The Many Faces of Gold Nanorods - The Journal of Physical

PERSPECTIVE pubs.acs.org/JPCL

The Many Faces of Gold Nanorods Catherine J. Murphy,* Lucas B. Thompson, Alaaldin M. Alkilany, Patrick N. Sisco, Stefano P. Boulos, Sean T. Sivapalan, Jie An Yang, Davin J. Chernak, and Jingyu Huang Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois 61801

ABSTRACT Gold nanorods exhibit optical properties that are tunable with their shape, leading to sensing, imaging, and biomedical therapeutic applications. Colloidal preparations of gold nanorods impart surfactants or other species on the nanorod surfaces; a popular preparation leads to a surfactant bilayer on the surface. The specific chemistry at three distinct interfaces has roles to play in the growth and subsequent usage of these nanomaterials; these interfaces are the gold-surfactant interface, the hydrophobic surfactant bilayer, and, finally, the surfactant interface with the aqueous bulk. Each one of these interfaces provides strategies for altering nanorod properties such as stability against aggregation, toxicity, and ease of assembly. It is the solvent-accessible interface that dictates nanorod interactions with other particles, macromolecules, and living cells.

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nterest in gold nanoparticles arises from the shapedependent physical properties of these materials at the nanoscale1-5 and, more recently, the interactions of these nanomaterials with biological systems.5-8 Many review articles show the beautiful shape-dependent optical spectra that gold nanoparticles exhibit when well-dispersed in solution, from strong extinction at ∼520 nm for spheres to the longitudinal plasmon bands at 600-1600 nm for nanorods; the higher the aspect ratio of the nanorod, the longer the wavelength.1-8 The basis for the strong absorption and scattering of visible and near-infrared light by gold nanoparticles and nanorods originates in the coherent, collective oscillation of conduction band electrons (plasmons) in the particles upon illumination with light.1-8 Aggregation of gold nanoparticles can further tune the position of the plasmon bands.1-8 The literature is rich with many proof-of-concept applications of gold nanorods in diverse fields such as chemical sensing and imaging,4 drug delivery,9 and photothermal destruction of cancer cells and pathogenic bacteria, all of which ultimately derive from the properties of the plasmon bands.10,11 For more explicit details about the synthesis, properties, and applications of gold nanorods, the reader is referred to excellent recent reviews.1-8 In this Perspective, we will focus on the interfacial chemistry of gold nanorods and address the questions:

coincident with the groups of M. El-Sayed, P. Mulvaney, and L. Liz-Marzan. The basic idea of these syntheses is to use a strong reducing agent in solution to prepare Au(0) seed particles from gold salts; then, a weak reducing agent is used to reduce more metal salt onto the seed particles. It is important to perform the second growth step in the presence of structure-directing agents (in our case, cationic surfactants) that will promote the formation of nonspherical shapes. There are two general methods to grow gold nanorods in this way: in the absence of additive impurity ions, which can result in longer rods but lower overall yields;12 and in the presence of additive impurity ions, principally silver, which results in finer control of the nanorod aspect ratio (length/width ratio), increases the yield of rod-shaped particles compared to spheres substantially, but does not work for growing longer nanorods.13,14 Surface ligands that bind too weakly to gold, such as citrate, or too tightly to gold, such as thiols, tend to produce truncated crystals that appear spherical in transmission electron micrographs. In the silver-assisted seed-mediated wet chemical synthesis, preformed 1.5-4.0 nm gold seed particles, quasi-spherical in shape and made in water at room temperature, grow to anisotropic shapes, including rods (Figure 1).13,14 This synthetic approach relies on four reactants in addition to the gold seeds, a surfactant (cetyltrimethylammonium bromide (CTAB), also called hexadecyltrimethylammonium bromide), gold ions from HAuCl4, a mild reducing agent (ascorbic acid), and silver ions from AgNO3. Although the details of the anisotropic growth mechanism are beyond the scope of this paper, there is strong experimental evidence that every ingredient/parameter in the synthesis procedure

