Multiplex DNA Assay Based on Nanoparticle Probes by Single Particle

Feb 28, 2014 - ABSTRACT: A multiplex DNA assay based on nanoparticle. (NP) tags detection utilizing single particle mode inductively coupled plasma ma...
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Multiplex DNA Assay Based on Nanoparticle Probes by Single Particle Inductively Coupled Plasma Mass Spectrometry Shixi Zhang, Guojun Han, Zhi Xing, Sichun Zhang,* and Xinrong Zhang Beijing Key Laboratory for Microanalytical Methods and Instrumentation, Department of Chemistry, Tsinghua University, Beijing 100084, China ABSTRACT: A multiplex DNA assay based on nanoparticle (NP) tags detection utilizing single particle mode inductively coupled plasma mass spectrometry (SP-ICP-MS) as ultrasensitive readout has been demonstrated in the article. Three DNA targets associated with clinical diseases (HIV, HAV, and HBV) down to 1 pM were detected by DNA probes labeled with AuNPs, AgNPs, and PtNPs via DNA sandwich assay. Single nucleotide polymorphisms in genes can also be effectively discriminated. Since our method is unaffected by the sample matrix, it is well-suited for diagnostic applications. Moreover, with the high sensitivity of SP-ICP-MS and the variety of NPs detectable by SP-ICP-MS, high-throughput DNA assay could be achieved without signal amplification or chain reaction amplification.

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are susceptible to self-fluorescence of proteins, DNA, or nonbiological compounds in the sample matrix, while the element signals of ICP-MS are unaffected because the extreme temperature in plasma torch can cause the decomposition of sample into individual atoms. Consequently, ICP-MS can collect more accurate and reliable information during the assay of biomolecules with fluorescent backgrounds compared with fluorescence- based methods. In a comparison with traditional integral mode in which the analytes are dissolved in solutions, higher sensitivity could be reached in the case of single particle ICP-MS (SP-ICP-MS) because of the large amount of detectable atoms in one nanoparticle (NP).20 Degueldre and co-workers outlined the theory of SP-ICP-MS for NPs suspension analysis: the timeresolved transient signals induced by the flash of ions arising from the ionization of NPs in the plasma torch can reflect the concentration of NPs.21 In 2009, our group proposed a highly sensitive immunoassay based on the detection of NP tags by SP-ICP-MS.22 Later, we developed an effective and ultrasensitive DNA assay method based on SP-ICP-MS using AuNPs as tags.23 This method has been proved to be effective for single DNA assay. Since a range of NPs are available as potential tags for different DNA molecules, we try to extend this method to achieve multiplex DNA assay. Here, we report a method for multiplex quantification of DNA targets via the determination of specific NP tagged DNA probes using SP-ICP-MS for ultrasensitive detection. As a proof-of-concept study, three DNA targets associated with clinical diseases (HIV, HAV, and HBV) were detected by DNA

ith the enhanced health concern worldwide, rapid, sensitive, and quantitative detection of sequence-specific nucleic acid (DNA) associated with human diseases has attracted much attention in early diagnosis and biological research.1 For example, both HIV and hepatitis virus are difficult to treat and highly infective, while coinfection with these viruses is considered to be deadly.2−4 Efficacious therapy and biological investigation of these diseases call for fast and effective multiplex assay of these viruses. A variety of methods based on colorimetry,5 electrochemistry,6,7 surface-enhanced Raman spectrometry,8 molecular beacon,9 and quantum dots (QDs)10 have been developed for multiplex detection of DNA. Among these, fluorescence-based methods are most widely applied.11,12 However, broad spectrum emission results in the spectral overlap to some extent, restricting their application in high-throughput quantification. Although QDs have been chosen for their broad absorption spectral window and narrow and size-tunable photoluminescence,13−15 the number of spectrally distinct codes that can be employed for encoding is very limited and far less than theoretical prediction. It is greatly desired to develop new strategy for facile and high-throughput DNA assay. Inductively coupled plasma mass spectrometry (ICP-MS) is a promising tool in bioassay because it can detect biomolecules through the development of chemically selective or biospecific element encoding strategies toward biomolecules.16,17 ICP-MS is superior in several aspects to fluorescence-based methods. First, ICP-MS is capable of multiplex analysis with mass-specific individual element or isotope resolution.18,19 This high resolution results simply from clear distinguishing of the mass to charge ratio of different elements in a mass spectrum. In practice, ICP-MS does not suffer from spectral overlap like the case in fluorescence spectrum. Second, the fluorescence signals © 2014 American Chemical Society

