Facundo M. Fernández

Mass Spectrometry: Recent Advances in Direct Open Air Surface Sampling/Ionization

1. Scope of this Review 2270 2. Ambient Ionization Techniques 2272 2.1. Solid−Liquid Extraction-Based Techniques 2272 2.1.1. Desorption Electrospray Ionization (DESI) 2272 2.1.2. Desorption Ionization by Charge Exchange (DICE) 2277 2.1.3. Easy Ambient Sonic-Spray Ionization (EASI) 2278 2.1.4. Liquid Micro Junction Surface Sampling Probe (LMJ-SSP) 2279 2.1.5. Liquid Extraction Surface Analysis (LESA) 2279 2.1.6. Nanospray Desorption Electrospray Ionization (nanoDESI) 2280 2.1.7. Desorption Atmospheric Pressure Photoionization (DAPPI) 2280 2.2. Plasma-Based Techniques 2281 2.2.1. Direct Analysis in Real Time (DART) 2282 2.2.2. Flowing Atmospheric-Pressure Afterglow (FAPA) 2286 2.2.3. Low Temperature Plasma (LTP) & Dielectric Barrier Discharge Ionization (DBDI) 2286 2.2.4. Chemical Sputtering/Ionization Techniques 2287 2.3. Two-Step Thermal/Mechanical Desorption/ Ablation (Non-Laser) Techniques 2288 2.3.1. Neutral Desorption Extractive Electrospray Ionization (ND-EESI) 2288 2.3.2. Beta Electron-Assisted Direct Chemical Ionization (BADCI) 2288 2.3.3. Atmospheric Pressure Thermal Desorption-Secondary Ionization (AP-TD/SI) 2289 2.3.4. Probe Electrospray Ionization (PESI) 2289 2.4. Two-Step Laser-Based Desorption Ablation Techniques 2290 2.4.1. Laser-Based Hybrid Techniques Coupled to ESI or Plasma Ionization 2290 2.4.2. Laser Electrospray Mass Spectrometry (LEMS) 2292 2.4.3. Laser Ablation Atmospheric Pressure Photoionization (LAAPPI) 2293 2.4.4. Laser Ablation Sample Transfer 2293 2.5. Acoustic Desorption Techniques 2294 2.5.1. Laser-Induced Acoustic Desorption (LIAD) 2294 2.5.2. Radiofrequency Acoustic Desorption Ionization (RADIO) 2295 2.5.3. Surface Acoustic Wave-Based Techniques 2295 2.6. Multimode Techniques 2296 2.6.1. Desorption Electrospray/Metastable-Induced Ionization (DEMI) 2296 2.7. Other Techniques 2296 2.7.1. Rapid Evaporative Ionization Mass Spectrometry (REIMS) 2296 2.7.2. Laser Desorption Ionization (LDI) 2297 2.7.3. Switched Ferroelectric Plasma Ionizer (SwiFerr) 2297 2.7.4. Laserspray Ionization (LSI) 2297 3. Remote Sampling 2298 3.1. Nonproximate Ambient MS 2298 3.2. Fundamentals of Neutral/Ion Transport 2298 3.3. Transport of Neutrals 2298 3.4. Transport of Ions 2299 4. Future Directions 2300 Author Information 2300 Corresponding Author 2300 Author Contributions 2300 Notes 2300 Biographies 2300 Acknowledgments 2301 References 2301

Counterfeit anti-infective drugs

The production of counterfeit or substandard anti-infective drugs is a widespread and under-recognised problem that contributes to morbidity, mortality, and drug resistance, and leads to spurious reporting of resistance and toxicity and loss of confidence in health-care systems. Counterfeit drugs particularly affect the most disadvantaged people in poor countries. Although advances in forensic chemical analysis and simple field tests will enhance drug quality monitoring, improved access to inexpensive genuine medicines, support of drug regulatory authorities, more open reporting, vigorous law enforcement, and more international cooperation with determined political leadership will be essential to counter this threat.