(1) What is on the surface of gold nanorods? (2) What chemistry can be carried out at their surfaces? (3) What “faces” do gold nanorods present to the local environment? For many biological and sensing applications, the nature of the “soft shell” around the gold nanorod core may be more important for interfacial chemistry than the gold core itself. Synthesis of Gold Nanorods. We concentrate this Perspective on gold nanorods prepared via the seed-mediated synthetic route that was developed by our group, nearly

r 2010 American Chemical Society

Received Date: July 20, 2010 Accepted Date: September 9, 2010 Published on Web Date: September 14, 2010

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DOI: 10.1021/jz100992x |J. Phys. Chem. Lett. 2010, 1, 2867–2875


analysis, and zeta potential analysis.21,22 The CTAB bilayer consists of two surfactant leaflets; one is associated with the gold surface via the quaternary ammonium head groups, and the other has the surfactant head groups facing the aqueous media. This bilayer assembly is energetically favored as it guarantees hydrophobic interactions between the surfactant tails in the bilayer core and hydrophilic interactions of the charged head group with the aqueous media at the nanoparticle-solvent interface. Three distinctive interfaces can be described for the system, the gold nanorod-CTAB interface, the CTAB bilayer itself, and the outer CTAB exposed to the bulk solution (Figure 2). Although the bilayer is drawn as two leaflets that are not interdigitated, the available data (FTIR; measured distances between nanorods in packed layers by transmission electron microscopy) do not actually distinguish between interdigitated and not interdigitated structures. Gold-Surfactant Interface: What Is on the Surface? The molecular-level interaction of CTAB molecules with the gold nanorod surface is not clearly understood. However, it is generally accepted that the surfactant is bound to the surface through electrostatic interactions between the cationic head group (quaternary ammonium) and anionic sites on the gold surface.23 Less understood is the nature of the anionic sites on the gold surface, which could be bromide ions, bromide-related species, silver-related species, or possibly other species, though conflicting reports exist as to what is actually present. The difficulty of understanding the molecular nature of the interface is amplified by the presence of counterions and possible leftover reagents from the synthesis that remain due to inadequate purification. We emphasize that most syntheses begin with ∼0.1 M CTAB and end with roughly micromolar concentrations of CTAB on nanomolar concentrations of gold nanorods. Thus, even if samples are purified at 99.99999%, substantial free CTAB may coexist with bound CTAB. At low pH, the weak reducing agent ascorbic acid may not fully reduce silver to Ag(0) during the synthesis, and therefore, some have proposed the formation of AgBr during nanorod growth.24 (The concentrations used are indeed above the Ksp of bulk silver bromide.) This AgBr would deposit on rod surfaces at the gold-CTAB interface to both stabilize the rods and help direct growth by hindering growth from a specific facet, thus promoting growth on the less densely covered facets. Evidence that points to the presence of AgBr on the nanorods includes chemical shifts in 1H NMR spectra for capped gold nanorods being identical to that of a AgBr-CTAB preformed complex and XPS data that suggest that the detectable silver is present as Ag(I).24,25 However, as noted above, leftover CTAB and silver nitrate from the synthesis can be responsible for the data as well. Another group has reported that AgBr2- and AuBr2- species are detected from gold nanorods (made by a different photochemical method that involves CTAB, silver, and organic components) by a laser desorption/ionization mass spectrometry technique after rather rigorous purification and therefore postulated that these are the key surface species.26 Elemental silver may still exist at the gold nanorod-CTAB interface due to underpotential deposition.19,20 In this case, a monolayer or submonolayer of silver can deposit onto a gold

Figure 1. Summary of silver-assisted gold nanorod synthesis, showing the CTAB bilayer. A representative transmission electron micrograph of aspect ratio 4.6 gold nanorods is shown; scale bar = 100 nm.

plays a critical role in determining the shape and resulting surface chemistry: (1) The properties of the surfactant such as chain length, head group structure, counterions, and even CTAB purity have been found to be critical to the synthesis of gold nanorods. For example, the longer the alkyl chain, the longer the nanorod; bromide favors nanorod growth far more than chloride or iodide; and part-permillion levels of iodide in 0.1 M CTAB are sufficient to drastically reduce the yield of nanorods.15-18 (2) Silver ions in the growth solution are necessary to form high yields of short rods, and the concentration of this reactant has been found to control the dimensions of the gold nanorods; in general, the higher the silver ion concentration, the higher the aspect ratio of the resulting nanorods.13,14,19,20 (3) Temperature, pH, ionic strength of the growth solution, and concentration of ascorbic acid play a critical role in rod formation and control their dimensions in a complex, interdependent manner.13,4,19,20

