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TiO photocatalysis–DESI-MS rotating array platform for high-throughput investigation of oxidation reactions Miina Ruokolainen, Ville Miikkulainen, Mikko Ritala, Tiina M. Sikanen, Tapio Kotiaho, and Risto Kostiainen Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b01638 • Publication Date (Web): 03 Oct 2017 Downloaded from http://pubs.acs.org on October 4, 2017
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Analytical Chemistry
TiO2 photocatalysis–DESI-MS rotating array platform for highthroughput investigation of oxidation reactions Miina Ruokolainen1, Ville Miikkulainen2, Mikko Ritala2, Tiina Sikanen1, Tapio Kotiaho1,2, Risto Kostiainen1* 1
Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, 00014 FINLAND 2Department of Chemistry, University of Helsinki, 00014 FINLAND
ABSTRACT: We present a new high-throughput platform for studying TiO2 photocatalytic oxidation reactions by performing reactions on a TiO2-coated surface, followed by direct analysis of oxidation products from the surface by desorption electrospray ionization mass spectrometry (DESI-MS). For this purpose, we coated a round glass wafer with photocatalytically active anatasephase TiO2 using atomic layer deposition. Approximately 70 aqueous 1 µL samples can be injected onto the rim of the TiO2-coated glass wafer, before the entire wafer is exposed to UV irradiation. After evaporation of water, the oxidation products can be directly analyzed from the sample spots by DESI-MS, using a commercial rotating sample platform. The method was shown to provide fast photocatalytic oxidation reactions and analysis with throughput of about four samples per minute. The feasibility of the method was examined for mimicking phase I metabolism reactions of amodiaquine, buspirone and verapamil. Their main photocatalytic reaction products were mostly similar to the products observed earlier in TiO2 photocatalysis and in in vitro phase I metabolism assays performed using human liver microsomes.
Redox reactions play a major role in several physiological and pathophysiological processes in the human body. For example, oxidative stress and free radical mediated oxidation of proteins and lipids are implicated in several diseases.1-4 Also, oxidation reactions are among the most important phase I metabolism pathways of xenobiotics, such as drugs5 and carcinogens.6 For example in drug discovery process, rapid assessment of drug metabolism and pharmacokinetic properties of numerous hit compounds found in bioactivity screens is critical for accelerating lead optimization and enhancing the success rate of drug candidates entering into drug development. Therefore, fast and easy in vitro methods are needed for screening metabolic behavior of new chemical entities in early phase of drug discovery process. Titanium dioxide (TiO2) photocatalysis provides a potential method for mimicking biological oxidation reactions, as it generates the same reactive oxygen species as biological systems, namely hydroxyl radicals (•OH), superoxide anions (O2•−) and singlet oxygen (1O2).7 TiO2 photocatalysis has been applied to the simulation of important phase I metabolic reactions typically catalyzed by cytochrome P450 isoenzymes.8-12 Our recent study showed that, compared to electrochemical oxidation and electrochemically assisted Fenton reaction, TiO2 photocatalysis produced the largest number of oxidation products equivalent to the phase I metabolites generated by human liver microsomes.11 Both electrochemical oxidation and electrochemically assisted Fenton reaction have been proposed as potential techniques for the imitation of drug metabolism.13, 14 In addition, TiO2 photocatalysis was considerably faster than the established enzymatic in vitro metabolism assays.11 Conventionally, performance of TiO2 photocatalysis reactions
involves micro- or nano-sized TiO2 particles and liquid chromatography – mass spectrometry (LC-MS) for analysis.8, 10, 11 However, both the removal of TiO2 particles and the LC-MS analysis steps increase the analysis time.10, 11 Our earlier work illustrates the microchip approach, combining TiO2-coated nanoreactor and on-chip micropillar electrospray ionization (µPESI), which provided much faster photocatalytic experiments than conventional methods.9 However, the fabrication of the silicon µPESI microchip is demanding and requires the use of expensive clean-room facilities. In this work, we present a new and very simple online TiO2 photocatalysis–desorption electrospray ionization (DESI-MS) rotating array platform for a high-throughput study of biologically relevant oxidation reactions. For this purpose, a round glass wafer was coated with photocatalytically active anatasephase TiO2 using atomic layer deposition (ALD). The samples introduced onto the TiO2-coated glass wafer were irradiated by UV light followed by direct analysis of oxidation products by DESI-MS. The feasibility of the platform for high-throughput screening of oxidation reactions of model drug compounds and for mimicking of phase I metabolism reactions was demonstrated. Experimental Amodiaquine dihydrochloride dihydrate, atenolol, buspirone hydrochloride, lidocaine hydrochloride monohydrate, metoprolol tartrate, moperone hydrochloride, nadolol, nicotine hydrogen tartrate, propranolol hydrochloride, quinidine sulphate dihydrate, verapamil hydrochloride, formic acid (98– 100%) and LC-MS grade methanol and acetonitrile were from Sigma-Aldrich Chemie GmbH (Steinheim, Germany). D-
