Ambient Ionization Mass Spectrometry for Point-of

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Oct 14, 2015 - Ambient ionization mass spectrometry (MS) allows direct chemical ...... continued until a handheld mass spectrometer was cre- ated (52, 53 ).
Papers in Press. Published October 14, 2015 as doi:10.1373/clinchem.2014.237164 The latest version is at http://hwmaint.clinchem.org/cgi/doi/10.1373/clinchem.2014.237164

Reviews

Clinical Chemistry 62:1 000 – 000 (2016)

Ambient Ionization Mass Spectrometry for Point-ofCare Diagnostics and Other Clinical Measurements Christina R. Ferreira,1 Karen E. Yannell,1 Alan K. Jarmusch,1 Valentina Pirro,1 Zheng Ouyang,1,2 and R. Graham Cooks1*

BACKGROUND: One driving motivation in the development of point-of-care (POC) diagnostics is to conveniently and immediately provide information upon which healthcare decisions can be based, while the patient is on site. Ambient ionization mass spectrometry (MS) allows direct chemical analysis of unmodified and complex biological samples. This suite of ionization techniques was introduced a decade ago and now includes a number of techniques, all seeking to minimize or eliminate sample preparation. Such approaches provide new opportunities for POC diagnostics and rapid measurements of exogenous and endogenous molecules (e.g., drugs, proteins, hormones) in small volumes of biological samples, especially when coupled with miniature mass spectrometers. CONTENT: Ambient MS-based techniques are applied in diverse fields such as forensics, pharmaceutical development, reaction monitoring, and food analysis. Clinical applications of ambient MS are at an early stage but show promise for POC diagnostics. This review provides a brief overview of various ambient ionization techniques providing background, examples of applications, and the current state of translation to clinical practice. The primary focus is on paper spray (PS) ionization, which allows quantification of analytes in complex biofluids. Current developments in the miniaturization of mass spectrometers are discussed. SUMMARY: Ambient ionization MS is an emerging technology in analytical and clinical chemistry. With appropriate MS instrumentation and user-friendly interfaces for automated analysis, ambient ionization techniques can provide quantitative POC measurements. Most significantly, the implementation of PS could improve the quality and lower the cost of POC testing in a variety of clinical settings.

© 2015 American Association for Clinical Chemistry

According to the American Clinical Laboratory. Association, over 7 billion laboratory tests are performed annually in the US. Nevertheless, the current emphasis is shifting toward point-of-care (POC)3 testing in nonlaboratory settings (e.g., clinician’s office, ambulance, in situ), to empower clinicians in making fast decisions, simplify healthcare delivery, and address challenges on health disparities (1 ). Laboratory tests are often performed on blood and urine samples and employ immunoassays or colorimetric screening (2 ) that can also be used for on-site testing. Profiling and quantification of biomolecules and synthetic drugs are best done by mass spectrometry (MS), usually hyphenated with chromatographic separation techniques [e.g., liquid chromatography (LC)]. In spite of the expense and complexity of the instrumentation and the extensive sample pretreatment required before analysis, the enormous diversity of molecules detectable from complex biological samples—ranging from small synthetic drugs to intact proteins and viruses—justifies the key role that MS-based techniques play in clinical laboratory testing (3 ). Hyphenated MS methods provide high throughput, great versatility, selectivity, accuracy, and precision in analytical measurements as well as multiplexing capabilities. These features often greatly exceed those of immunoassays. However, the expense and complexity of the instrumentation and analytical protocols make the translation of current hyphenated MS techniques into POC testing unlikely. This is because the requirements are very different from those of laboratory testing, especially in (a) the limited time for sample preparation, which precludes extraction, preconcentration, and reconstitution processes, (b) the individualized nature of the measurements, for which the analytical measurements are specific to a particular patient and dispersed instruments are operated at low efficiency even if they are capable of high throughput when used in a batch mode (e.g., LC-MS/MS), (c) the physical size limitations,