There is strong experimental evidence that every ingredient/ parameter in the synthesis procedure plays a critical role in determining the shape and resulting surface chemistry. The crystal faces of gold that exist on the different types of gold nanorods are given in Table 1, as judged by single-area electron diffraction and high-resolution transmission electron microscopy. Gold nanorods prepared in either version of the seedmediated wet chemical approach are produced with a CTAB bilayer (Figure 1).21,22 The existence of a bilayer as opposed to a monolayer is widely accepted and has been supported experimentally with IR spectroscopy, thermogravimetric


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Table 1. Crystallographic Information on the Gold in Gold Nanorods1-3 gold nanorod type

synthetic method

“long” (aspect ratios 10-20)

with CTAB; no silver

“short” (aspect ratios 1-5)

with CTAB; with silver

long (side) faces

end faces

comment

five faces; mixture of {110}, {100} four {110} faces

10 {111} faces (five faces per end)

pentatetrahedral twinned

two {100} faces (one face per end)

single crystalline

Figure 2. A cartoon that shows the CTAB bilayer on the surface of a gold nanorod with three distinctive subregions for different chemical reactions. See text for details. Figure 3. A cartoon that demonstrates the electrostatic interactions of CTAB's head group with anionic sites on the surface of gold nanorods, as well as the idealized products of exchange (blue molecule) or displacement (red molecule) reactions with other quaternary ammonium surfactants or thiols, respectively.

surface at a potential much less than what is needed for bulk deposition. If silver underpotential deposition has occurred, adjusting the Ag(I) concentration should modulate the relative silver coverage on different gold facets and dictate the growth along these facets, which is consistent with the standard synthetic protocol. Evidence for Ag(0) on gold nanorods comes from EXAFS studies and from nanorods made using the same photochemical procedure referenced in the previous paragraph.27 The amount of silver in/on the gold nanorods has been quantified by inductively coupled atomic emission spectroscopy; this technique does not distinguish between Ag(I) and Ag(0), but the data suggest that about four monolayers worth of silver is present on the final purified nanorods.20 For gold nanorods grown in the absence of silver, a different growth mechanism is operative as the gold-CTAB interface obviously will not contain any silver species.12,28 We have single-area electron diffraction evidence for a pentatwinned structure of silver-ion-free gold nanorods, with five {111} triangular facets at the ends of the rods and a mixture of the {100} and {010} facets on the side faces of the rods (Table 1).28 Bromide appears to be the key component that produces nanorod growth, albeit at low yield; growth solutions that are low in CTAB concentration can be supplemented with sodium bromide to produce nanorods.16,17 One conclusion suggested by the data is that preferential adsorption of the bromide to different faces of the gold controls particle shape.16,17 CTAB with greater than ∼50 ppm iodide prohibits nanorod growth due to disruptive adsorption of iodide to Au{111} surfaces.18 Chemistry at the Gold Nanorod Surface: Displacement and Exchange. A number of groups have sought to replace the CTAB, postsynthesis, with other gold binding ligands. Putative exchange of the CTAB bilayer with ligands such as alkanethiols9,29-32 or phospholipids23,33 has been used to modify gold nanoparticles. In these cases, the chemisorbed halide-on-gold/silver-CTAB complex needs to be replaced


