TECHNICAL NOTE pubs.acs.org/ac
Impedimetric Immobilized DNA-Based Sensor for Simultaneous Detection of Pb2+, Ag+, and Hg2+ Zhenzhen Lin,†,^ Xiaohong Li,*,† and Heinz-Bernhard Kraatz*,‡,§ † ‡
Department of Chemistry, Beijing Normal University, Beijing, China, 100875 Department of Chemistry, University of Western Ontario,1151 Richmond Street, London, N6A 5B7, Canada
bS Supporting Information ABSTRACT: An unlabeled immobilized DNA-based sensor was reported for simultaneous detection of Pb2+, Ag+, and Hg2+ by electrochemical impedance spectroscopy (EIS) with [Fe(CN)6]4/3 as redox probe, which consisted of three interaction sections: Pb2+ interaction with G-rich DNA strands to form G-quadruplex, Ag+ interaction with CC mismatch to form CAg+C complex, and Hg2+ interaction with TT mismatch to form THg2+T complex. Circular dichroism (CD) and UVvis spectra indicated that the interactions between DNA and Pb2+, Ag+, or Hg2+ occurred. Upon DNA interaction with Pb2+, Ag+, and Hg2+, respectively, a decreased charge transfer resistance (RCT) was obtained. Taking advantage of the RCT difference (ΔRCT), Pb2+, Ag+, and Hg2+ were selectively detected with the detection limit of 10 pM, 10 nM, and 0.1 nM, respectively. To simultaneously (or parallel) detect the three metal ions coexisting in a sample, EDTA was applied to mask Pb2+ and Hg2+ for detecting Ag+; cysteine was applied to mask Ag+ and Hg2+ for detecting Pb2+, and the mixture of G-rich and C-rich DNA strands were applied to mask Pb2+ and Ag+ for detecting Hg2+. Finally, the simple and cost-effective sensor could be successfully applied for simultaneously detecting Pb2+, Ag+, and Hg2+ in calf serum and lake water.
L
ead ion (Pb2+), silver ion (Ag+), and mercury ion (Hg2+), which are three of the most toxic forms of heavy metal, may affect the environment adversely and pose severe risks to human health. Also, they usually induce toxic effects in plants and animals when circulating in soil and groundwater, delay physical or mental development in children, and damage nervous, renal, immune, and cardiovascular systems once introduced into the body excessively.13 Therefore, sensitive and on-site tracking Pb2+, Ag+, and Hg2+ both in vitro and in vivo is highly desirable in environmental protection, as well as disease prevention and treatment. In recent years, much effort has been devoted toward the design of DNA-based sensors for the detection of metal ions. For Pb2+ detection, most were based on the Pb2+-dependent DNAzyme46 and Pb2+-stabilized G-quaduplex.7,8 As for Hg2+ and Ag+, it had been reported that TT mismatches selectively captured Hg2+ to form THg(II)T base pairs912 and CC mismatches exclusively recognized Ag+ to form CAg(I)C complex.1315 Accordingly, various detection techniques adopting fluorescence, colorimetry, and electrochemical methods were applied to selectively detect Pb2+,1622 Ag+,13,23 or Hg2+.2429 Although these assays are effective, most of them were focused on single metal ion detection. In fact, various metal ions (such as Pb2+, Ag+, Hg2+, et al.) are usually coexisting, which are widely distributed in ambient air,30 water,31,32 soil,33 food,34 and even biological systems.35 Under this situation, the monitoring of these heavy metal ions at a trace level in the environment or biological matrixes could not be achieved with only one sensor. Though the application of several different sensors could achieve the goal, it is not a perfect r 2011 American Chemical Society
strategy because of a lot of inconvenience in the detection, such as cost, waste of time, and complexity. Thus, the achievement of simultaneous detection of two or more metal ions with only one sensor is imperative. When it comes to sensors designed for the simultaneous detection of two metal ions, there are only a few relevant reports.36,37 Liu et al. adopted a fluorescence-labeled thrombin binding aptamer (TBA) as a probe to detect Pb2+ and Hg2+ simultaneously.36 Nevertheless, this sensor may suffer certain limitations in practical application, such as relatively lower sensitivity (the detection limit is 0.3 nM for Pb2+ and 5.0 nM for Hg2+) and the use of poisonous masking agent (sodium cyanide). Subsequently, Lin et al. presented an assay for sensing both Hg2+ and Ag+ using Tween 20-stabilized AuNPs (Tween 20-AuNPs).37 To date, simultaneous detection of Pb2+, Ag+, and Hg2+ remains a challenge. In this paper, a label-free immobilized DNA-based sensor for simultaneous detection of Pb2+, Ag+, and Hg2+ by electrochemical impedance spectroscopy (EIS) was reported. The high sensitivity and selectivity were evaluated through the use of the RCT difference (ΔRCT) before and after the DNA interactions with Pb2+, Ag+, and Hg2+. Circular dichroism (CD) and UVvis spectra were adopted to further confirm these occurred interactions. To simultaneously detect all the three metal ions coexisting Received: June 3, 2011 Accepted: July 28, 2011 Published: July 28, 2011 6896
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Analytical Chemistry in a sample, EDTA was applied to mask Pb2+ and Hg2+ for detecting Ag+; cysteine was applied to mask Ag+ and Hg2+ for detecting Pb2+, and the mixture of G-rich and C-rich DNA strands were applied to mask Pb2+and Ag+ for detecting Hg2+, respectively. Finally, the sensor was challenged in real serum and water samples.