Characterization of Solid Counterfeit Drug Samples by Desorption Electrospray Ionization and Direct- analysis-in-real-time Coupled to Time-of-flight Mass Spectrometry

The search for more versatile, sensitive, and robust ionization methods is a recurring theme in mass spectrometry (MS). Since the discovery of electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI), many developments such as atmospheric pressure MALDI, nanospray ionization, Venturi-assisted electrospray, and ion-funnel atmospheric pressure interfaces, have paved the way to improved characterization of small molecules and biomolecules. One of the bottlenecks in achieving high sample throughput with both ESI and MALDI is the need to dissolve, extract, and/or filter the sample prior to analysis. Moreover, vacuum-incompatible materials cannot be easily investigated by MS without disturbing their innate structure. Recently, two novel methods for the direct ionization of solid samples under atmospheric pressure by MS were reported: desorption electrospray ionization (DESI) and direct analysis in real time (DART). More recently, McEwen et al. described a modified atmospheric pressure chemical ionization (APCI) technique for the direct analysis of solids which they named atmospheric pressure solids analysis probe (ASAP). DESI makes use of a high-speed liquid spray directed at a sample held or deposited on a surface at atmospheric pressure. Ions generated during this process are sampled by a mass spectrometer. Several DESI applications such as the mapping of analytes separated by thin-layer chromatography, the detection of explosives, and the screening of pharmaceutical tablets and illicit drugs quickly followed the proof-of-principle description of the method. DART involves an ionizing beam of metastable He atoms (S1, 19.8 eV) generated by a corona discharge. The DART ionization mechanism is still not completely understood. In negative ion mode, the metastable He atoms generate electrons that produce negatively charged oxygen–water clusters, which then form the corresponding adducts. In positive ion mode, metastable He atoms generate protonated gaseous water clusters by Penning ionization. Then, by proton exchange, these clusters form [M+H] ions, which are generally the predominant species. DART’s high throughput coupled with the high mass accuracy now attainable with modern time-of-flight mass (TOF) analyzers and accurate isotopic abundance measurements make it especially suitable for the rapid identification of unknown species in solid materials. One particularly relevant example is counterfeit drug samples. Counterfeit drugs are defined as those that are “deliberately and fraudulently mislabeled with respect to identity and/or source”. They may include products with the “wrong” ingredient(s), without active ingredient(s), or with an insufficient amount of active ingredient(s). In recent years, a particularly alarming case of drug counterfeiting has been reported by field researchers who have detected counterfeit products that mimic the vital antimalarial, artesunate. The consumption of fake antimalarials has resulted in the death of many patients. Evidence suggests that the production of counterfeit artesunate tablets is on an industrial scale. For example, one health care organization in southeast Asia unwittingly purchased 100,000 artesunate tablets which were later shown to be counterfeit. Classic hyphenated analysis methods, such as liquid chromatography–mass spectrometry (LC–MS), lack the required sample throughput to survey such large numbers of samples in a reasonable amount of time. Figure 1a shows a schematic of the DART TOF MS setup used to screen 52 representative samples of a database containing more than 400 artesunate-based antimalarial tablets. Figure 1b and 1c show the negative ion mode DART TOF MS data of genuine and counterfeit artesunate (M) tablets, respectively. The spectrum shown in Figure 1b has signals corresponding to the diagnostic [M H] artesunate anion (experimental m/z=383.1702, calculated m/z=383.1711) and palmitic acid, a ubiquitous contaminant. Artesunate fragment ions due to dissociation of the highly labile artesunate carboxylic acid side [a] Prof. Dr. F. M. Fern ndez, C. Y. Hampton School of Chemistry and Biochemistry Georgia Institute of Technology 770 State St. Atlanta, GA 30332 (USA) Fax: (+1)404-385-6447 E-mail : facundo.fernandez@chemistry.gatech.edu [b] Dr. R. B. Cody JEOL USA, Inc. 11 Dearborn Road, Peabody, MA 01960 (USA) [c] Dr. M. D. Green Division of Parasitic Diseases, National Center for Infectious Diseases Center for Disease Control and Prevention 1600 Clifton Road, Mailstop F12, Atlanta, GA 30333 (USA) [d] Dr. R. McGready Shoklo Malaria Research Unit Mae Sot Tak (Thailand) [e] Dr. S. Sengaloundeth Food and Drug Department Ministry of Health, Government of the Lao PDR Vientiane (Lao PDR) [f] Prof. N. J. White, Dr. P. N. Newton Microbiology Laboratory, Mahosot Hospital Wellcome Trust–Mahosot Hospital–Oxford Tropical Medicine Research Collaboration, Vientiane (Lao PDR) and Centre for Clinical Vaccinology and Tropical Medicine Churchill Hospital, Oxford University, Oxford, OX37LJ (UK) [] Prof. White is also affiliated with: Wellcome Trust–Mahidol University–Oxford Tropical Medicine Research Programme, Faculty of Tropical Medicine Mahidol University, Bangkok, 10400 (Thailand)

Desorption electrospray ionization mass spectrometry reveals surface-mediated antifungal chemical defense of a tropical seaweed