with a gold-sulfur bond. The difficulty that many groups have found in doing so30,32 suggests that the CTAB interaction is not a weak one, and the thiols or lipids that have been used could simply sequester in the CTAB bilayer or replace the more weakly bound outer leaflet of the CTAB bilayer rather than truly replace the entire bilayer. Quantification of the organic component on the gold nanorods then is the best way to determine the surface composition; methods to do so are discussed below. It is possible to use an ion exchange approach to replace the CTAB with a molecule that has a similar cationic head group.23,34 For example, Orendorff and co-workers were able to displace the CTAB molecules with a phospholipid (containing a quaternary ammonium head group, just like “real” CTAB) that rendered the gold nanorods more biocompatible.23 Our own research group used a tail-modified version of CTAB containing a polymerizable moiety (Figure 3) to exchange the CTAB bilayer for a polymerizable CTAB (pCTAB) analogue.34 The percent of the polymerizable surfactant in the bilayer was determined to be 77%, indicating that the pCTAB replacement occurred in both leaflets of the bilayer. The methods to quantify the surface composition included purification of the nanorods, followed by cyanide digestion to dissolve the gold, followed by liquid chromatography/mass spectrometry compared to standards to quantify the organic components.34 As desorption of weakly bound molecules is an issue, a “capture coat” step before digestion works well to fix the composition of the bilayer for analysis. This capture coat step consists of overcoating the nanorods with polyelectrolytes to trap surface-bound molecules, so that they do not desorb upon purification and processing. Overall, the ability to exchange the CTAB molecules on the surfaces allows

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Polyelectrolyte layer-by-layer (LbL) assembly on colloidal nanoparticles was first demonstrated in 1998 and has since been applied to many colloidal nanoparticles. In the LbL approach, polyelectrolytes of opposite charge are sequentially added to a colloidal dispersion, with intermediate purification steps; the zeta potential flips between positive (cationic) to negative (anionic) as the layers build up.40,41 One particular issue with the native CTAB bilayer on gold nanorods is that the CTAB in the outer leaflet of the bilayer can desorb over time to equilibrate with its surroundings (if the surroundings are CTAB-free); the desorbed CTAB itself has some toxicity to cells,42 and the reduced surface charge on the remaining nanorods makes them more susceptible to irreversible aggregation. Polyelectrolyte LbL coating offers a way to overcome this issue as the polyelectrolyte overcoats and traps the CTAB molecules on the gold nanorod surface. The LbL approach also has the added benefit of being used as a capture coating to fix the composition of the bilayer for quantitative analysis of the degree of exchange, as mentioned earlier.34 The polyelectrolytes used are generally carboxylate-, sulfonate-, or aminecontaining polymers that bear charges at pH 7 in water.

Figure 4. A cartoon that demonstrates the ability of the CTAB bilayer to sequester species (metal ions, drugs, polymerizable monomers) from water. “Release” comes about due to either passive diffusion or active heating of the nanorod by near-infrared illumination.

for a diverse range of potential chemistries to be imparted on the surfaces of the gold nanorods. Chemistry in the CTAB Bilayer. The CTAB bilayer on the gold nanorods provides a ∼2-3 nm thick hydrophobic region that is intriguingly near both a metal and the aqueous environment. This hydrophobic region can be considered as an organic solvent layer with the ability to concentrate/sequester hydrophobic molecules from the aqueous bulk (Figure 4).35 As we have just seen, on-particle polymerization reactions can occur in the bilayer if the tail of the bilayer bears a polymerizable group.34 We found that the CTAB bilayer is effective at concentrating hydrophobic yet water-soluble molecules, such as 1-naphthol, from the aqueous bulk, with a maximum concentration of ∼15000 molecules taken up per nanorod (15 nm 60 nm) and an equilibrium binding constant of ∼2 104 M-1.36 This corresponds to a thermodynamic free energy to binding of 36 kJ/mol, consistent with several van der Waals interactions of 1-napthol with the bilayer.36 The ability to load the bilayer with hydrophobic molecules provides an opportunity to perform in-bilayer chemistry.34 We showed that exposure of gold nanorods to styrene monomers followed by addition of an initiator to polymerize the monomers resulted in polystyrene-coated gold nanorods.37 Another excellent example is the work of Sun et al., in which they employed the CTAB bilayer to concentrate metal thiobenzoate (insoluble in water) and reduce the metal to form a gold-metal sulfide core-shell structure.38 Molecules that have been taken up by the bilayer could be released over time due to passive diffusion. A more active form of desorption is possible, however, due to the unique plasmonic properties of gold nanorods that give them enormous extinction coefficients in the red and near-infrared.20 Near-infrared laser irradiation into the gold nanorod plasmon band can trigger controlled release of molecules from the CTAB bilayer, as demonstrated by the release of octadecylrhodamine B chloride by ultrafast pulsed laser irradiation.39 This conversion of light into heat by the nanorods is the same principle used for killing pathogenic cells.5-7,9-11 Chemistry on Top of the CTAB Bilayer. The CTAB bilayer provides a net positive surface charge to the gold nanorods, as measured by zeta potential analysis, suggesting that counterions are only loosely associated with the particles in water.


