Design Consideration for Surface-Enhanced (Resonance) Raman

Article pubs.acs.org/JPCC

Design Consideration for Surface-Enhanced (Resonance) Raman Scattering Nanotag Cores Iain A. Larmour,† Erick A. Argueta,‡ Karen Faulds,† and Duncan Graham*,† †

Centre for Molecular Nanometrology, WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, U.K. ‡ Connecticut College, 270 Mohegan Avenue, New London, Connecticut 06320, United States S Supporting Information *

ABSTRACT: Surface-enhanced (resonance) Raman spectroscopy (SE(R)RS) holds great promise for the in vivo detection of multiple disease markers. Nanotags consisting of a metallic nanoparticle decorated with reporter molecules encapsulated in either an inert or biofunctionalized shell, for inactive or active targeting, have been developed. To improve the tissue depth from which the signal can be detected, it is preferable to operate with excitation in the nearinfrared wavelengths; however, this reduces the inherent Raman signal intensity. The signal strength can be reestablished by matching the absorbance of the nanoparticle with the laser excitation. However, nanoparticles must get physically larger to support absorbances in the near-infrared region, which can have an adverse affect on cellular uptake. In this paper we compare the use of silver nanoparticles with plasmon absorbances at longer wavelengths with clusters (2−4 nanoparticles) formed from much smaller nanoparticles which support so-called “hot spots”. We find that the small clusters outperform the resonant single nanoparticles with respect to the observed SE(R)RS signal. It has also previously been shown in the literature that small nanoparticles are more readily taken up into cells than larger nanoparticles. This knowledge combined with the results reported here highlight an important design consideration in that new SE(R)RS active nanotags should be made from coupled small dimensional nanoparticles rather than large single nanoparticles that support absorbances in the near-infrared region. biological species.10 Many synthetic routes exist for the controlled growth of nanoparticles, and for gold nanoparticles, control of the reactant ratios can provide monodisperse populations of differently sized nanoparticles.11 In contrast, growth of silver nanoparticles involves the use of surfactants and capping agents to direct the size increase.12−14 Although these can provide the necessary growth control, the agents tend to bind strongly to the nanoparticle surface and are difficult to remove.15 For nanotag formation, it is necessary to introduce reporter molecules along with species suitable for the growth of the inert shell onto the nanoparticle surface.7 Unfortunately, these species may not be able to replace the capping agents used to direct the nanoparticle growth. Therefore, it is necessary to use a method which can provide control over the position of the nanoparticle LSPR while providing a surface chemistry suitable for subsequent nanotag formation. Photoreduction-based methods allow the controlled reduction of metal salts. These were originally based on the use of intense white light sources16−18 or laser excitation,19,20 and as such the choice of wavelengths available was restricted.

1. INTRODUCTION Surface-enhanced (resonance) Raman scattering (SE(R)RS) is currently being explored for the in vivo detection of biological species of interest such as disease markers. This requires the development of SE(R)RS nanotags which contain a metallic core to enhance the signal from reporter molecules bound to their surface as well as an inert shell which can be biofunctionalized for active targeting.1−3 The majority of nanotags are currently based around gold nanoparticles due to the ease of preparation of monodisperse solutions and the ability to tune the native colloidal plasmon band.4 However, it is well-known that silver provides a larger SE(R)RS enhancement than gold,5 and work has been carried out to form silverbased nanotags for in vivo applications.6,7 In an effort to maximize the generated signal from the nanotags, it is possible to tune the localized surface plasmon resonance (LSPR) of the base nanoparticle. It has been previously shown that the largest signal is achieved if the LSPR maximum is to the red of the laser excitation wavelength but below the Raman wavelengths.8,9 The nanoparticle LSPR can be red-shifted by increasing the physical size of the nanoparticle. This red-shift allows the use of longer-wavelength excitation which is of 2-fold benefit as it improves the laser penetration depth in tissue and reduces autofluorescence from © 2012 American Chemical Society