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amphetamine hemisulphate was synthesized in house. A MilliQ Plus (Millipore, Molsheim, France) purification system enabled water purification. TiO2 films were deposited on Pyrex glass wafers (diameter 100 mm, thickness 0.5 mm) by ALD from titanium(IV) isopropoxide (TTIP, 97%, Aldrich) and deionized water at a temperature of 250 °C with PicosunTM R-150 ALD reactor. TTIP was evaporated from a heated source and water from an external vessel, held at 60 °C and room temperature, respectively. Reactor pressure was in the order of 5 mbar, maintained by mass flow controlled, constant nitrogen (99.999% N2) flow and vacuum pump. Deposition sequence of 1.6 s TTIP pulse-5 s purge-0.1 s water pulse-5 s purge was repeated for 4000 cycles. The TiO2 films were characterized by UV-VIS reflectometry (Hitachi U-2000) and X-ray diffraction (PANalytical X’Pet Pro, Cu Kα radiation). The TiO2-coated glass wafer was placed on a rotating platform (Thorlabs CR1-Z7/M, Thorlabs Sweden AB, Gothenburg, Sweden), which was placed on an x-, y-, z-stage (Fig. S1). The rotation of the platform was controlled by Thorlabs computer software APT motor controller. Aqueous samples (1 µl) of the model drug compounds (100 µM, except buspirone and verapamil 50 µM in MS/MS experiments) were dispensed on the rim of the glass wafer. The diameter of a sample spot was approx. 2.5 mm and the sample spots were approx. 1 mm apart. The sample spots were UV exposed (for 15-180 s) from above either online or offline. The UV exposed droplets were allowed to evaporate before DESI-MS analysis. For online reactions, a UV lamp (TEK-Lite, Union Bridge, MD, USA, maximum at peak 365 nm, intensity of 100 mW cm-2) was positioned 3.5 mm above the sample wafer (Fig. 1 and S1). Offline reactions were performed using a 5000-PC Series Dymax UV Curing Flood Lamp with a metal halide lamp (Dymax Light Curing Systems, Torrington, CT, USA; wavelengths between 290-450 nm, nominal intensity 225 mW cm-2). The whole glass wafer was placed under the UV lamp (at a distance of approximately 15 cm). In DESI-MS, a home-built sprayer was used with Agilent Ion Trap 6330 (Agilent Technologies, Walbronn, Germany) in positive ion mode. The ESI capillary (i.d. 83 µm, o.d. 184 µm) was grounded and the MS inlet capillary voltage was 2000 V. Nebulizer gas (N2) was introduced at 9.5 bar through the outer capillary (i.d. 0.25 mm). The sprayer was attached to an x-, y-, z-stage, aligned parallel to the MS inlet, on-axis, with the following geometry: impact angle ∼60°, vertical distance from sprayer to sampling surface ∼4 mm. The sampling surface was levelled with the lower edge of flared capillary extension inlet (i.d. 1.6 mm). The horizontal distance of the sample to the MS inlet was ∼10 mm. The spray solvent used was methanol/water (1:1, v:v) + 0.1% formic acid at a flow rate of 3 µL min−1. Results and Discussion The X-ray diffraction analysis of the TiO2-coated 100 mm glass wafer proved that the film crystal structure was photoactive polycrystalline anatase, which provides efficient and fast TiO2 photocatalytic oxidation reactions.9, 15-17 Microscopic examination of the coated wafer appearance and the UV-VIS reflectometry, however, showed the TiO2 film was uniform with a thickness of 100 nm ensuring repeatable oxidation
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experiments. Owing to the stability of the film, the TiO2coated glass wafer can be reused by washing the sample residues from the surface after DESI analysis. The volume of sample needed for the oxidation reaction was only 1 µL. This is significantly less than in nanoparticle-based photocatalytic methods and in vitro metabolism assays, where the sample volumes are typically hundreds of microliters. Approximately 70 samples can be introduced onto one TiO2coated glass wafer, thus allowing for high-throughput experimentation. All samples on the 100 mm diameter wafer can be exposed to UV at the same time using large diameter UV lamp (offline approach, Fig. 1a). Alternatively, the samples can also be UV exposed using a UV point source, upon rotation of the TiO2-coated glass wafer prior to transferring the exposed samples to DESI-MS analysis (online approach, Fig. 1b). In the online approach, the exposure time is dependent on the diameter of the UV beam and the rotation speed, which need to be optimized to allow proper exposure and analysis times. While the online approach provides straightforward and easy analysis for a smaller set of compounds, the offline approach often provides higher total throughput and thus all further analyses in this work were performed using offline UV exposure.