Received: December 31, 2013 Accepted: February 28, 2014 Published: February 28, 2014 3541

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Materials. All glassware was thoroughly washed with aqua regia diluted solution, rinsed with ultrapure H2O sequentially, and then dried in drying oven prior to use. Chloroauric acid (HAuCl4·4H2O) and chloroplatinic acid hexahydrate (H2PtCl6· 6H2O) were obtained from Sigma-Aldrich (ACS reagent). Silver nitrate (AgNO3), trisodium citrate, citric acid, ascorbic acid, and sodium borohydride were purchased from Beijing Chemical Work (Beijing, China). Ultrapure H2O was obtained from a Millipore water purification system (resistance ≥ 18 MΩ cm−1, Barnstead Nanopure, Thermo Scientific). The sequences of all oligonucleotides are listed in Tables 1 and 2. All the oligonucleotides were purchased from Sangon Inc. (Shanghai, China).

probes labeled with AuNPs, AgNPs, and PtNPs via DNA hybridization assay. Our method might find use in fast and ultrasensitive detection of genetic diseases for clinical diagnostic and life science research.

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EXPERIMENTAL SECTION As shown in Figure 1, we designed three capture strands functionalized with amino groups (−NH2) at 5′-end, three

Table 1. Sequences of Oligonucleotides Used in DNA Sandwich Assay name

sequence (5′−3′)

HIV capture strand HAV capture strand HBV capture strand HIV probe HAV probe HBV probe HIV target

Figure 1. Sequence information of DNA sandwich assay.

probe strands functionalized with thiol groups (−SH) at 3′-end, and three target oligonucleotides which were conserved sequences of HIV, HAV, and HBV as models for demonstrating NP probes for multiple DNA detection by SP-ICP-MS. Each target oligonucleotide was complementary to one corresponding capture strand and one NP probe. HIV capture strands and HIV probe strands labeled with AuNPs were used to recognize and detect HIV targets. HAV capture strands and HAV probe strands labeled with AgNPs were used to recognize and detect HAV targets. Meanwhile, HBV capture strands and HBV probe strands labeled with PtNPs were used to recognize and detect HBV targets. As can be seen in Scheme 1, citrate-protected NPs were functionalized with DNA probes at first, while DNA capture strands were immobilized on a 96-well plate. During DNA assay procedure, DNA targets were added into the well and mixed with three NP labeled DNA probes. Then, DNA targets were hybridized with DNA capture strands and NP labeled DNA probes to form sandwich conjugations in buffer solution. Finally, by increasing the temperature over the melting temperature (Tm), NP labeled DNA probes were released in the supernatant and measured by SP-ICP-MS. The solution of NPs was then introduced into the plasma torch by the nebulizer. Also, at approximately 6000−7000 K in the ICP zone, NPs underwent desolvation, particle vaporization, atomization, and ionization. Finally, the frequencies and intensities of the 196Au, 107Ag, and 195Pt pulse signals were recorded by the electron multiplier detector.

TGC ATC CAG GTC ATG TTA TTC TTT GCT AAA A TAC CAC ATC ATC CAT

HAV target HBV target SBMa HIV target SBM HAV target SBM HBV target a

TTC CAA ATA TCT TCT CTG GAT CCT CAA TTG ATA ACT GAA AGC CAA AGA AGA TAT TTG GAA TAA CAT GAC CTG GAT GCA CAA TTG AGG ATC CAG TTT TAG CAA AGA A TTG GCT TTC AGT TAT ATG GAT GAT GTG GTA AGA GGA TAT TTG GAA TAA CAT GAC CTG GAT GCA CAA TTG AGG ATC TAG TTT TAG CAA AGA A TTG GCT TTC AGT TAT ATG GAT GAT GTA GTA

SBM: Single base-pair-mismatch.