Received: September 24, 2011 Revised: January 9, 2012 Published: January 9, 2012 2677

dx.doi.org/10.1021/jp2092219 | J. Phys. Chem. C 2012, 116, 2677−2682

The Journal of Physical Chemistry C

Article

tial illumination was investigated as well as the introduction of additional silver nitrate aliquots. Specifically, a final concentration of 0.165 mM AgNO3 was introduced after illumination of the seed solution at 470 nm but before illumination at 590 nm. 2.3. Characterization. UV−visible spectra were recorded on a Cary 300 Bio UV−visible spectrophotometer using 1 cm path length cells. UV−vis studies were carried out with 400 μL aliquots of the colloid, diluted to 2000 μL, and all UV−vis spectra were normalized. SEM investigations were carried out by preparing poly(diallyldimethylammonium) (PDDA) coated silicon wafers. Silicon wafers were cleaned with methanol followed by 2 min in an oxygen plasma (Diener electronic femto oxygen plasma cleaner, 72 cm3/min gas flow). They were then coated with a 10 mg/mL PDDA solution in 1 mM NaCl for 25 min. After this time, the wafers were rinsed with DDDI water and dried with N2. For sizing of particles, 20 μL of sample was placed on the wafer for 30 min, and this was then replaced with another 20 μL for a further 30 min before the wafer was washed and dried with N2. This provided a surface particle density suitable for sizing. To investigate the state of aggregation in the partially aggregated seed sample, 20 μL of the solution was deposited on a wafer and allowed to rest for only 15 min, which was found to be the optimal deposition time as it did not lead to surfaceinduced aggregation which occurred at longer deposition times. Imaging was carried out on a Sirion 200 Schottky field-emission electron microscope (FEI) operating at an accelerating voltage of 5 kV. The samples did not require additional metallic coating before imaging. Image analysis was carried out using Image J, v1.43u. SE(R)RS studies were carried out by mixing 200 μL of the colloid with 2 μL of 1 × 10−6 M Nile Blue A solution and 200 μL of DDDI water. Partial aggregation of the seed solution was carried out by mixing 200 μL of the seed solution with 2 μL of 1 × 10−6 M Nile Blue A and 200 μL of 20 mM KCl. All samples were allowed to equilibrate for 4 h before analysis. SE(R)RS using 532 nm laser excitation was carried out on an Avalon Instruments Ramanstation R3 with a fiber optic probe, and the power at the sample was measured at ∼24 mW. Spectra were recorded between 250 and 2000 cm−1 at a resolution of 2 cm−1, and 5 × 2 s accumulations were taken with five replicates from three independent solutions. The 592 cm−1 peak intensity of Nile Blue A was monitored. SE(R)RS experiments using 632.8 and 785 nm laser excitation were carried out on an inverted Renishaw inVia Raman Microscope/Leica DMI 5000 M spectrometer using glass-bottomed 96-well plates. The unfocused laser power at the sample was ∼13 and ∼150 mW, respectively, and a 20×/N.A. 0.4 objective was used to focus the laser into the sample. Spectra were centered at 600 cm−1, and 5 × 2 s accumulations were recorded with five replicates from three independent solutions. Spectra were normalized to a cyclohexane standard.

However, the development of high power light emitting diodes (LEDs) has allowed intense, narrow (±10 nm) light sources to be employed which can be used to control the LSPR position.21 After the formation of a seed solution, LEDs are used to excite the LSPR which causes the oxidation of surface-bound citrate molecules which release an electron into the nanoparticle, which leads to the reduction of metal salt ions from solution and the growth of the nanoparticle.20 Although the synthesis of red-shifted silver nanoparticles using LEDs has recently been reported,21 the process leads to broad LSPR bands. Therefore, we have optimized the approach by employing sequential wavelength illumination to keep the absorbance band more coherent at longer wavelengths and the size range of the formed nanoparticles smaller. The SE(R)RS activity of the LED formed nanoparticles has not been previously investigated. The work reported here focuses on their SE(R)RS properties and their potential as the basis for silver nanotags for biological applications. Matching the nanoparticle LSPR to the laser excitation is not the only way to improve the recorded SE(R)RS signal. An alternative method is by the formation of small clusters that allow the LSPRs on individual nanoparticles to couple together and significantly increase the electromagnetic field the molecules experience.22−26 Therefore, we compare the LSPR/ excitation matched individual nanoparticles with small clusters formed from the seed solution used for the LED directed growth process. These small clusters are found to be physically smaller than the red-shifted nanoparticles and produce a SE(R)RS signal equivalent to or greater than the single resonant nanoparticles. These small clusters should be better suited to in vivo studies due to their smaller size, making them more likely to pass through a cell membrane compared to larger particles.27,28 This work highlights a fundamental design rule for silver core SE(R)RS nanotags for use in in vivo applications.