Fig. 1. A schematic picture of the experimental a) offline and b) online DESI-MS setups (not in scale). HV = high voltage.
Fig. 2. Extracted ion profiles of verapamil (six parallel samples) and its main TiO2 photocatalytic reaction products after 30 s offline TiO2 photocatalysis.
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Table 1. The product ions of buspirone and its photocatalytic reaction products. A similar fragmentation pattern of buspirone has previously been reported in references 8, 19. observed product ions (m/z)
Reaction product [M+H]
+
A
B
386
122
150
265
M+O
402
138, 122
166
265
M+O-2H
400
122
150
M+O-CH2
388
122
Buspirone
C
D
E
F
G
H
222
180
168
other
Main products
418
M+2O-2H
416
M-C2H2
360
M-2H
384
279
384 [M+O-H2O+H]+
222 236
372 [M+O-2H-CO+H]+
194
370 [M+O-CH2-H2O+H]+, 360 [M+O-CH2-CO+H]+
Minor products M+2O
177
251
The fragmentation scheme of buspirone
Table 2. The product ions of verapamil and its photocatalytic reaction products. A similar fragmentation pattern of verapamil has previously been reported in reference 20. Reaction product
observed product ions (m/z) [M+H]+
A
455
260
M-CH2
441
260
M-2xCH2
427
M+O
471
M+O-2H
469
260
M-164, N-dealkylation
291
260
Verapamil
B
C
D
E
303
165
150
291
303, 289
165, 151
150
277
289
165, 151
F
other
Main products
Minor products M+2O
487
M+2O-CH2
473
291
303, 317
398
165
150
453 [M+O-H2O+H]+, 441 [M+O-CH2O+H]+
165, 151
150
441 [M+O-2H–CO+H]+ 248
The fragmentation scheme of verapamil
The rotation speed affects the sensitivity and stability of the DESI-MS analysis. In our experiments, the optimal rotation speed for maximum sensitivity and stability was 15 mm min-1, which allowed analysis of four samples within one minute (15 s/sample). The repeatability and sensitivity of DESI-MSanalysis was also dependent on the positioning of the DESI sprayer and the sample spot relative to the flared capillary extension inlet. As previously described18, the positioning of the sample spot relative to the flared capillary extension inlet was not as critical as with a conventional “straight” capillary extension inlet. The signal to noise ratio was highest when the distance of the sample from the flared capillary extension inlet was between 10 and 17 mm and did not significantly change within this range. The repeatability of the method was tested
with verapamil samples exposed to UV offline for 30 s (Fig. 2). The average relative standard deviation of the peak areas of six replicated DESI-MS-analysis of verapamil and its main oxidation products was 16 %. This indicates typical repeatability of DESI-MS-analysis presented in earlier works21-23, although it also includes the repeatability of TiO2 photocatalysis. To characterize the effect of UV exposure time (offline approach), we tested 0, 15, 30, 45, 60, 120 and 180 s of which 30 s, 45 s, and 120 s were the most suitable for producing oxidation products of verapamil, buspirone, and amodiaquine, respectively. Longer exposure times only resulted in increased decomposition of both the parent compound and the products. The reaction products of amodiaquine, buspirone and verapamil obtained using online (100-120 s) UV exposure were
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similar to those obtained via offline exposure (data not shown). Analysis of the samples not exposed to UV (on TiO2 coated glass) or exposed to UV without TiO2 (on uncoated glass) showed no oxidation products. This confirmed that the oxidation products of the model compounds were only formed upon UV initiated TiO2 photocatalysis. The feasibility of the TiO2 photocatalysis–DESI-MS rotating array platform for high-throughput screening of oxidation products was demonstrated with 12 drug compounds using 30 s UV exposure offline (Table S1, Fig. S2). The results show that it is possible to produce oxidation products using only one exposure time for all