’ EXPERIMENTAL SECTION Materials. DNA sequences were synthesized by standard solid phase techniques using a fully automated DNA synthesizer in Shanghai (Shanghai Sangon Biological Engineering Technology & Service Co. Ltd.):
The working gold electrodes, 99.99% (w/w) polycrystalline with a diameter of 1 mm, were purchased from Aida Instrument Inc. in Tianjin and cleaned prior to use. NaClO4, K3[Fe(CN)6], K4[Fe(CN)6], Pb(ClO4)2 3 3H2O, Zn(ClO4)2 3 6H2O, Ni(ClO4)2 3 6H2O, Co(ClO4)2 3 6H2O, Cd(ClO4)2 3 xH2O, Cu(ClO4)2 3 6H2O, Mn(ClO4)2 3 6H2O, Al(ClO4)3 3 9H2O, LiClO4, Tris(Tris-(hydroxymethyl)-aminomethane), EDTA, cysteine, and 6-mercaptohexanol were purchased from Aldrich and used without further purification. Mg(ClO4)2 was purchased from Fluka and used as received. Deionized water (18.2 MΩ cm resistivity) from a Millipore Milli-Q system was used through this work. Newborn calf serum was purchased from invitrogen corporation (New Zealand). Lake water was collected from Baiyangdian in Hebei province and used without further purification. Monolayer Preparation. Ten micromolar DNA (1), (2), and (3) were prepared in the 20 mM TrisClO4 buffer (pH = 7.4) containing 300 mM NaClO4. Before use, the three solutions were mixed for hybridization with equal volume, and the final concentration for DNA (1 + 2+ 3) was 3.33 μM. DNA (1) (50 -TCA-GAC-TAGC---30 ) hybridized with DNA (2) (30 -AGTCTG-ATCG----50 ) forming partially hybridized DNA (1 + 2) and then simultaneously hybridized with DNA (3) forming DNA (1 + 2+ 3). The gold electrodes (1.0 mm diameter) were cleaned according to the reported procedures38 and incubated in the DNA (1 + 2 + 3) solution for 5 days. Then, the electrodes were washed with the buffer solution and subsequently incubated in 1 mM 6-mercaptohexanol for 2 h. The electrodes were then washed with TrisClO4 buffer and mounted into an electrochemical cell. After rinsing with the buffer, the electrodes were incubated in the solution of Hg(ClO4)2, AgClO4, and Pb(ClO4)2 with different concentrations for 2 h, 2 h, and 1 day, respectively. The EIS of the films were recordzed. To simultaneously detect every metal ion in the buffer solution in which Pb2+, Ag+, and Hg2+ coexisted, DNA (1 + 2 + 3) films on the gold electrodes were incubated in the buffer solution containing 10 μM cysteine (masking Ag+ and Hg2+) for Pb2+ detection, containing 10 μM EDTA (masking Pb2+ and Hg2+) for Ag+ detection, and containing 10 μM G-rich DNA (4) (masking Pb2+) and 10 μM C-rich DNA (5) (masking Ag+) for Hg2+ detection. The same procedure
TECHNICAL NOTE
was applied in newborn calf serum and lake water samples instead of buffer solution. Electrochemical Measurements. As reported before,38 a conventional three-electrode system was used, and all the measurements were carried out at room temperature in an enclosed and grounder Faraday cage. Impedance spectra were measured using a potentiostat frequency analyzer (EG&G 2273). The ac voltage amplitude was 5 mV, and the voltage frequency was from 100 kHz to 100 mHz. The applied potential was 250 mV vs Ag/AgCl (formal potential of the redox probe [Fe(CN)6]3/4 in the buffer solution). All measurements were repeated for a minimum of five times with separate electrodes to obtain statistically meaningful results. CD Measurements and UVVis Spectroscopic Analysis. A JASCO J-810 spectropolarimeter was utilized to collect CD spectra of the hybridization solution of 2 μM DNA (1 + 2 + 3) at room temperature in the absence and presence of 10 μM Hg2+, Ag+, and Pb2+, respectively. The optical chamber is 1 cm path length and 1.5 mL volume. Two scans (200 nm/min) from 375 to 225 at 0.5 nm intervals were accumulated and averaged. The background of the buffer solution was subtracted from the CD data. The UVvis spectroscopy was applied to investigate the interaction of 2 μM DNA (1 + 2 + 3) with 10 μM Pb2+ at room temperature. The absorption spectra of the reaction mixture were recorded with a Cazy 50 Scan UVvis spectrophotometer in the wavelength range from 400 to 200 nm and a scan rate of 600 nm/min.