2. MATERIALS AND METHODS 2.1. Seed Preparation. All chemicals were bought from Sigma Aldrich and used without further purification. Seed solutions were prepared following the method described by Stamplecoskie and Scaiano.21 Briefly, 1.3 mg of photoinitiator I2959 was dissolved in 1 mL of doubly distilled, deionized (DDDI) water; 8.5 mg of silver nitrate was dissolved in 1 mL of DDDI water; and 14.7 mg of trisodium citrate was dissolved in 1 mL of DDDI water. The full 1 mL of I-2959 was added to a small cell culture flask; 120 μL of the AgNO3 solution was added; and 600 μL of the trisodium citrate solution was added. The solution was made up to 30 mL with DDDI water before being degassed with nitrogen for 15 min. The solution was then illuminated with UVA light (365 nm) for 5 min, and the solution was observed to go a straw color. 2.2. Particle Growth. High power (3 W) LEDs were purchased from Roithner Lasertechnik GmbH at four set wavelengths: 470, 530, 590, and 625 nm. These LEDs were attached to heat sinks before being wired in parallel to individual DC power units for each wavelength, and they were operated in the voltage window as recommended by the manufacturer. For sample illumination, the LEDs were positioned in a spiral formation around a clear four-sided cuvette. LED directed seed growth experiments initially consisted of the direct illumination of the seed solution at the set wavelengths employed. Following initial experiments, sequen-

3. RESULTS AND DISCUSSION An important consideration for the design of the base nanoparticle used in nanotags is that they are a consistent shape and produce a uniform activity. A small size distribution is represented by a narrow absorbance band in the UV−vis spectrum, and as such, a narrow band, centered at the laser excitation wavelengths, was the initial goal of this work. The prepared photoreduced seed solution had a narrow absorbance band with a full width at half-maximum of 63 nm, centered at 2678



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392 nm. This correlates with a physical diameter, measured by SEM, of 9.1 ± 3.2 nm (N = 500). The seed solution was then illuminated with the different high-power LED wavelengths, and this illumination excited the LSPR of the seed solution which provided the energy to oxidize surface-bound citrate molecules. Upon oxidation of the citrate molecules, an electron is released into the nanoparticle which is then used to reduce a silver ion from solution,20 thus growing the nanoparticle and leading to a red-shift of the LSPR. It was found that the longer the wavelength used for seed illumination the broader the absorbance band became (Figures S1−S8, Supporting Information). It was also observed that the time required for all the seeds to be consumed increased as the wavelength of illumination increased. This is not surprising since the growth mechanism depends on the LEDs exciting the localized surface plasmons of the nanoparticles to cause the oxidation of the citrate molecules. The small seed particles cannot support longer wavelength plasmons, and therefore the growth starts out slowly until the particles increase in size to a point where longer wavelength plasmons can be supported and the rate of citrate oxidation increases. The case of direct seed illumination with LEDs at 625 nm is shown in Figure 1A. It can be seen that after 24 h of

Table 1. Summary of the Size Evolution of Nanoparticles Following Direct Illumination of a Seed Solution with Different Wavelengths of LEDs illumination wavelength/nm time/h 0 3 12 24

470 9.1 82.6 78.9 78.2

± ± ± ±

530

3.2 9.9 8.9 10.7

9.1 38.5 81.9 108.8

± ± ± ±

590 3.2 16.6 37.2 36.2

9.1 22.9 89.3 150.7

± ± ± ±

625 3.2 23.5 61.2 68.9

9.1 53.4 104.6 170.8

± ± ± ±

3.2 65.2 77.1 81.2

minimized illumination time but maximized the LSPR shift while maintaining peak coherence. This optimized illumination time at 470 nm was then used to create a stock solution which was used in a timed 24 h illumination series at 530 nm. However, direct sequential illumination of the sample solution with LEDs at wavelengths beyond 530 nm did not lead to the desired shift in the absorbance band (Figures S9−S11, Supporting Information). Calculation of the amount of silver incorporated into the nanoparticles after the primary illumination step (optimized 470 nm illumination of 6 h) revealed that all the available silver in the solution had been incorporated into the nanoparticles. Therefore, it was necessary to introduce additional silver nitrate before a second illumination step. It was hoped that the first illumination would cause the growth of all the seed particles, “locking in” the morphology of the particles. Subsequent illumination would therefore cause the particles to grow rather than lead to the formation of different structures, such as plates, which were seen during direct seed illumination at longer wavelengths. This was indeed observed (Figures S12−S14, Supporting Information). Although an optimized growth procedure was found which led to a coherent plasmon at longer wavelengths, λmax ∼ 790 nm (i.e., 6 h at 470 nm, followed by an additional 0.165 mM AgNO3 and then 3 h at 590 nm), when stored in the dark the LSPR was observed to blue-shift toward a final value of 690 nm (Figure 1B). It was decided that this stock solution could be used in the subsequent SE(R)RS studies as the absorbance band was positioned after and before the laser excitation wavelengths of 632.8 and 785 nm, respectively, allowing preand postresonance effects to be probed. Optimization of the LED directed growth of nanoparticles resulted in two stock solutions (Figure 2), which had λmax