Table 2. Sequences of Irrelevant Oligonucleotides Used as Sample Matrix name

sequence (5′−3′)

HCV HPV EV TP VV BA FT SARS

AAC TAC TGT CTT CAC GCA GAA AGC GTT GTG AAT GGC ATT TGT TGG GGT AAC CAA CTA TTT AAT GGC ATT TGT TGG GGT AAC CAA CTA TTT TCA GGT AGA AGG GAG GGC TAG TAC ACG CAA AGT TGT AAC GGA AGA TGC AAT AGT AAT CAG GGA TTA TTG TTA AAT ATT GAT AAG GAT CAT GTC AGT GAT TAT TAT AAC CCA CCA AGA TGC AAT AGT AAT CAG GTA GAG AC

Scheme 1. Schematic of Multiplex DNA Assay Based on NP Probes by SP-ICP-MS

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Figure 2. TEM images and photographs of AuNPs, AgNPs, and PtNPs dispersions: A = 25 nm AuNPs, B = 25 nm AgNPs, C = 20 nm PtNPs.

Preparation of Nanoparticles. Citrate-protected NPs were synthesized according to previously reported methods.24−26 Briefly, to synthesize AuNPs, 1% (w/v) HAuCl4 solution was added into 30 mL of ultrapure H2O and heated to boiling for 15 min under vigorous stirring, and then 1.7 mL of 1% (w/v) sodium citrate solution was added. Heating was continued for another 20 min while the color of solution remained unchanged; they were kept stirring for 15 min successively. After cooling to room temperature, the prepared AuNPs solution was diluted to 50 mL with ultrapure H2O. To synthesize AgNPs, 1% (w/v) AgNO3 solution was added into 30 mL of ultrapure H2O and heated to boiling for 15 min under vigorous stirring. Then, 1 mL of 1% (w/v) sodium citrate solution followed by 100 μL 1% (w/v) sodium borohydride was added. Heating was continued for another 20 min while the color of solution remained unchanged, and then the solution was kept stirring for 15 min. After cooling to the room temperature, the prepared AgNPs solution was diluted to 50 mL with ultrapure H2O. The synthesis of PtNPs was first conducted by synthesizing 5 nm platinum seeds.27 A 1 mL portion of platinum seeds was added into 25 mL of ultrapure H2O, and mixed with 325 μL of 1% (w/v) H2PtCl6 followed by 500 μL 1% (w/v) sodium citrate and 1.25% ascorbic acid solution. Then, the solution was heated to boiling for 15 min under vigorous stirring. After cooling to room temperature, the prepared PtNPs solution was diluted to 25 mL with ultrapure H2O. AuNPs (25 nm), AgNPs (25 nm), and PtNPs (20 nm) were characterized by transmission electron microscopy (TEM), as shown in Figure 2. The calculated particle concentrations of AuNPs, AgNPs, and PtNPs were approximately 7.35 × 1011, 1.47 × 1012, and 1.47 × 1011 particles/mL, respectively. Assay Procedure. The preparation of DNA-modified probes, immobilization of DNA capture strands on 96-well plates, and hybridization of NP probes and NP capture strands with DNA targets were conducted according to literature.28 DNA probes were chemically attached to NPs at 3′-end sulfhydryl. DNA capture strands were immobilized on a 96-well plate (Sangon Inc.) at 5′-end amino via covalent bond. HIV, HAV, and HBV probes (20 μL, 100 μM) were modified by 300 μL of the prepared solutions of 25 nm-diameter AuNPs, 25 nmdiameter AgNPs, and 20 nm-diameter PtNPs, respectively. After standing for 24 h at room temperature, the mixtures were brought to 0.3 M of NaCl by dropwise addition of 2 M NaCl in a stepwise manner three times in 24 h during the subsequent salt aging progress. The solutions were centrifuged to remove excess DNA strands (8000 rpm for 15 min). Finally, the NP labeled probes were kept in phosphate buffered saline (PBS buffer) containing 0.2 M sodium, 0.1 M phosphate, pH 7.0.