’ RESULTS AND DISCUSSION Detection of Pb2+, Ag+, and Hg2+. The DNA films were
prepared by incubating freshly cleaned gold electrodes in 3.33 μM DNA (1 + 2 + 3), followed by backfilling potential pinholes and defects by soaking the film in 1 mM 6-mercaptohexanol.38 Scheme 1 illustrates the sensing strategy toward the three target metal ions (Pb2+, Ag+, and Hg2+): (i) in the presence of Pb2+, the hybridized parts among DNA strand (1), (2), and (3) were dehybridized to form Pb2+ stabilized G-quadruplex and release free DNA strand (3) at the same time; (ii) DNA strand (1) and (2) are C-rich and T-rich in the form of interleaving. In the presence of Ag+ or Hg2+, DNA strand (1) and (2) could bind Ag+ or Hg2+ forming CAg+C or THg2+T complex for recognizing Hg2+ and Ag+, respectively. The modified electrodes were then incubated in 10 μM Pb2+, Ag+, and Hg2+ solution, respectively. EIS was applied to track this process, and the representative Nyquist plots for the films were shown in Figure 1. The impedance spectra were analyzed with the help of a modified Randles’ equivalent circuit, relating specific properties to resistive and capacitive components (see inset, Figure 1), and the fitting results are listed in Table 1. As reported before,40 the solution resistance, Rs, is the resistance between the reference electrode and the films of DNA on the gold electrodes. For each measurement, the position of the two electrodes was kept the same. All measurements were carried out in the identical solution (20 mM TrisClO4) and at room temperature to minimize variations in Rs, which ranged from 5.1 to 5.8 Ω 3 cm2. Cmonolayer accounts for the capacitance of the DNA films on the gold electrodes. In the presence of Pb2+, Ag+, and Hg2+, the film capacitance Cmonolayer decreased. The results could be interpreted that the induced structural switches of hybridized DNA (1 + 2 + 3) would lead to the increased film thickness.40 6897
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Scheme 1. Schematic Illustration of the Immobilized DNA-Based Sensor for Simultaneous Detection of Pb2+, Ag+, and Hg2+
Figure 1. Representative Nyquist plots (Zim vs Zre) for DNA (1 + 2 + 3) films before (9) and after incubating with 10 μM Pb2+ (O); 10 μM Ag+ (0); 10 μM Hg2+ (b), respectively. Measured data are shown as symbols with calculated fit to the equivalent circuit as solid lines. Inset: the measured data are fit to the equivalent circuit: 4 mM Fe(CN)63/ Fe(CN)64(1:1) as redox probe.