Figure 1. (A) Effect of direct illumination with 625 nm wavelength LEDs. Insets show representative SEM images (note the very broad absorbance at longer wavelengths). (B) Effect of sequential illumination. The first step involves illumination of the seed solution at 470 nm for 6 h. This is followed by the addition of extra silver nitrate before illumination at 590 nm for 3 h. The spectrum shown is after the stock solution has been stored and the main absorbance band has blue-shifted slightly.

illumination at 625 nm the LSPR is red-shifted and significantly broadened. This band broadening was also reflected in the particle diameters measured by SEM where the average size and standard deviation were seen to increase substantially (Table 1). Therefore, to combat this inherent broadening, a sequential illumination sequence was employed. First, a full 24 h illumination time series was recorded at one LED wavelength, i.e. 470 nm, and an optimized time was then chosen which

Figure 2. UV−vis spectra of the stock solutions used in the SE(R)RS experiments. The laser excitation wavelengths are shown as solid vertical lines.

values of 530 nm (6 h at 470 nm followed by 2 h at 530 nm) and 690 nm (6 h at 470 nm followed by the addition of 0.165 mM AgNO3 and illumination at 590 nm for 3 h). The physical 2679



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sizes measured by SEM were: seed solution; 9.1 ± 3.2 nm, “530 nm stock” 71.5 ± 13.2 nm, and “690 nm stock” 83.8 ± 22.1 nm (N = 500). These results clearly demonstrate that sequential illumination reduced the inherent increase in the nanoparticle size distribution which occurs for direct illumination, i.e., a standard deviation of 22.1 nm for the “690 nm stock” compared to a seed solution that has been directly illuminated with 590 nm LEDs which also provides an absorbance maximum ∼690 nm but results in a much larger standard deviation of 68.9 nm. Before SE(R)RS studies were carried out, it was necessary to confirm that the prepared nanoparticles retained a native citrate surface layer. This is an important design consideration as the presence of a weakly bound citrate layer allows simple control of the surface chemistry by ligand replacement. Use of surfactants and capping agents that have previously been used to direct nanoparticle growth can prevent the adsorption of some types of ligands and therefore limit the amount of control that can be exerted on the surface chemistry. To probe the surface species present, the stocks were aggregated with MgSO4 which causes aggregation without displacing citrate ions,29 should they be present. Figure S15 (Supporting Information) shows the resultant SERS spectra along with a reference citrate spectrum, and it is clear that all the stock solutions have their surface functionalized with citrate which will allow greater flexibility with respect to changing the surface chemistry. Three standard laser excitation wavelengths were used for the SE(R)RS study: 532, 632.8, and 785 nm. Nile Blue A (λmax, 627 nm) was chosen as the probe analyte due to it having a strong Raman spectrum and previous investigations where we have shown that a low concentration, ∼5 nM, does not lead to aggregation of the colloid.24,25 Such aggregation if present could complicate subsequent analysis of the SE(R)RS results for the individual nanoparticle samples. In this manuscript, we want to compare individual nanoparticles with absorbance bands overlapping the laser and samples that contain “hot spots”; therefore, it is important that the individual nanoparticle solutions do not have “hot spots” present, thus the need to prevent aggregation induced by the probe analyte. Figure 2 shows the position of the laser excitation wavelengths with respect to the absorbance profiles of the nanoparticle solutions under study. Figure 3 shows the observed SE(R)RS response from Nile Blue A at 532 nm excitation from the individual nanoparticles as well as a partially aggregated seed solution which contains “hot spots” which is the alternative method of increasing the SE(R)RS signal which we are investigating in this report. It can clearly be seen that the greatest signal from solutions of single particles is obtained when the laser wavelength coincides with the nanoparticle absorbance. However, a larger signal is observed when the seed solution is partially aggregated in the presence of 20 mM KCl. Use of a controlled amount of salt compresses and partially destabilizes the electrical double layer around the nanoparticles without the total removal of the Coulomb repulsion barrier.30 This partial aggregation does not lead to an observable change in the absorbance profile of the solution within our measurements (Figure S16, Supporting Information). However, from the SEM analysis (see below) it is clear that nanoparticles are interacting and creating “hot spots” where the localized surface plasmons on individual nanoparticles are coupling together, creating sites of intense electromagnetic radiation. The SE(R)RS response of the 592 cm−1 peak at all three wavelengths under investigation is shown in Figure 4. It is

