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Advances in Ionization for Mass Spectrometry † ‡ ‡ Patricia M Review pubs.acs.org/ac Advances in Ionization for Mass Spectrometry † ‡ ‡ Patricia M. Peacock, Wen-Jing Zhang, and Sarah Trimpin*, † First State IR, LLC, 118 Susan Drive, Hockessin, Delaware 19707, United States ‡ Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, United States ■ CONTENTS ■ EMERGING DEVELOPMENTS RELATED TO NEWER IONIZATION TECHNOLOGIES Scope 372 Emerging Developments Related to Newer Ioniza- A relatively new means of transferring small, large, volatile, and tion Technologies 372 nonvolatile compounds from the solid or solution state directly Electrospray-Based Ambient Ionization 375 into the gas phase as ions, falling under the general term inlet Discharge-Based Ambient Ionization 377 ionization and individually termed matrix-assisted ionization Traditional Ionization Methods for MS 381 (MAI), solvent-assisted ionization (SAI), or laserspray Technologies Using a Laser for Ionization 381 ionization inlet (LSI) if a laser is used, continues to be API Ionization 383 developed as a sensitive and robust ionization method in MS. Author Information 384 In MAI, specific small molecule matrix compounds have been Corresponding Author 384 discovered which require only exposure to subatmospheric ORCID 384 pressure conditions, by default available with all mass Notes 384 spectrometers, to produce gas-phase ions of peptides, proteins, Biographies 384 lipids, synthetic polymers, and carbohydrates for analysis by Acknowledgments 385 MS.16 Some MAI matrixes produce abundant ions without the References 385 need to apply thermal energy. Out of over 40 such matrixes, the top 10 have been categorized for positive and negative mode measurements. These matrixes sublime when placed under subatmospheric pressure so that, similar to solvents, they are pumped from the mass spectrometer eliminating matrix contamination.17 Several studies related to MAI were published in this period ■ SCOPE by Trimpin and collaborators. MAI was used with MS/MS Integral to advances in mass spectrometry (MS) are develop- including electron transfer dissociation (ETD) by Marshall and ments in ionization technology, which is constantly evolving co-workers to characterize components in tissue and labile 18 because of advances in fundamental understanding, enhance- posttranslationally modified peptides. They also observed a ments in instrumentation and optimization, and the evolution membrane-associated protein directly from nonsprayable of novel techniques for ionizing analytes of interest. With the electrospray ionization (ESI) solution. Fischer et al. reported rapid, almost continual emergence of new developments, that a Europium-PEG complex, potential magnetic resonance staying up-to-date can be a significant challenge. This review, imaging (MRI) contrast agents, difficult to observe using ESI or therefore, is intended to provide a concise summary of matrix-assisted laser desorption/ionization (MALDI), was advancements in MS ionization from January 2015 through readily observed by MAI because the complex ionized Downloaded via UNIV DEGLI STUDI DI TORINO on November 11, 2020 at 18:52:45 (UTC). September 2016. There are a number of helpful review articles especially well in MAI using 1,2-dicyanobenzene as matrix See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. and book chapters on specific aspects of ionization that have but not the other components in the mixture.19 The multiply been published in the last 2 years, which will not be covered charged ions separate better in the ion mobility spectrometry − here.1 15 The reader is encouraged to consult them for further (IMS) gas-phase separation than singly charged ions. study. Because of overlaps with recent reviews on the topics Chakrabarty et al. demonstrated quantification of illicit drugs “imaging” and “SIMS”, respectively, these areas are not covered using MAI with internal standards on two different in this review if the focus was not specifically on the manufacturers’ mass spectrometers and obtained quantification improvements surrounding an ionization method. The authors similar to that obtained on the same instruments using ESI.20 of this review have attempted to be as comprehensive as Drugs were detected and quantified directly from tissue possible on new developments in terms of fundamentals, samples with excellent sensitivity by Wang and co-workers instrumentation, and key applications, and any omission of using MAI and SAI.21 High throughput analyses were papers from the literature on MS ionization is unintentional. It demonstrated by Woodall et al. with the MAI method using should be noted that searching for key novelties on “ionization” various different samples holders.22 Lu et al. demonstrated low using “mass spectrometry” is ultimately difficult because these two search terms are intrinsic to nearly every paper published Special Issue: Fundamental and Applied Reviews in Analytical on MS. Therefore, searches have also included names, Chemistry 2017 technologies, or methods surrounding well established groups and newcomers to the field. Published: November 15, 2016 © 2016 American Chemical Society 372 DOI: 10.1021/acs.analchem.6b04348 Anal. Chem. 2017, 89, 372−388 Analytical Chemistry Review femtomole sensitivity for peptides and drugs using a (MAIV) with a MALDI-LTQ-Orbitrap XL, a high-resolution, customized probe to insert a MAI matrix (3-nitrobenzonitrile accurate mass instrument.24 The softness of MAI ionization (3-NBN))−analyte (Figure 1) into the intermediate pressure allowed labile post-translational modification (PTM) analysis as well as extended mass range of protein detection due to multiple charging. MAI also yielded more information-rich MS/ MS spectra. The sensitivity of MAI was demonstrated by Hoang et al. using a 1 μL syringe method on a Thermo Q- Exactive mass spectrometer. Only ∼5 fmol in 50 nL of analyte solution produced a clean mass spectrum of angiotensin I (Figure 2) using the syringe method developed by MSTM. The Figure 2. Matrix-assisted ionization (MAI) mass spectrometry from a few femtomoles of the peptide angiotensin I acquired on an Orbitrap Q-Exactive using the MSTM platform which is shown in the inset as a scheme. Abundant multiply charged ions are observe even at this low amount of sample used in the analysis. Springer Journal of the American Figure 1. (A) Scheme of the modified vacuum housing to perform Society for Mass Spectrometry, High Sensitivity Analysis of Nanoliter MAI: (1) probe, (2) vacuum lock, (3) flange, (4) gas control valve, (5) Volumes of Volatile and Nonvolatile Compounds using Matrix commercial inlet cap, and (6) hexapole housing. (B) A solution Assisted Ionization (MAI) Mass Spectrometry, 27, 2016, 1591, containing a mixture of leucine enkephalin (MW 555.3), angiotensin I Hoang, K.; Pophristic, M.; Horan, A. J.; Johnston, M. V.; McEwen, C. (MW1295.6), and ubiquitin (MW 8559) with 6 pmol each and N., (original copyright notice as given in the publication in which the combined with 3-NBN solution, applied to the probe, and dried before material was originally published). With permission of Springer. insertion into the vacuum housing. Mass spectra and insets of the duration (in minutes) based on the total ion chronogram of ion formation/detection: (1) 1st acquisition, (2) 4th acquisition in which drug azithromycin was detected in urine diluted 5× with water − fi only 3-NBN matrix solution (9:1 ACN H2O) was added to the probe 12 days after the nal dose was administered. Interestingly, successively suggesting that little analyte is lost during sublimation, neither sodium nor potassium adducts are observed in the salty ubiquitin remains on the probe surface after exposure to high urine sample which underwent no cleanup.25 Chubatyi and acetonitrile matrix solution and after cleaning the probe surface no McEwen reported that for basic compounds, adding contamination from analyte is observed. Reproduced from Simplifying ammonium salts to the MAI matrix solutions significantly the ion source for mass spectrometry, Lu, I. C.; Pophristic, M.; Inutan, increased the analyte ion abundance or lowered chemical E. D.; McKay, R. G.; McEwen, C. N. Rapid Commun. Mass Spectrom. Vol. 30, Issue 23 (ref 23), 2568. Copyright 2016 Wiley. background or both. Addition of ammonium salts also suppressed ionization of compounds without basic function- ality.26 MAI was used by McLaughlin and co-workers as a MALDI housing of a Waters SYNAPT G2 mass spectrometer means to ionizing 2-methoxydiphenidine (MXP) directly from but without the laser, ion extraction lens, or hexapole ion the surface of a tablet.27 guide.23 The authors demonstrated that by placing matrix− An interesting use of the 3-NBN matrix was reported by analyte solution on the probe and drying before inserting into Santos and coauthors in Eberlin’s group.28 These authors added the ionization chamber, analyte ions were spontaneously 10 μgmL−1 of 3-NBN as a dopant to the solvent used with easy produced in good abundance for over 8 min before the matrix ambient sonic-spray ionization (EASI) and achieved a 2 to 4- was depleted by sublimation. Interestingly, just loading matrix fold gain in total ion current and signal-to-noise for the analyte. solution onto the probe thereafter produced nearly equal The sensitivity of DESI was also improved with the 3-NBN abundant analyte ions even repeating the ionization and loading dopant in the tested vegetable oil sample. Interestingly, with 3- several times without adding analyte. NBN EASI and DESI
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