The combination of Rx and the constant phase element (CPE) accounts for the behavior of the 6-mercaptohexanol-diluted films on the electrode surfaces as reported before.39 Diffusion of the redox probe from the solution to the DNA film was ignored in this system because of the absence of Warburg impedance as shown in Figure 1. The most important parameter is the charge-transfer resistance, RCT, which is the result of the resistance to charge transfer between the solution-based redox probe [Fe(CN)6]3/4 and the electrode surface. As shown in Figure 1 and Table 1, in the presence of Pb2+, RCT decreased from 2925(40) Ω 3 cm2 to 1379(47) Ω 3 cm2 and the RCT difference (ΔRCT) is 1546(47) Ω 3 cm2. Upon DNA (1 + 2 + 3) interacting with Pb2+, DNA (1) and (2) bound with Pb2+ to form G-quadruplex and released DNA (3) from the films, which could provide an easier penetration channel for the redox probe. In the presence of Ag+, RCT decreased from 2925(40) Ω 3 cm2 to 1551(19) Ω 3 cm2 and ΔRCT is 1374(19) Ω 3 cm2. Similarly, for the case of Hg2+, RCT decreased from 2925(40) Ω 3 cm2 to 1513(73) Ω 3 cm2 and ΔRCT is 1412(64) Ω 3 cm2. The decreased RCT for Ag+ and Hg2+ could be rationalized that metal ion-mediated CAg+C
or THg2+T formed DNA duplex-like enhance the electron transfer.41,42 In order to further confirm the interactions of DNA (1 + 2 + 3) with Pb2+, Ag+, and Hg2+, CD measurements were carried as shown in Figure 2A. In the absence of Pb2+, Ag+, and Hg2+, DNA(1 + 2 + 3) demonstrated a chirality due to its possessing duplex structure. In the presence of 10 μM Pb2+, the CD spectrum almost had no change, which can be rationalized that a symmetrical Pb2+-stabilized G-quadruplex can be formed as shown in Scheme 1. UVvis analysis as shown in Figure 2B demonstrated that the peak at 260 nm almost did not shift, but an obvious increase in intensity was observed, which indicated more bases were exposed owing to the release of free DNA (3) and formation of G-quadruplex. On the basis of the two experiments, it was believed that Pb2+ interacted with DNA (1 + 2 + 3) as illustrated in Scheme 1. As for the cases of Ag+ or Hg2+, new negative peaks for DNA (1 + 2 + 3) binding with 10 μM Hg2+ at 280 nm and binding with 10 μM Ag+ at 271 nm appeared and a positive peak for DNA (1 + 2 + 3) at 278 nm disappeared as shown in Figure 2A, which indicated the formation of CAg+C complexes and THg2+T complexes, respectively.10,36 On the basis of the results discussed above, the interactions between DNA and Pb2+, Ag+, and Hg2+ led to the decreased RCT, and ΔRCT was a very important parameter to be used for the detection of Pb2+, Ag+, and Hg2+. As a result, Pb2+, Ag+, and Hg2+ could be separately detected by this assay. Sensitivity and Selectivity. The detection limits of the assay for the three metal ions were explored by EIS. Starting from 10 μM, ΔRCT decreased with the decreased concentrations of Pb2+, Ag+, or Hg2+ as shown in Figure 3, Tables S1, S2, and S3 (see Supporting Information). As shown in Figure 3A, upon decreasing the concentration of Pb2+ from 10 μM to 1 pM, only a part of DNA(1 + 2 + 3) on the electrodes could form G-quadruplex to release DNA (3) and led to the decreased ΔRCT until no distinct change in ΔRCT was observed when the concentration of Pb2+ was decreased to 1 pM (see Table S1, Supporting Information). ΔRCT decreased linearly with the logarithm of Pb2+ concentration within a range from 10 μM to 10 pM, and the detection limit is 10 pM, which is lower 6898
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TECHNICAL NOTE
Table 1. Equivalent Circuit Element Values for DNA Films in the Absence and Presence of 10 μM Pb2+, Ag+, and Hg2+ a equivalent circuit elements
a
Rs (Ω 3 cm2)
Cmonolayer (μF 3 cm2)
RCT (Ω 3 cm2)
Rx (Ω 3 cm2)
CPE (μF 3 cm2)
n
ΔRCT (Ω 3 cm2)
DNA
5.5(0.1)
12.1(0.2)
2925(40)
2.1(0.6)
23.1(1.7)
0.9(0.01)
DNA + Pb2+
5.4(0.1)
9.4(0.6)
1379(47)
3.2(0.3)
16.1(4.4)
0.9(0.01)
1546(47)
DNA + Ag+
5.6(0.1)
9.5(0.1)
1551(19)
2.4(0.1)
14.6(0.1)
0.9(0.02)
1374(19)
DNA + Hg2+
5.6(0.1)
8.7(0.5)
1513(73)
3.6(0.5)
20.9(2.5)
0.9(0.01)
1412(64)
The values in parentheses represent the standard deviations from at least five electrode measurements.