Organism surfaces represent signaling sites for attraction of allies and defense against enemies. However, our understanding of these signals has been impeded by methodological limitations that have precluded direct fine-scale evaluation of compounds on native surfaces. Here, we asked whether natural products from the red macroalga Callophycus serratus act in surface-mediated defense against pathogenic microbes. Bromophycolides and callophycoic acids from algal extracts inhibited growth of Lindra thalassiae, a marine fungal pathogen, and represent the largest group of algal antifungal chemical defenses reported to date. Desorption electrospray ionization mass spectrometry (DESI-MS) imaging revealed that surface-associated bromophycolides were found exclusively in association with distinct surface patches at concentrations sufficient for fungal inhibition; DESI-MS also indicated the presence of bromophycolides within internal algal tissue. This is among the first examples of natural product imaging on biological surfaces, suggesting the importance of secondary metabolites in localized ecological interactions, and illustrating the potential of DESI-MS in understanding chemically-mediated biological processes.

Manslaughter by fake artesunate in Asia - will Africa be next?

Fake artesunate could compromise the hope that artemisinin-based combination therapy offers for malaria control in Africa and Asia.

Impact of poor-quality medicines in the ‘developing’ world

Since our ancestors began trading several millennia ago, counterfeit and substandard medicines have been a recurring problem, with history punctuated by crises in the supply of anti-microbials, such as fake cinchona bark in the 1600s and fake quinine in the 1800s. Unfortunately this problem persists, in particular afflicting unsuspecting patients in ‘developing’ countries. Poor-quality drugs are a vital (but neglected) public health problem. They contribute to a ‘crevasse’ between the enormous effort in therapeutic research and policy decisions and implementation of good-quality medicines.

Ambient generation of fatty acid methyl ester ions from bacterial whole cells by direct analysis in real time (DART) mass spectrometry

Direct analysis in real time (DART) is implemented on a time-of-flight (TOF) mass spectrometer, and used for the generation of fatty acid methyl esters (FAMEs) ions from whole bacterial cells.

Optimization of a direct analysis in real time/time-of-flight mass spectrometry method for rapid serum metabolomic fingerprinting

Metabolomic fingerprinting of bodily fluids can reveal the underlying causes of metabolic disorders associated with many diseases, and has thus been recognized as a potential tool for disease diagnosis and prognosis following therapy. Here we report a rapid approach in which direct analysis in real time (DART) coupled with time-of-flight (TOF) mass spectrometry (MS) and hybrid quadrupole TOF (Q-TOF) MS is used as a means for metabolomic fingerprinting of human serum. In this approach, serum samples are first treated to precipitate proteins, and the volatility of the remaining metabolites increased by derivatization, followed by DART MS analysis. Maximum DART MS performance was obtained by optimizing instrumental parameters such as ionizing gas temperature and flow rate for the analysis of identical aliquots of a healthy human serum samples. These variables were observed to have a significant effect on the overall mass range of the metabolites detected as well as the signal-to-noise ratios in DART mass spectra. Each DART run requires only 1.2 min, during which more than 1500 different spectral features are observed in a time-dependent fashion. A repeatability of 4.1% to 4.5% was obtained for the total ion signal using a manual sampling arm. With the appealing features of high-throughput, lack of memory effects, and simplicity, DART MS has shown potential to become an invaluable tool for metabolomic fingerprinting.

Guidelines for Field Surveys of the Quality of Medicines: A Proposal

Paul Newton and colleagues propose guidelines for conducting and reporting field surveys of the quality of medicines.

Simulations and Experimental Investigation of Atmospheric Transport in an Ambient Metastable-Induced Chemical Ionization Source

Since its inception, Direct Analysis in Real Time (DART) has seen utility in a wide range of applications including chemical reaction monitoring, pharmaceutical screening, and forensic mass spectrometry. Despite the growing interest in DART applications, there has been limited research into the fundamental physiochemical phenomena affecting sampling, ionization, and atmospheric ion transport. Presented here are the first experimentally validated finite element method simulations of an ambient DART-type metastable-induced chemical ionization source. It was found that complex coupled fluid dynamics, heat transfer, and electrostatic phenomena within the sampling region determine the variability in ion transmission efficiencies affecting the overall sensitivity of analysis. Particle tracing plots of a circular acetaminophen tablet placed in various positions and orientations yielded insight into optimal sample placement and evidence for sweet spots conducive to better ion transport. Experiments in a wide range of electric field conditions were performed, finding that under optimum sample placement, sensitivity could be improved by as much as 128% if ion mobility contributions were minimized.