the test compounds. However, optimization of the UV exposure time separately for each compound might enable more efficient conversion of the compounds to the products. The capability of the TiO2 photocatalysis–DESI-MS rotating array platform for mimicking biological oxidation reactions was studied in more detail using buspirone, verapamil and amodiaquine as model drug compounds. Their TiO2 photocatalysis products were compared to those reported in earlier studies.9, 11 The DESI-MS spectra of the model compounds and their oxidation products showed abundant protonated molecules ([M+H]+), which were used as precursor ions in MS/MS analysis. The main TiO2 photocatalytic oxidation products detected were formed by oxidation, hydroxylation, demethylation, and dehydrogenation and their various combinations (Tables 1-3). The main photocatalytic reaction products of buspirone were M+O (m/z 402), M+O-2H (m/z 400), and M+O-CH2 (m/z 388). In addition, some minor oxidation products were detected (Table 1). The MS/MS spectrum of M+O product of buspirone shows product ions at m/z 138 (fragment A) and m/z 166 (fragment B). Those are 16 mass units higher than the respective fragments of intact buspirone, indicating that the oxidation site is either piperazine or pyrimidine moiety. This suggests that possible oxidation reactions are aromatic hydroxylation of the pyrimidine ring or N-oxidation of piperazine. The same oxidation products are detected also in phase I metabolism reactions of buspirone.11, 19 The fragment m/z 194 in the product ion spectrum of the M+O-2H product indicates that the oxidative modification is in the azaspirone group or in the methylene nearest to the azaspirone. The product ion spectrum of the M+O-CH2 product did not allow for identification of the oxidation site. The main reaction products of verapamil were M-CH2 (m/z 441), M-2xCH2 (m/z 427), M+O (m/z 471), M+O-2H (m/z 469), and a product formed by N-dealkylation (M-164, m/z 291) (Table 2). The photocatalytic demethylation reaction products m/z 441 and m/z 427 are both mixtures of at least two isomers based on the product ion spectra. The fragment ion m/z 289 (fragment C), which is 14 mass units lower than the respective fragment of intact verapamil, indicates demethylation, either N-demethylation or O-demethylation from A-ring. The ion at m/z 151 (fragment E), however, indicates Odemethylation of the methoxy moiety at B-ring. The product ion spectrum of m/z 469, reveals at least three isomers of the M+O-2H product. The fragment ion m/z 317 (hydroxylated and dehydrogenated fragment C, 14 mass units higher than the respective intact fragment) together with m/z 291 (intact fragment B) suggest, that the oxidation site is α carbon to the
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amino group. However, the intact fragment ions m/z 303 (fragment C) and m/z 165 (fragment D) suggest two additional isomers, in which the oxidation sites are at the respective counterparts of the fragments C and D. The oxidation site(s) of the M+O product(s) could not be elucidated based on the product ion spectrum. Table 3. The product ions of amodiaquine and its photocatalytic reaction product. Reaction product
observed product ions (m/z) [M+H]+
A
Amodiaquine
356
283
M+O
372
299
The fragmentation scheme of amodiaquine