The hybridization experiments were performed in PBS buffer. After the immobilization of HIV, HAV, and HBV capture strands (5 μL, 10 μM) on a 96-well plate for 8 h at 37 °C, each well was blocked by blocking buffer (PB 0.01 M, S 0.02 M, BSA 5%) for 5 h at 37 °C and then washed by washing buffer (PB 0.01 M, S 0.02 M, Tween 20 0.04%) three times and PBS buffer twice. In the hybridization process, AuNP probes, AgNP probes, and PtNP probes were diluted and added into each well (4 μL each). DNA targets (240 μL) were then added. For artificial samples, equal amounts of different irrelevant DNA targets were premixed to prepare the stock solutions of HIV, HIV + HAV, and HIV + HAV+ HBV, respectively. Then, the stock solutions were diluted to 10 pM as three kinds of artificial samples. During the assay procedure, 240 μL of artificial samples and 4 μL of each kind of NP probes were added into each well for hybridization. The mixture was first heated to 95 °C for 5 min and then cooled to 37 °C. After 2 h, each plate was washed by washing buffer twice and ultrapure H2O twice. Then, 250 μL of ultrapure H2O was added to each well and heated at 95 °C for 20 min. The solution was diluted into 2 mL with ultrapure H2O and measured by SP-ICP-MS. In the signal analysis part, different thresholds were used for different elements and even for each experiment. This is because the state of the equipment could be different from time to time; one needs to measure the background and define the thresholds for each element in each measurement. Instrument. An X series ICP-MS (Thermo Electron Corp., Winsford, U.K.) was used for the experiments. The signal of 196 Au, 107Ag, and 195Pt ions was recorded per 0.5 ms, and 20 000 data points were acquired continuously in 10 s in TRA mode. The operating parameters of ICP-MS instrument are listed in Table 3. Table 3. Operating Parameters of SP-ICP-MS

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param

value

RF power (W) cool gas flow (L/min) auxiliary gas flow (L/min) nebulizer gas flow (L/min) sample uptake rate (mL/min) torch cones dwell time (ms) duration time resolution analogue detector voltage (V) PC detector voltage (V)

1200 13 0.8 0.82 0.5 shield torch nickel, HPI design 0.5 10 standard 2130 1750

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Figure 3. (a) Relationship between the frequencies and concentrations of NPs. The signals of 196Au, 107Ag, and 195Pt ions were recorded per 0.5 ms, and 20 000 data points were acquired continuously in 10 s. The error bars represent the standard deviations of five measurements. The lowest concentrations of AuNPs, AgNPs, and PtNPs detectable by SP-ICP-MS were defined as one concentration units. (b) SP-ICP-MS profile spectra of three samples from left to right containing AuNPs, AuNPs + AgNPs, and AuNPs + AgNPs + PtNPs, respectively. The three lines from top to bottom are signals of 196Au (red), 107Ag (yellow), and 195Pt (gray). The results show the measurement of the first 8 s. All of the concentrations of AuNPs, AgNPs, and PtNPs were 106- 107 particles mL−1.

Figure 4. (a) Selectivity of the multiplex DNA assay with SP-ICP-MS in three different samples containing 10 pM HIV targets, 10 pM HIV + HAV targets, and 10 pM HIV + HAV + HBV targets. The dwell time was 0.5 ms in a duration of 10 s. The error bars represent the standard deviations of four independent experiments. (b) SP-ICP-MS profile spectra of the samples. The results show the measurement of the first 8 s.

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196

Au, 107Ag, and 195Pt are proportional to the concentrations of AuNPs, AgNPs, and PtNPs, respectively. This relationship could be used as the foundation for quantitative detection of NPs tags. As shown in Figure 3, the signal numbers of AuNPs in 10 s were linearly dependent on its number concentration in the range of 1.47 × 104 and 7.35 × 106 particles mL−1, with the

RESULTS AND DISCUSSION

Detection of Multiplex Nanoparticles by SP-ICP-MS. To demonstrate the feasibility of homogeneous multiplex DNA assay using SP-ICP-MS, we first conducted an analysis of three nanosized tags (AuNPs, AgNPs, and PtNPs) that will be labeled to DNA probes. In fact, the pulse signal frequencies of 3544