Figure 2. (A) CD spectra of DNA (1 + 2 + 3) in the absence (black) and presence of 10 μM Pb2+ (red);10 μM Ag+ (green); or 10 μM Hg2+ (blue). (B) UVvis spectra of DNA (1 + 2 + 3) in the absence (black) and presence of 10 μM Pb2+ (red).
Figure 3. Sensitivity for Pb2+(A), Ag+(B), and Hg2+(C): relationship between ΔRCT and concentrations of the metal ions and selectivity (D) with 10 μM metal ion (such as Co2+, Mg2+, Ni2+, Zn2+, Cd2+, Cu2+, Ca2+ Mn2+, Al3+, Fe3+, Li+). Error bars are derived from minimum of five electrodes.
than those of electrochemical, fluorescent, and colorimetric assays for Pb2+.5,6,8 As for Ag+, as shown in Figure 3B, with the
concentrations of Ag+ decreased, only part of CC mismatches could react with Ag+ to form CAg+C, which led to the 6899
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Figure 4. Simultaneous detection of Pb2+, Ag+, and Hg2+ coexisting in the samples: (A) in the buffer solution; (B) in 10-fold diluted newborn calf serum; and (C) in lake water. Error bars are derived from a minimum of five electrodes.
decrease in ΔRCT until no change was observed when the concentration of Ag+ was as low as 1 nM (see Table S2, Supporting Information), and the detection limit was 10 nM. The inset of Figure 3B showed the linear relationship between ΔRCT and the Ag+ concentrations ranging from 100 nM to 800 nM. Accordingly, the smaller the concentration of Hg2+, the less was the quantity of THg2+T complexes formed, which resulted in decreased ΔRCT. The linear responses of ΔRCT against the logarithm of Hg2+ concentration from 10 μM to 0.1 nM was shown in Figure 3C, and the detection limit was 0.1 nM (see Table S3, Supporting Information). The selectivity of the assay was also explored: the values of ΔRCT were analyzed upon adding other metal ions (such as 10 μM Co2+, Mg2+, Ni2+, Zn2+, Cd2+, Cu2+, Ca2+, Mn2+, Al3+, Fe3+, Li+) to the sensing system instead of Pb2+, Ag+, and Hg2+. The result was shown in Figure 3D. We observed that only Pb2+, Ag+, and Hg2+ caused a considerable decrease in RCT while other ions yielded little changes, which indicated that the sensor was specifically responding to the three metal ions. Simultaneous Detection of Pb2+, Ag+, and Hg2+. Finally, the simultaneous (or parallel) detections of Pb2+, Ag+, and Hg2+ coexisting in a sample were investigated. As discussed above, the interactions of Pb2+, Ag+, and Hg2+ with DNA (1 + 2 + 3) all presented a decreased RCT. For the sake of simultaneously detecting Pb2+, Ag+, and Hg2+, masking agents were used to achieve this goal, such as 10 μM EDTA used for masking Pb2+ and Hg2+, 10 μM cysteine used for masking Hg2+ 43 and Ag+,23 and even the mixture of 10 μM G-rich DNA (4) and 10 μM C-rich DNA (5) used for masking Pb2+ 44 and Ag+.1315 EDTA successfully masked Pb2+ and Hg2+ for detection of 1 μM Ag+(see Figure S1, Supporting Information), 10 μM cysteine
masked Hg2+45 and Ag+23 for detection of 1 μM Pb2+(see Figure S2, Supporting Information), and also the mixture of 10 μM G-rich DNA(4) and 10 μM C-rich DNA(5) masked Pb2+ and Ag+ for the detection of 1 μM Hg2+(see Figure S3, Supporting Information). As shown in Figure 4A, the simultaneous detection of Pb2+, Ag+, and Hg2+ coexisting in the buffer solution was achieved. In order to further explore the potential application of the sensor in the practical samples, the assay was used to simultaneously detect Pb2+, Ag+, and Hg2+ in the 10-fold diluted newborn calf serum and lake water. The biological exposure indices (BEIs) for Hg2+ and Pb2+ defined by American Conference of Governmental Industrial Hygienists (ACGIH) in blood samples are 1.5 μg/100 mL(75 nM) and 30 μg/100 mL (1.45 μM), respectively, and the concentration of Ag+ can be 2 μM