Mass spectrometry imaging with high resolution in mass and space (HR2 MSI) for reliable investigation of drug compound distributions on the cellular level

AbstractMass 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. FigureMass spectrometry imaging of drug compounds in biological tissue acquired with high resolution in space and mass reveals deep information on biochemical and biomedical mechanisms

[1]  Liam A McDonnell,et al.  Imaging mass spectrometry. , 2007, Mass spectrometry reviews.

[2]  A. Marshall,et al.  Fourier transform ion cyclotron resonance detection: principles and experimental configurations , 2002 .

[3]  Richard A Yost,et al.  Imaging of lipids in spinal cord using intermediate pressure matrix-assisted laser desorption-linear ion trap/Orbitrap MS. , 2009, Analytical chemistry.

[4]  R. Heeren,et al.  Examples of Fourier Transform Ion Cyclotron Resonance Mass Spectrometry Developments: From Ion Physics to Remote Access Biochemical Mass Spectrometry , 2005, European journal of mass spectrometry.

[5]  B. Spengler,et al.  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. , 2010, Rapid communications in mass spectrometry : RCM.

[6]  Alfons Hester,et al.  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. , 2008, Rapid communications in mass spectrometry : RCM.

[7]  E. Bucci,et al.  Matrix-assisted laser desorption ionization imaging mass spectrometry detection of a magnetic resonance imaging contrast agent in mouse liver. , 2009, Analytical Chemistry.

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

[9]  Richard M. Caprioli,et al.  MALDI-FTICR imaging mass spectrometry of drugs and metabolites in tissue. , 2008, Analytical chemistry.

[10]  M. Clench,et al.  Matrix-assisted laser desorption/ionization-ion mobility separation-mass spectrometry imaging of vinblastine in whole body tissue sections. , 2008, Analytical chemistry.

[11]  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.

[12]  Bernhard Spengler,et al.  Scanning microprobe matrix-assisted laser desorption ionization (SMALDI) mass spectrometry: Instrumentation for sub-micrometer resolved LDI and MALDI surface analysis , 2002, Journal of the American Society for Mass Spectrometry.

[13]  J. Wade,et al.  Expression of NHERF-1, NHERF-2, PDGFR-alpha, and PDGFR-beta in normal human kidneys and in renal transplant rejection. , 2002, Pathobiology : journal of immunopathology, molecular and cellular biology.

[14]  A. Woods,et al.  In situ structural characterization of phosphatidylcholines in brain tissue using MALDI-MS/MS , 2005, Journal of the American Society for Mass Spectrometry.

[15]  J. Wade,et al.  Expression of NHERF-1, NHERF-2, PDGFR-α, and PDGFR-β in Normal Human Kidneys and in Renal Transplant Rejection , 2003, Pathobiology.

[16]  M. Stoeckli,et al.  Imaging mass spectrometry: A new technology for the analysis of protein expression in mammalian tissues , 2001, Nature Medicine.

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

[18]  Lingjun Li,et al.  Mass spectral analysis of neuropeptide expression and distribution in the nervous system of the lobster Homarus americanus. , 2010, Journal of proteome research.

[19]  Bernhard Spengler,et al.  Laser spot size and laser power dependence of ion formation in high resolution MALDI imaging , 2010 .

[20]  B. Spengler,et al.  AP-MALDI imaging of neuropeptides in mouse pituitary gland with 5μm spatial resolution and high mass accuracy , 2011 .

[21]  Zoltan Takats,et al.  Histology by mass spectrometry: label-free tissue characterization obtained from high-accuracy bioanalytical imaging. , 2010, Angewandte Chemie.

[22]  Michelle L. Reyzer,et al.  MALDI-MS-based imaging of small molecules and proteins in tissues. , 2007, Current opinion in chemical biology.

[23]  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.

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

[25]  Liam A. McDonnell,et al.  Imaging Mass Spectrometry , 2012 .

[26]  Markus Stoeckli,et al.  Molecular imaging of amyloid beta peptides in mouse brain sections using mass spectrometry. , 2002, Analytical biochemistry.

[27]  A. Makarov,et al.  Orbitrap Mass Analyzer – Overview and Applications in Proteomics , 2006, Proteomics.

[28]  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.

[29]  R. Heeren,et al.  Mass spectrometric imaging for biomedical tissue analysis. , 2010, Chemical reviews.