The implications of a possibly dynamic and certainly complex overcoating on engineered nanoparticles are profound. Is this one fundamental reason why the vast majority of nanoparticles that are engineered to bind to a specific biological target never make it to that target in a whole organism? The implications of a possibly dynamic and certainly complex overcoating on engineered nanoparticles are profound. Is this one fundamental reason why the vast majority of nanoparticles that are engineered to bind to a specific biological target never make it to that target in a whole organism? The physical properties of the polyelectrolytes, as well as the deposition conditions, must be optimized in order to obtain a high-quality coating with no deleterious side effects. The success of wrapping the polyelectrolyte chains around the nanorod depends on the linear charge density of the polymer and on the initial charge distribution of the CTAB-capped nanorods. Nanoparticle dimensions need to be smaller than the Debye-Huckel screening length for optimal coating without nanophase aggregation.43 Monte Carlo simulations have shown that the wrapping of polyelectrolytes is dependent not just on the nanoparticle charge density and ionic concentration but also on a finite balance between monomer nanoparticle attraction and

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Scheme 1. Three Pathways to Conjugate a Protein to Gold Nanorods

Top: Overcoating of CTAB-coated gold nanorods with a polystyrene sulfonate-maleic acid copolymer renders the nanorods with a net negative charge at pH 7; the sulfonates maintain charge through subsequent processes, while the carboxylic acid groups may react. Pathway 1: An amine-PEG-azide molecule is conjugated to the carboxylates on the nanorods, using a water-soluble carbodiimide (EDC) to make amide bonds. The terminal amine groups on the protein are modified with a pentynoic acid to yield accessible alkynes on the protein. Finally, the nanorods and protein are clicked together with a Cu(I) catalyst. Pathway 2: The terminal amines on the protein are reacted with the terminal carboxylic acid groups on the nanorods to form amide linkages using EDC chemistry. Pathway 3: At pH 7, nanorods bear a net negative charge from the terminal acid groups, and the protein bears a net positive charge from the terminal amine groups; simple mixing results in electrostatic adsorption. For all pathways, although only one protein is shown binding to the nanorods, thousands of proteins can in fact be loaded onto the surface.

and azide-alkyne “click” chemistry; we also quantified the degree to which the protein retained its activity (Scheme 1).45 Ultimately, one-half to two-thirds of the available surface area was bound by protein for all reaction strategies, as judged by ICP-MS quantitation of the metal and a fluorescence assay for the protein (total minus free equals bound).45 On the basis of on-particle reactions of the bound protein, quantified by fluorescence assays of isolated products, 10-20% of the bound protein retained its specific activity for electrostatic adsorption and amide bond linkages; 57% of protein activity was retained in the case of the click reaction.45 It must be noted, however, that the click chemistry produces a longer chain length between the protein and the nanorod surface than the other two methods and may improve any steric hindrance associated with the protein performing its reaction on the nanorod. In addition to using polyelectrolytes and further organic coupling reactions to tailor the surface chemistry of the gold nanorods, it is possible to create inorganic shells on gold nanorod cores. By far, the most common inorganic coating is silica.46-48 Gold nanoparticles have a low inherent affinity for silica because, unlike most other metals, gold does not form a passivating oxide film in solution. For this reason, most of the silica coating routes involve a pretreatment of the metal surface with coupling agents, surfactants, or polymers. Some of the more traditional methods for coating gold nanospheres