Amodiaquine (m/z 356) was oxidized to M+O (m/z 372). The product ion spectrum of the M+O product of amodiaquine shows only a fragment at m/z 299. This is 16 mass units higher than the respective fragment of intact amodiaquine and indicates that the oxidation site is not in the diethylamine moiety (Table 3). Minor oxidation of amodiaquine compared to verapamil and buspirone may relate to amodiaquine solution containing 0.25 % acetonitrile (the stock solution was made in acetonitrile). Our previous studies illustrate the inhibition of photocatalytic oxidation by acetonitrile.10, 11 The main photocatalytic reaction products of buspirone and verapamil conform to earlier studies.8, 9, 11 All photocatalytic oxidation product types of buspirone observed in this study were also observed in photocatalytic experiments using TiO2 particles. All product types, except M+O-2H (m/z 416) and M+O-CH2 (m/z 388) were observed in phase I HLM metabolism of buspirone.11 The photocatalytic main reaction product types of verapamil, except M-2xCH2 (m/z 427), were observed with a TiO2-coated µPESI chip, whereas all the observed product types, except M+2O-CH2 (m/z 473), were produced by HLM.9, 24 Aromatic hydroxylation of amodiaquine has been reported to occur in human in vivo metabolism25-26 as well as with recombinant cytochrome P450 enzymes27, but in combination with other reactions, such as deethylation. However, the major metabolite of amodiaquine is deethylamodiaquine.25-26 In addition, the reactive metabolite, amodiaquine quinone imine, can only be detected after phase II glutathione conjugation.28 Combining conjugation reactions to TiO2 photocatalysis has been demonstrated previously12, and the wider applicability of this approach would be an interesting field of future studies. Conclusions We have developed a simple platform to integrate TiO2 photocatalytic reactions into ambient mass spectrometric analysis. Major advantages include straightforward fabrication of the platform and quick experiments to study biologically relevant oxidation reactions. This approach omits the need for the time-
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Analytical Chemistry
consuming sample preparation step, which is necessary in conventional biological metabolic assays. It also allows fast DESI-MS analysis of samples directly from the same surface. Although DESI-MS does not allow separation of isomeric reaction products, the MS/MS analysis provides information of the modification site. The time-consuming LC-MS/MS analysis does not necessarily allow any more precise determination of the modification site, even if the reaction products were chromatographically separated. The TiO2 photocatalysis–DESI-MS rotating array platform allows high-throughput screening of photocatalytic oxidation products and imitation of drug metabolism. The main photocatalytic reaction products of the model compounds were mainly similar to the products earlier observed in TiO2 photocatalysis and in in vitro phase I metabolism assays performed using human liver microsomes. Moreover, the rotating platform can be applied to study various catalytic reactions and to ambient mass spectrometric analysis using other techniques than DESI, for example direct analysis in real time, desorption atmospheric pressure photoionization, and various plasmabased techniques.
ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. Online photocatalysis–DESI-MS setup, reaction products observed in high-throughput screening of TiO2 photocatalytic oxidation products of 12 compounds, extracted ion profiles of the 12 compounds and their most intensive photocatalytic reaction products. (PDF)
AUTHOR INFORMATION Corresponding Author * Email:
[email protected] Tel.: +358 2941 59134
ACKNOWLEDGMENT The research leading to these results received funding from the Finnish Cultural Foundation, the Finnish Concordia Fund, Academy of Finland (Finnish Centre of Excellence in Atomic Layer Deposition) and the European Research Council under the European Union’s Seventh Framework Program (FP/2007-2013)/ERC grant agreement no. 311705. We acknowledge Dr. Anu Vaikkinen and Dr. Markus Haapala for their help with the DESI-MS-setup. REFERENCES (1) Butterfield, D. A.; Lauderback, C. M. Free Radical Biol. Med. 2002, 32, 1050-1060. (2) Butterfield, D. A.; Perluigi, M.; Reed, T.; Muharib, T.; Hughes, C. P.; Robinson, R. A. S.; Sultana, R. Antiox. Redox Signaling. 2012, 17, 1610-1655.
