemistry and Cell Biology.

[29]  Donglu Zhang,et al.  Mass defect filter technique and its applications to drug metabolite identification by high-resolution mass spectrometry. , 2009, Journal of mass spectrometry : JMS.

[30]  R. Murphy,et al.  Sublimation as a method of matrix application for mass spectrometric imaging , 2007, Journal of the American Society for Mass Spectrometry.

[31]  Hyunjin Shin,et al.  Comparison of normalization methods for the identification of biomarkers using MALDI-TOF and SELDI-TOF mass spectra. , 2010, Omics : a journal of integrative biology.

[32]  I. Fournier,et al.  Direct analysis and MALDI imaging of formalin-fixed, paraffin-embedded tissue sections. , 2007, Journal of proteome research.

[33]  J. Sweedler,et al.  A mass spectrometry primer for mass spectrometry imaging. , 2010, Methods in molecular biology.

[34]  O. Cars,et al.  Tissue concentrations: do we ever learn? , 2007, The Journal of antimicrobial chemotherapy.

[35]  Prabha Dwivedi,et al.  Ion mobility-mass spectrometry. , 2008, Journal of mass spectrometry : JMS.

[36]  M. Stoeckli,et al.  Compound and metabolite distribution measured by MALDI mass spectrometric imaging in whole-body tissue sections , 2007 .

[37]  K. Ulbrich,et al.  Poly[N-(2-hydroxypropyl)methacrylamide]-based tissue-embedding medium compatible with MALDI mass spectrometry imaging experiments. , 2011, Analytical chemistry.

[38]  R. Cooks,et al.  Orbitrap mass spectrometry: instrumentation, ion motion and applications. , 2008, Mass spectrometry reviews.

[39]  R. Murphy,et al.  MALDI imaging of lipids after matrix sublimation/deposition. , 2011, Biochimica et biophysica acta.

[40]  A. Makarov,et al.  The Orbitrap: a new mass spectrometer. , 2005, Journal of mass spectrometry : JMS.

[41]  R. Knochenmuss.  Ion formation mechanisms in UV-MALDI. , 2006, The Analyst.

[42]  O. Langer,et al.  Methods to assess tissue-specific distribution and metabolism of drugs. , 2004, Current drug metabolism.

[43]  M. Stoeckli,et al.  Matrix-assisted laser desorption/ionization mass spectrometric imaging of complete rat sections using a triple quadrupole linear ion trap. , 2009, Rapid communications in mass spectrometry : RCM.

[44]  Marcel J. T. Reinders,et al.  Comparison of normalisation methods for surface-enhanced laser desorption and ionisation (SELDI) time-of-flight (TOF) mass spectrometry data , 2008, BMC Bioinformatics.

[45]  Pierre P Massion,et al.  High‐throughput proteomic analysis of formalin‐fixed paraffin‐embedded tissue microarrays using MALDI imaging mass spectrometry , 2008, Proteomics.

[46]  Richard M Caprioli,et al.  MALDI imaging mass spectrometry of human tissue: method challenges and clinical perspectives. , 2011, Trends in biotechnology.

[47]  Klaus Dreisewerd,et al.  The desorption process in MALDI. , 2003, Chemical reviews.

[48]  Amina S Woods,et al.  The application and potential of ion mobility mass spectrometry in imaging MS with a focus on lipids. , 2010, Methods in molecular biology.

[49]  David C Muddiman,et al.  Mass spectrometry-based biomarker discovery: toward a global proteome index of individuality. , 2009, Annual review of analytical chemistry.

[50]  Lanao Jm,et al.  Drug tissue distribution: study methods and therapeutic implications. , 2005 .

[51]  H. Shion,et al.  Distribution of chloroquine in ocular tissue of pigmented rat using matrix-assisted laser desorption/ionization imaging quadrupole time-of-flight tandem mass spectrometry. , 2011, Rapid communications in mass spectrometry : RCM.

[52]  A. Svatoš.  Mass spectrometric imaging of small molecules. , 2010, Trends in biotechnology.

[53]  E. Solon.  Autoradiography: high-resolution molecular imaging in pharmaceutical discovery and development , 2007, Expert opinion on drug discovery.

[54]  M. Pellegatti,et al.  Drug and metabolite concentrations in tissues in relationship to tissue adverse findings: a review , 2011, Expert opinion on drug metabolism & toxicology.

[55]  Kristina Schwamborn,et al.  Molecular imaging by mass spectrometry — looking beyond classical histology , 2010, Nature Reviews Cancer.

[56]  M. Karas,et al.  Compelling Evidence for Lucky Survivor and Gas Phase Protonation: The Unified MALDI Analyte Protonation Mechanism , 2011, Journal of the American Society for Mass Spectrometry.

[57]  Joseph L. Cantone,et al.  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. , 2007, Journal of pharmacological and toxicological methods.

[58]  Mitsutoshi Setou,et al.  Imaging Mass Spectrometry for Visualization of Drug and Endogenous Metabolite Distribution: Toward In Situ Pharmacometabolomes , 2010, Journal of Neuroimmune Pharmacology.

[59]  Donglu Zhang,et al.  Mass defect profiles of biological matrices and the general applicability of mass defect filtering for metabolite detection. , 2008, Rapid communications in mass spectrometry : RCM.

[60]  P. Chaurand,et al.  Profiling and imaging proteins in tissue sections by MS. , 2004, Analytical chemistry.

[61]  Larissa S Fenn,et al.  Structurally selective imaging mass spectrometry by imaging ion mobility-mass spectrometry. , 2010, Methods in molecular biology.

[62]  D. M. Ryan,et al.  The use of antibiotic serum levels to predict concentrations in tissues. , 1986, Scandinavian journal of infectious diseases.

[63]  J. Sweedler,et al.  MALDI-MS imaging of features smaller than the size of the laser beam , 2005, Journal of the American Society for Mass Spectrometry.