1

Department of Chemistry and Center for Analytical Instrumentation Development (CAID), Purdue University, West Lafayette, IN; 2 Weldon School of Biomedical Engineering and Department of Electrical and Computer Engineering, Purdue University, West Lafayette, IN. * Address correspondence to this author at: Department of Chemistry and Center for Analytical Instrumentation Development (CAID), Purdue University, 560 Oval Dr., West Lafayette, IN 47907. Fax 1 765 494-9421; e-mail [email protected]. Received June 17, 2015; accepted August 14, 2015. Previously published online at DOI: 10.1373/clinchem.2014.237164

3

Nonstandard abbreviations: POC, point-of-care; MS, mass spectrometry; LC, liquid chromatography; PS, paper spray; DESI, desorption electrospray ionization; DBS, dried blood spots; MRM, multiple reaction monitoring; DOPA, dihydroxyphenylalanine; DART, direct analysis in real time; APTDCI, atmospheric pressure thermal desorption chemical ionization; LTP, low temperature plasma; SPE, solid phase extraction; Chol, cholesterol; BA, betaine aldehyde; FDA, Food and Drug Administration.

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Copyright (C) 2015 by The American Association for Clinical Chemistry

Reviews and (d) the need for analytical simplicity and automation. New developments in ambient ionization techniques and MS miniaturization (4 ) present an opportunity for translation of MS technology to POC testing (5 ). The term ambient ionization refers to a group of ionization techniques that produce gas-phase ions in the open air, removing chromatographic separation and minimizing prior sample preparation. Such ionization techniques promote straightforward sample introduction and analysis that emphasize simplicity, low cost, and speed (6 ). This review begins with a brief overview of ambient ionization techniques. The clinical implementation and potential of ambient ionization is illustrated by focusing on paper spray (PS) ionization, highlighting the ability to perform quantitative analysis of small molecules in minute volumes of biofluids. We discuss the capability of performing reactive ambient ionization, i.e., chemical derivatization during ionization, to improve chemical specificity and sensitivity. Furthermore, the current state of miniature MS development is described, because it is a fundamental element of an ambient MS-based POC system. Finally, some challenges and future directions in further developing ambient MS for POC applications are discussed. Ambient Ionization MS Ambient ionization was introduced over a decade ago with desorption electrospray ionization (DESI) (7 ). Since then, a number of ambient techniques have been developed that differ in ionization method (e.g., spraybased, plasmabased, laserbased) and in the degree to which desorption and ionization are coupled (8 ), but they all share the capability of generating gas-phase ions directly from untreated samples, greatly reducing or eliminating analyte extraction and prior separation (9 ). Simplicity and rapid analysis are emphasized as characteristics of the ambient techniques (scores of which have been reported, as shown in Table 1 in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/content/vol62/issue1), which make them well suited in POC applications. They all use the sensitivity and specificity of MS, and rely on mass-tocharge ratios and/or fragmentation to acquire information on individual components of mixtures. Extensive literature exists on qualitative and quantitative analysis of endogenous biomolecules and on therapeutic and illicit drugs, performed in both a targeted and untargeted fashion. A selection of techniques with potential for use in POC applications is listed in Table 1, with some details regarding target analytes, biological matrix, and analytical methodology. Briefly, DESI generates ions via direct desorption and ionization using charged solvent droplets that impact a sample surface. Tissue analysis by DESI-MS, particu2

Clinical Chemistry 62:1 (2016)