according to the secondary maximum contaminant level (SMCL) for Ag+ set by the U.S. Environmental Protection Agency (EPA).2,45 Thus, the concentrations in newborn calf serum were chosen to contain 10 nM Hg2+, 1 μM Pb2+, and 1 μM Ag+, respectively, which were below the stated level. Figure 4B indicated the sensor could be applied to simultaneously detect Pb2+, Ag+, and Hg2+ in newborn calf serum. In addition, the toxic levels for Pb2+, Ag+, and Hg2+ in drinking water are defined by the United States Environmental Protection Agency (USEPA) to be 72 nM, 10 nM, and 460 nM, respectively.19,25,37 Therefore, the concentration of Pb2+, Ag+, and Hg2+ in lake water were chosen to contain 10 nM Pb2+, 5 nM Ag+, and 200 nM Hg2+, respectively. As shown in Figure 4C, simultaneous detection of Pb2+, Ag+, and Hg2+ in the lake water was achieved. Because the used masking agents are nontoxic and compatible with biological systems, this multifunctional sensor holds great potential in practical applications. 6900
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’ CONCLUSION In this paper, an unlabeled immobilized DNA-based sensor was reported to detect Pb2+, Ag+, and Hg2+ through use of the difference in charge-transfer resistance (ΔRCT) before and after DNA interactions with Pb2+, Ag+, and Hg2+, which were monitored by electrochemical impedance spectroscopy (EIS). ΔRCT is sufficiently sensitive to detect Pb2+, Ag+, and Hg2+ as low as 10 pM, 10 nM, and 0.1 nM, respectively. Moreover, the sensor maintained high selectivity over other nonspecific metal ions. EDTA (masking Pb2+ and Hg2+), cysteine (masking Ag+ and Hg2+), and the mixture of G-rich and C-rich DNA strands (masking Pb2+ and Ag+), which acted as masking agents, were applied to simultaneously (or parallel) detect Ag+, Pb2+, and Hg2+. This simple and cost-effective assay was successfully applied to detect Ag+, Pb2+, and Hg2+ in newborn calf serum and lake water. These attributes suggest our approach is well suitable for simultaneous detection of Ag+, Pb2+, and Hg2+ in medical diagnosis and environmental monitoring, and it is hopeful that the electrode array will be applied to achieve a high-throughput detection of Ag+, Pb2+, and Hg2+. ’ ASSOCIATED CONTENT
bS
Supporting Information. Additional information as noted in text. This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected] (X.L.);
[email protected] (H.-B.K.). Present Addresses
^ Zhengzhou No. 2 Middle School, Zhengzhou, Henan Province, China, 450000. § Department of Physical and Environmental Sciences, University of Toronto at Scarborough, 1265 Military Trail, Toronto, M1C 1A4, Canada.
’ ACKNOWLEDGMENT This work is supported by NBRPC (Grant No. 2009CB421605) and the NSFC (Grant No. 21073019). Financial support from the Fundamental Research Funds for the Central Universities is acknowledged. We also acknowledge the financial support from NSERC. ’ REFERENCES (1) Wang, H.; Kim, Y.; Liu, H.; Zhu, Z.; Bamrungsap, S.; Tan, W. J. Am. Chem. Soc. 2009, 131, 8221–8226. (2) Tan, S. S.; Teo, Y. N.; Kool, E. T. Org. Lett. 2010, 12, 4820–4823. (3) Zahir, F.; Rizwi, S. J.; Haq, S. K.; Khan, R. H. Environ. Toxicol. Pharmacol. 2005, 20, 351–360. (4) Li, J.; Lu, Y. J. Am. Chem. Soc. 2000, 122, 10466–10467. (5) Swearingen, C.; Wernette, D.; Cropek, D.; Lu, Y.; Sweedler, J.; Bohn, P. Anal. Chem. 2005, 77, 442–448. (6) Xiao, Y.; Rowe, A.; Plaxco, K. J. Am. Chem. Soc. 2007, 129, 262–263. (7) Li, T.; Dong, S.; Wang, E. J. Am. Chem. Soc. 2010, 132, 13156–13157. (8) Li, T.; Wang, E.; Dong, S. Anal. Chem. 2010, 82, 1515–1520. (9) Tanaka, Y.; Oda, S.; Yamaguchi, H.; Kondo, Y.; Kojima, C.; Ono, A. J. Am. Chem. Soc. 2007, 129, 244–225.
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