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Figure 5. (a) SP-ICP-MS profile spectra of 196Au, 107Ag, and 195Pt corresponding to HIV, HAV, and HBV from left to right. SP-ICP-MS profile spectra of ultrapure H2O, blank solution, 1 pM, 10 pM, 100 pM, 1 nM DNA targets are shown from top to bottom. The results show the measurement of the first 8 s. (b) Relationships between the frequencies and the concentrations of HIV, HAV, and HBV targets from 1 to 100 pM. The dwell time was 0.5 ms in a duration of 10 s. The error bars represent the standard deviations of four independent experiments.

squared correlation coefficient (R2) of 0.996. For AgNPs, the linear ranges were from 3.67 × 104 to 1.47 × 107 particles mL−1 with R2 of 0.997. Also, the linear ranges for PtNPs were from 3.68 × 104 to 1.47 × 107 particles mL−1 with R2 of 0.997. Figure 3b shows the profile spectra of pulse counts versus time of samples containing AuNPs, AuNPs + AgNPs, and AuNPs + AgNPs + PtNPs, respectively. No cross signal was observed in the mixture of different NPs, indicating SP-ICP-MS could be a very effective tool to measure multiplex NPs quantitatively. To prove that SP-ICP-MS based multiplex DNA detection is unaffected by sample matrix, we compared the signals obtained by ICP-MS of NPs and NP tagged DNA probes, which showed no difference. In the case of real sample detection of DNA, the sample matrix may consist of many biomolecules. Those biomolecules like DNA itself may have self-fluorescence effect. Once excited, the self-fluorescent molecules could also emit fluorescence. Thus, self-fluorescent molecules can affect the measurement of fluorescence in the fluorescence-based methods. ICP-MS uses an argon-based ICP with an average temperature of as high as 6000 K. Samples are readily dried and vaporized, and all the biomolecules are decomposed into individual atoms, which have no influence on the detection because ICP-MS is capable of distinguishing the mass to charge

ratio of different element. Consequently, ICP-MS based detections are unaffected by the sample matrix while fluorescent methods are. ICP-MS detection may be affected by polyatomic ion or the unwanted introduction of target element during the sample processing. Such problems could be avoided by choosing element or isotope tags not naturally existing in biological samples, in this case, 196Au, 107Ag, and 195 Pt. Moreover, the utilization of ICP-MS to analyze biomolecules containing or labeled with ICP-detectable tags is well established in real sample analysis. Multiplex Assay of HIV, HAV, and HBV by SP-ICP-MS. In the DNA hybridization assay, three artificial samples containing HIV, HIV + HAV, and HIV + HAV + HBV (10 pM for each species) were prepared, and then all three NP labeled probes were added and hybridized with DNA targets. Figure 4a shows the results for multiplex DNA detection using our method. In the presence of HIV targets, only signals of 196 Au were observed. Similarly, in the presence of HIV and HAV targets, signals of 196Au and 107Ag were observed. While in the presence of HIV, HAV, and HBV targets, signals of 196 Au, 107Ag, and 195Pt were observed (Figure 4a). As shown in Figure 4b, no cross hybridization signal can be seen, proving 3545

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the method we developed is selective and suitable for multiplex DNA assay using purified DNA. The quantitative relationship between the frequencies and concentrations of the DNA targets is illustrated in Figure 5. A series of solutions containing the unique DNA sequences of HIV, HAV, and HBV from 0 M to 1 nM were employed to the quantitative assay. As shown in Figure 5a, samples of different concentrations (0 M, 1 pM, 10 pM, 100 pM, 1 nM) were added in the DNA hybridization assay; the increment of the pulse signals could be seen from the profile spectra. The average frequencies of background noise signals (signals with intensities higher than the threshold intensities) are below 1. Also, the average frequencies of 1 pM DNA targets are between 1 and 3. Since the limit of detection is defined as the concentration of DNA at which the signal-to-noise ratio is greater than 3, the detection limit of purified DNA targets is around 1 pM. The frequency no longer increased when the concentration of DNA targets reaches 1 nM, because all the detectable NP labeled DNA probes were hybridized with DNA targets. Therefore, concentrations of the target DNA in the range from 1 to 100 pM were chosen to test calibration linearity. Figure 5b demonstrates good linear relationship between the signal frequencies of NPs and the corresponding DNA targets. Detection of Single Base-Pair-Mismatched DNA Targets. We also applied this method to determine matched DNA targets in the presence of single base-pair-mismatched (SBM) DNA targets. Three different SBM DNA targets were studied, and the results are shown in Figure 6. Three samples