larly DESI imaging, can provide exogenous drug and/or drug metabolite distributions (10 ). It also provides diagnostic information on human brain cancers (11 ) and delineates tumor margins in brain, kidney, and liver via detection of altered lipid profiles that reflect the structural composition of cellular membranes. Moving toward POC diagnostics, DESI has been shown to have a potential application in screening of inborn errors of metabolism (12 ) and therapeutic drug monitoring (10, 13 ) by means of direct detection of free amino acids and drugs in dried blood spots (DBS), respectively. In the DBS study, the DESI sprayer was moved laterally to rapidly scan the DBS spots and detect target analytes in the multiple reaction monitoring (MRM) mode. In these early applications, ion suppression due to matrix effects was highlighted as the biggest analytical challenge for direct surface analysis of DBS by ambient MS (10, 13 ). The selection of the solvent system for the DESI spray allows targeting of the method toward specific analytes, while other parameters like pneumatic pressure (e.g., nitrogen) and geometry of the spray affect the efficiency of the desorption/ionization process and the spatial resolution in the case of DESI imaging experiments (14 ). More recently, DESI has been used for therapeutic monitoring of salicylic acid using a 3-layer DBS paper card. In this experiment, blood (6 ␮L) was applied on a card yielding DBS with an average diameter of 9 mm that was analyzed by DESI-MS (15 ). A linear response was achieved over the concentration range 10 –2000 mg/L, with relative SDs ⬍14% and a limit of quantification of 10 mg/L (15 ). In another experiment, nanospray desorption electrospray ionization was reported for chiral analysis (by the kinetic method) of ibuprofen, dihydroxyphenylalanine (DOPA), and ephedrine in DBS (13 ). Direct analysis in real time (DART) has been applied to DBS for newborn screening of phenylketonuria (16 ) and to conduct pharmacokinetic/toxicokinetic studies without additional manipulation of the samples (17 ). In DART, a discharge occurs far from the sample surface, and a stream of heated gas is used to carry the active species toward the sample. During transit, metastable helium atoms originating in the plasma react with ambient water, oxygen, or other atmospheric components to produce the reactive ions (6 ). Laser diode thermal desorption–atmospheric pressure chemical ionization has been used to quantify metformin and sitagliptin in mouse and human DBS (18 ). An atmospheric pressure thermal desorption chemical ionization (APTDCI) interface has been described for profiling of free carnitine, acylcarnitines, and sterols in dried blood and plasma spots (19 ). The mechanism of APTDCI involves analyte desorption due to the nitrogen flow, and then analyte gas-phase ionization by APCI from a corona discharge. A liquid microjunction surface sampling probe has also been applied to DBS samples

Propranolol, atenolol (exo)

Acetaminophen, bezethonium, citalopram, dextrorphan, ibuprofen, paclitaxel, proguanil, simvastatin, sunitinib, telmisartan, verapamil, sitamaquine, amitriptyline (exo)

2008

2011

2011

Nanospray DESI

PS

Pazopanib, tamoxifen, imatinib, cyclophosphamide, paclitaxel, irinotecan, docetaxel, topotecan (exo)

Acylcarnitines(endo)

Nicotine, cotinine, trans-3`hydroxycotinine, anabasine (exo)

Acylcarnitines (C2–C18)

Amphetamine, methamphetamine, MDA, MDMA, MDEA, morphine, cocaine, Δ9-THC (exo)

Tacrolimus (exo)

Sunitinib and benzethonium (exo)

2012

2012

2013

2013

2014

2015

2015

DOPA, ephedrine, and ibuprofen

Sitamaquine, terfenadine, prazosin (exo)

Methadone, amitriptyline, nortriptyline, andpethidine

2010

Phenylalanine, leucine, valine, tyrosine, and methionine

2007

2013

Androstadienedione, stigmastadienone, androsteronehemisuccinate, 5␣androstan-3␤,17␤-diol-16-one, androsterone glucuronide, epitestosterone, and 6dehydrocholestenone

2007

DESI coupled with TLME*

Cocaine and amphetamine-like stimulants

2006

DESI

Dimethylamylamine (exo)

2014

Cocaine, diazepam (exo)

Phenylalanine PKU screening (endo)

2013

2014

Ranitidine (exo)

Compounds

2005

Year

TM-DART

DART

Ambient ion sources

Plasma

2 μL

10 μL

Quantitative

Quantitative

Quantitative

DBS

Quantitative 12 μL

Quantitative

Quantitative

Quantitative

Quantitative

Qualitative

Qualitative, chiral

Qualitative

Quantitative

Qualitative

Qualitative

Qualitative

Quantitative

Qualitative

Quantitative

Qualitative

Study type

Blood

5 μL

0.5 μL

10 μL

10 μL





150 μL

15 μL

3.1 μL

10 μL



0.3–1.5 mL







Sample volume

Urine

Blood, oral fluid, urine

Blood, serum

DBS

DBS

DBS

DBS

Urine

DBS

DBS

Urine

DBS

Urine, plasma

Urine

DBS

Urine

Biological matrix



1 ng/mL

0.2 ng/mL