(3) Adibhatla, R. M.; Hatcher, J. F. Antiox. Redox Signaling. 2010, 12, 125-169. (4) Rani, V.; Deep, G.; Singh, R. K.; Palle, K.; Yadav, U. C. S. Life Sci. 2016, 148, 183-193. (5) Guengerich, F. P. Chem. Res. Toxicol. 2008, 21, 70-83. (6) Rendic, S.; Guengerich, F. P. Chem. Res. Toxicol. 2012, 25, 1316-1383. (7) Fujishima, A.; Zhang, X.; Tryk, D. A. Surf. Sci. Rep. 2008, 63, 515-582. (8) Calza, P.; Pazzi, M.; Medana, C.; Baiocchi, C.; Pelizzetti, E. J. Pharm. Biomed. Anal. 2004, 35, 9-19. (9) Nissilä, T.; Sainiemi, L.; Karikko, M.; Kemell, M.; Ritala, M.; Franssila, S.; Kostiainen, R.; Ketola, R. A. Lab Chip. 2011, 11, 14701476. (10) Ruokolainen, M.; Valkonen, M.; Sikanen, T.; Kotiaho, T.; Kostiainen, R. Eur. J. Pharm. Sci. 2014, 65, 45-55. (11) Ruokolainen, M.; Gul, T.; Permentier, H.; Sikanen, T.; Kostiainen, R.; Kotiaho, T. Eur. J. Pharm. Sci. 2016, 83, 36-44. (12) Raoof, H.; Mielczarek, P.; Michalow, K. A.; Rekas, M.; Silberring, J. J. Photochem. Photobiol. B. 2013, 118, 49-57. (13) Jurva, U.; Wikström, H. V.; Weidolf, L.; Bruins, A. P. Rapid Commun. Mass Spectrom. 2003, 17, 800-810. (14) Jurva, U.; Wikström, H. V.; Bruins, A. P. Rapid Commun. Mass Spectrom. 2002, 16, 1934-1940. (15) Luttrell, T.; Halpegamage, S.; Tao, J.; Kramer, A.; Sutter, E.; Batzill, M. Sci. Rep. 2014, 4, 4043-4049. (16) Zhang, J.; Zhou, P.; Liu, J.; Yu, J. Phys. Chem. Chem. Phys. 2014, 16, 20382-20386. (17) Xu, M.; Gao, Y.; Moreno, E. M.; Kunst, M.; Muhler, M.; Wang, Y.; Idriss, H.; Wöll, C. Phys. Rev. Lett. 2011, 106, 138302138305. (18) Wu, S.; Zhang, K.; Kaiser, N.K.; Bruce, J.E.; Prior, D.C.; Anderson G.A J. Am. Soc. Mass Spectrom. 2006, 17, 772-779. (19) Zhu, M.; Zhao, W.; Jimenez, H.; Zhang, D.; Yeola, S.; Dai, R.; Vachharajani, N.; Mitroka, J. Drug Metab. Dispos. 2005, 33, 500507. (20) Walles, M.; Thum, T.; Levsen, K.; Borlak, J. J. Chromatogr. A. 2002, 970, 117-130. (21) Gurdak, E.; Green, F. M.; Rakowska, P. D.; Seah, M. P.; Salter, T. L.; Gilmore, I. S. Anal. Chem. 2014, 86, 9603-9611. (22) Da Costa, C.; Reynolds, J. C.; Whitmarsh, S.; Lynch, T.; Creaser, C. S. Rapid Commun. Mass Spectrom. 2013, 27, 2420-2424. (23) Green, F. M.; Stokes, P.; Hopley, C.; Seah, M. P.; Gilmore, I. S.; O'Connor, G. Anal. Chem. 2009, 81, 2286-2293. (24) Rousu, T.; Herttuainen, J.; Tolonen, A. Rapid. Commun. Mass Spectrom. 2010, 24, 939-957. (25) Churchill, F.C.; Patchen, L.C; Campbell, C.C.; Schwartz, I.K.; Phuc, N.; Dickinson, C.M. Life Sci. 1985, 36, 53-62. (26) Churchill, F.C.; Mount, D.L.; Patchen, L.C.; Björkman, A. J. Chromatogr. B. Biomed. Appl. 1986, 377, 307-318. (27) Johansson, T.; Jurva, U.; Grönberg, G.; Weidolf, L.; Masimirembwa, C. Drug Metab. Dispos. 2009, 37, 571-579. (28) Zhang, Y.; Vermeulen, N. P. E.; Commandeur, J. N. M. Br. J. Clin. Pharmacol. 2017, 83, 572-583.
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