Figure 7. DNA detection using SP-ICP-MS in the presence of eight irrelevant DNA oligonucleotides as sample matrix: sample 1, HIV targets + eight irrelevant DNA oligonucleotides; sample 2, HAV targets + eight irrelevant DNA oligonucleotides; sample 3, HBV targets + eight irrelevant DNA oligonucleotides. Each target was at a concentration of 10 pM.

of eight irrelevant DNA oligonucleotides. The recovery rates of HIV, HAV, and HBV targets are 92.93%, 107.14%, and 96.72%, respectively. The results demonstrate that multiplex DNA detection using NP probes by SP-ICP-MS could capture and quantify specific DNA targets among irrelevant DNA, showing the potential applications of our method in clinical study.

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CONLUSIONS In conclusion, a novel NP labeling method for quantitative multiplex DNA assay was developed. The DNA targets can be detected at 1 pM by using AuNP, AgNP, and PtNP probes, which increases the sensitivity by 3 orders of magnitude over that of colorimetric methods29 and is comparable with the ultrasensitive electrochemical detection.30 It is worth noticing that the ultrasensitive detection could be further improved by combining with PCR. Compared with other techniques for multiplex NPs detection in homogeneous solutions such as colorimetric method, ICP-MS is able to detect NPs without any special requirements for optical and electrochemical properties, so a wide range of NPs such as TiO2, Al2O3, ZrO2, ThO2, etc. could be applied for multiplex assay by SP-ICP-MS.31−34 Thus, our method could be further extended to high-throughput assay of DNA with multiplex NP tags. As the signal of SP-ICP-MS is unaffected by sample matrix, our method has the potential to provide accurate determination of DNA in real sample detection.

Figure 6. Selectivity of the method in SBM DNA detection: sample 1, 5′-termini one base-pair-mismatched HIV targets + matched HAV targets + matched HBV targets; sample 2, middle one base-pairmismatched HAV targets + matched HIV targets + matched HBV targets; sample 3, 3′-termini one base-pair-mismatched HBV targets + matched HIV targets + matched HAV targets. The targets were all at a concentration of 10 pM.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. containing two matched DNA targets and one SBM DNA target were tested. The frequencies of SBM DNA targets were much lower than that of matched DNA targets, indicating a good distinction in the presence of SBM DNA targets. Therefore, our method is effective in discriminating SBM DNA targets from matched DNA targets. Detection of DNA Targets in the Presence of Eight Irrelevant DNA Oligonucleotides. In the clinical detection of genetic diseases, DNA is extracted from real samples including a lot of unwanted DNA targets. To confirm the selectivity of SP-ICP-MS based multiplex DNA detection, we added eight irrelevant DNA targets of about the same length compared with the DNA targets to simulate the situation of real sample detection. As shown in Figure 7, HIV, HAV, and HBV targets of 10 pM could be clearly distinguished in the presence

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by the 973 Program (2013CB933800), the National Natural Science Foundation of China (Grants 21390410 and 21125525), and Innovation Method Fund of China (No. 2012IM030400).

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REFERENCES

(1) Collins, F. S.; Green, E. D.; Guttmacher, A. E.; Guyer, M. S. Nature 2003, 422, 835−847. (2) Keeffe, E. J. Viral Hepatitis 2000, 7 (Suppl 1), 15−17. (3) Hoffmann, C. J.; Thio, C. L. Lancet Infect. Dis. 2007, 7, 402−409. (4) Peters, P. J.; Marston, B. J. J. Infect. Dis. 2012, 205, 166−168.