Figure 3. SE(R)RS spectral response at 532 nm excitation of all the stock solutions as well as the partially aggregated seed solution. All samples contained 5 nM final Nile Blue A concentration and were allowed to equilibrate for 4 h before analysis. The spectra shown were accumulated for 10 s and are the average of 15 replicates. They are offset for clarity. The 592 cm−1 Nile Blue A peak used for subsequent analysis is highlighted, and the structure of the dye is also shown.

Figure 4. Wavelength-dependent SE(R)RS response of the 592 cm−1 peak of the Nile Blue A analyte with all stock solutions containing individual nanoparticles as well as the partially aggregated seed solution that was aggregated using 20 mM KCl (seed P20). Fifteen replicates were analyzed, and the error bars represent the standard deviation of each sample.

important to note that the analyte under investigation, Nile Blue A, has an absorbance at 627 nm, and therefore there is a resonance contribution from the dye at 632.8 nm. However, in this study we are comparing different samples at the same wavelength rather than absolute signal intensities between excitation wavelengths. Therefore, any analyte resonance contribution should be similar across all nanoparticle samples when the same excitation wavelength is used. At 632.8 nm excitation it is clear that the “690 nm stock” provides the highest enhancements compared to any other sample, including the partially aggregated sample. It has been reported in the literature that the most significant SE(R)RS enhancements are obtained when the substrate absorbance maximum falls between the laser excitation and the Raman band wavelengths.9 In the “690 nm stock” case the substrate absorbance is red-shifted compared to the laser and Raman wavelengths and therefore produces a greater SE(R)RS response compared to any other sample at any other wavelength. For 785 nm excitation, very little signal was observed above the noise level for any of the single nanoparticle solutions, and the greatest signal came from the “690 nm stock”. A much 2680



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possess a range of morphologies and sizes within the same sample, the required assumptions would be too great, and therefore we have presented the normalized experimental results in this work. From the experimental results, it is clear that it is not necessary to expend energy in the tuning of the localized surface plasmon of nanoparticle solutions, but rather the focus should be on the reliable formation of small clusters and their subsequent purification. In our case 10.0 ± 0.75% of species were observed to be small clusters. If the solution could be purified and made to contain 100% small clusters, it is not unreasonable to expect the observed SE(R)RS signal to increase by a further factor of 10. When that is compared to the single nanoparticle solutions, with localized surface plasmons matching the laser excitation wavelength, there is no contest with respect to which produces the greatest signal. Developing methods for the reliable formation and purification of small clusters based on silver nanoparticles will be the focus of future research in our laboratory.