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(5) Liu, X.; Wang, F.; Aizen, R.; Yehezkeli, O.; Willner, I. J. Am. Chem. Soc. 2013, 135, 11832−11839. (6) Wang, J.; Liu, G. D.; Merkoci, A. J. Am. Chem. Soc. 2003, 125, 3214−3215. (7) Drummond, T. G.; Hill, M. G.; Barton, J. K. Nat. Biotechnol. 2003, 21, 1192−1199. (8) He, S.; Liu, K.-K.; Su, S.; Yan, J.; Mao, X.; Wang, D.; He, Y.; Li, L.-J.; Song, S.; Fan, C. Anal. Chem. 2012, 84, 4622−4627. (9) Song, S.; Liang, Z.; Zhang, J.; Wang, L.; Li, G.; Fan, C. Angew. Chem., Int. Ed. 2009, 48, 8670−8674. (10) Zhang, C.-y.; Hu, J. Anal. Chem. 2010, 82, 1921−1927. (11) Zheng, W.; He, L. J. Am. Chem. Soc. 2009, 131, 3432−3433. (12) Li, Y. G.; Cu, Y. T. H.; Luo, D. Nat. Biotechnol. 2005, 23, 885− 889. (13) Chan, W. C. W.; Maxwell, D. J.; Gao, X. H.; Bailey, R. E.; Han, M. Y.; Nie, S. M. Curr. Opin. Biotechnol. 2002, 13, 40−46. (14) Algar, W. R.; Krull, U. J. Anal. Chem. 2009, 81, 4113−4120. (15) Algar, W. R.; Krull, U. J. Anal. Chem. 2010, 82, 400−405. (16) Sanz-Medel, A.; Montes-Bayon, M.; de la Campa, M. D. R. F.; Encinar, J. R.; Bettmer, J. Anal. Bioanal. Chem. 2008, 390, 3−16. (17) Yan, X.; Yang, L.; Wang, Q. Anal. Bioanal. Chem. 2013, 405, 5663−5670. (18) Han, G.; Zhang, S.; Xing, Z.; Zhang, X. Angew. Chem., Int. Ed. 2013, 52, 1466−1471. (19) Luo, Y.; Yan, X.; Huang, Y.; Wen, R.; Li, Z.; Yang, L.; Yang, C. J.; Wang, Q. Anal. Chem. 2013, 85, 9428−9432. (20) Allabashi, R.; Stach, W.; de la Escosura-Muniz, A.; Liste-Calleja, L.; Merkoci, A. J. Nanopart. Res. 2009, 11, 2003−2011. (21) Degueldre, C.; Favarger, P. Y. Colloids Surf., A 2003, 217, 137− 142. (22) Hu, S.; Liu, R.; Zhang, S.; Huang, Z.; Xing, Z.; Zhang, X. J. Am. Soc. Mass Spectrom. 2009, 20, 1096−1103. (23) Han, G.; Xing, Z.; Dong, Y.; Zhang, S.; Zhang, X. Angew. Chem., Int. Ed. 2011, 50, 3462−3465. (24) Frens, G. Nat. Phys. Sci. 1973, 241, 20−22. (25) Zeng, J.; Zheng, Y.; Rycenga, M.; Tao, J.; Li, Z.-Y.; Zhang, Q.; Zhu, Y.; Xia, Y. J. Am. Chem. Soc. 2010, 132, 8552−8553. (26) Bigall, N. C.; Haertling, T.; Klose, M.; Simon, P.; Eng, L. M.; Eychmueller, A. Nano Lett. 2008, 8, 4588−4592. (27) Brown, K. R.; Walter, D. G.; Natan, M. J. Chem. Mater. 2000, 12, 306−313. (28) Hirayama, H.; Tamaoka, J.; Horikoshi, K. Nucleic Acids Res. 1996, 24, 4098−4099. (29) Elghanian, R.; Storhoff, J. J.; Mucic, R. C.; Letsinger, R. L.; Mirkin, C. A. Science 1997, 277, 1078−1081. (30) Gasparac, R.; Taft, B. J.; Lapierre-Devlin, M. A.; Lazareck, A. D.; Xu, J. M.; Kelley, S. O. J. Am. Chem. Soc. 2004, 126, 12270−12271. (31) Degueldre, C.; Favarger, P. Y. Talanta 2004, 62, 1051−1054. (32) Degueldre, C.; Favarger, P. Y.; Bitea, C. Anal. Chim. Acta 2004, 518, 137−142. (33) Degueldre, C.; Favarger, P. Y.; Rosse, R.; Wold, S. Talanta 2006, 68, 623−628. (34) Degueldre, C.; Favarger, P. Y.; Wold, S. Anal. Chim. Acta 2006, 555, 263−268.

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