more intense signal was obtained from the partially aggregated seed sample. From SEM investigations where the deposition was controlled to ensure no surface-induced aggregation occurred as previously reported,24 it was found that 10.0 ± 0.75% of the species observed were small clusters (mostly dimers; Figure S17, Supporting Information) which equates to ∼17% of nanoparticles being included within small clusters. This was compared to a dimer percentage of 1.2 ± 0.1% in control experiments (Figure S18, Supporting Information). Although this is lower than we have previously observed,24,25 it should be noted that partial aggregation by controlled salt addition is sample specific and will depend on the amount of stabilizing ions already present in solution, nanoparticle concentration, and nanoparticle surface area. The partially aggregated seed solution was observed to be stable for seven months when stored in the dark (Figure S18, Supporting Information). To summarize the wavelength investigations, it is clear that when considering individual nanoparticles the most intense SE(R)RS signal is achieved from the nanoparticle solution which has the largest absorbance closest to the laser excitation, while off-resonant colloids show a lower SE(R)RS response as demonstrated by the relative peak heights in Figure 4. However, the formation of some small clusters produces a solution with an average SE(R)RS response much larger than any single nanoparticle solution when excited by 532 or 785 nm illumination. In the case of 632.8 nm excitation, the partially aggregated solution produced a signal slightly below that obtained from the “690 stock”. Here it is interesting to consider the low level of cluster formation achieved as the observed SE(R)RS increase is due to the formation of a very small number of clusters. Not all clusters will be SE(R)RS active, and therefore a smaller percentage is most likely responsible for the observed signal increase. This result highlights an important consideration for the design of nanotags; considering the “530 nm stock” particles with an average diameter of 71.5 nm, assuming a diameter of 70 nm and a seed diameter of 10 nm, it is possible to fit ∼250 seed particles in the same volume as one 70 nm particle. We have shown that to achieve a significant increase in the SE(R)RS response all that is needed is the formation of dimers rather than clusters made up of hundreds of particles. A dimer made up of seed particles necessarily has a longest axis of 20 nm, much smaller than the diameters of the other stock solutions. This has important implications when nanotags are introduced in vivo, as smaller nanoparticles can enter cells much more readily than larger nanoparticles.27,28 A fundamental design criterion for nanotags is therefore the formation of intense nanotags while minimizing their physical size. We have shown here that a larger SE(R)RS response is possible when small clusters are formed, irrespective of laser wavelength. Although this experimental finding is different from previous reports in the literature,8,9 such a disconnect between SE(R)RS enhancement and bulk absorption profile when “hot spots”, made up of coupled plasmons, are present has been theoretically demonstrated by Le Ru et al.31 We considered calculating the enhancement factors of the various solutions; however, during such calculations a number of assumptions must be made32 which can oversimplify reality especially in the case of solution-based nanoparticles. The resultant values can be somewhat disconnected from reality and are hard for other workers to replicate. In this instance where we are investigating a solution-based system with many degrees of freedom, as well as solutions containing particles which

4. SUMMARY We have investigated the use of silver nanoparticles as the basis for SE(R)RS nanotags. A photochemical method was employed to control the absorbance maximum of the colloid solutions, and it was found that sequential illumination of the colloid produced a more coherent plasmon band and thus a narrower size distribution of the formed nanoparticles compared to direct illumination of a seed solution with long-wavelength LEDs. Importantly, the method employed led to the nanoparticles retaining a citrate surface layer which minimizes the requirement for complicated surface functionalization. The SE(R)RS response of the single nanoparticles, over three standard laser excitation wavelengths, was probed, and it was found that the biggest signal was obtained when the substrate plasmon was in resonance with the laser excitation, as expected. However, a similar or greater SE(R)RS response was obtained when partial aggregation of the seed particles was carried out to create “hot spots”. Only 10.0 ± 0.75% of the species were found to be small clusters, but these led to a significant increase of the SE(R)RS signal above single seed particles and other stock solutions. The results presented here highlight a fundamental design criteria for SE(R)RS nanotags. It is more important to form “hot spots” between nanoparticles than to tune the absorbance of individual nanoparticles to match the laser wavelength. Effort expended on controlling the morphology of nanoparticles would be better spent developing robust purification methods for small clusters. Minimizing the physical size of the nanoparticles/clusters will also improve cellular uptake due to the fact that small particles can traverse the cell membrane easier than larger particles. These results should be of particular interest to researchers developing SE(R)RS nanotags for in vivo applications and may also be of interest to the wider research community who are developing other probe systems for ultimate in vivo applications.

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ASSOCIATED CONTENT

S Supporting Information *

UV−vis and SEM results of direct and sequential LED illumination of the seed solution and the partial aggregation of the seed solution. This material is available free of charge via the Internet at http://pubs.acs.org. 2681



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(30) Meyer, M.; Le Ru, E. C.; Etchegoin, P. G. J. Phys. Chem. B 2006, 110, 6040. (31) Le Ru, E. C.; Galloway, C.; Etchegoin, P. G. Phys. Chem. Chem. Phys. 2006, 8, 3083. (32) Le Ru, E. C.; Blackie, E.; Meyer, M.; Etchegoin, P. G. J. Phys. Chem. C 2007, 111, 13794.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

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ACKNOWLEDGMENTS The authors thank the EU Seventh Framework Programme, NMP-2008-1.1-1; SMD-229375 for funding and the Royal Society for a Wolfson research merit award to DG. E.A.A thanks the ACS for an IREU Scholarship.

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REFERENCES

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Design Consideration for Surface-Enhanced (Resonance) Raman

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