monomer-monomer repulsion.44 A necessary component of the LbL technique is the addition of a salt to optimize the electrostatic screening of the polyelectrolyte in solution while keeping in mind that excessive salt will aggregate the nanorods.40 Use of higher-molecular-weight polymers allows for lower salt concentrations but can cause flocculation via bridging or group coating of the particles. Taking all of these factors into consideration has led to the use of polyelectrolytes with molecular weights in the range of ∼15000-70000 g/mol in 1 mM NaCl for coating our rods (dimensions of 10-15 nm wide 15-400 nm long).41 Due to the protocol associated with the LbL technique, gold nanorods typically are limited in the number of layers that can be deposited. The main difficulties occur with smaller nanorods (aspect ratio 1-5, 100 nm in length), 8-10 layers are possible. After LbL coating, gold nanorods bear charged groups that face the solvent. These terminal functional groups are capable of further conventional reactions (e.g., amide bond formation between surface-anchored amines or acids, with free acids or amines). We have quantitatively compared three different strategies to immobilize proteins on the surface of gold nanorods: electrostatic adsorption, amide bond formation,


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solution “see” is not necessarily what was engineered to be on the surface of the nanorod.42,50-52 We have recently shown that exposure of gold nanorods (triple-coated with polyelectrolytes, terminating in poly(styrene sulfonate)) to cardiac fibroblasts altered the cell phenotype, and we speculated at the time that unintentional protein adsorption altered the cells' “equilibrium position” in a LeChatelier-like manner.53 Recent data from our lab do indeed suggest, as has been observed by others,54 that dozens of proteins are taken up by nanoparticles upon nanoparticle exposure to biological “soup”. The challenge is, then, to understand these effects and try to mitigate them with surface chemistry that promotes resistance to protein adsorption or make use of them to potentially control cell fate. Many interesting applications of gold nanorods do not require them to be exposed to such complex aqueous systems. The anisotropic nature of the rod shape suggests that different chemistry can be operative on the ends of the nanorods compared to those on the sides. If true, then it should be possible to create “two-toned” nanorods in which the ends of the nanorods bear different chemical functionality than the sides. For rational assembly of nanoscale objects or for designed coupling of the longitudinal but not transverse plamson bands of gold nanorods, such asymmetry in surface groups is greatly desired.

with silica rely on the affinity of amines as a primer for citratecapped gold nanospheres followed by the addition of active silica. Graf et al. used poly(vinylpyrrolidone) (PVP), an amphiphilic polymer that adsorbs to a wide variety of metal nanoparticles and allows the direct transfer of the colloids into ammonia/ethanol solvent, as a coating strategy that was independent of pH.47 From there, smooth and homogeneous silica coatings were grown by the addition of tetraethoxysilane.47 Even though these methods work well for citratecapped gold nanoparticles, they have largely failed for the silica coating of CTAB-coated gold nanoparticles due in part to the strong binding of CTAB surfactant to the surface of the gold nanoparticles, making displacement by silane coupling agents difficult (citrate is evidently only weakly bound to gold nanospheres). Furthermore, the presence of the CTAB monomer promotes the formation of mesoporous silica.48 In order to overcome these limitations imparted by CTAB, a polyelectrolyte LbL technique was employed by Pastoriza-Santos et al. to shield the effect of CTAB on the gold nanoparticle surface before coating the nanoparticles with PVP.48 Recently, Fernandez-L opez et al. used methoxypoly (ethylene glycol)thiol (mPEG-SH) to “displace” the CTAB at the surface of gold nanoparticles in order to transfer the particles into ethanol while providing a surface that has an affinity for silica nuclei as well as providing stability against aggregation. From there, silica was directly grown on the particle surface using the standard St€ ober method.49 Despite numerous papers on silica coating of gold nanorods, there are still problems with reproducibility between laboratories. This is probably due to the sensitivity of these methods to reagent concentrations, surface chemistry at the surface of the nanoparticles, pH of solutions, and so forth. Applications such as surface-enhanced Raman scattering, where gold nanoparticles are used for signal enhancement of Raman-active molecules, require analytes to be at a close distance (∼10 nm or less) to the gold nanoparticle core. While a thin (sub-5 nm) layer of silica using the mPEG-SH is achievable on gold nanorods, in our own group, we have found it hard to obtain homogeneous layers. In contrast, there are seemingly better methods to harness the ability of the CTAB bilayer to sequester hydrophobic molecules and use them as a source for the subsequent growth of a wide array of metal sulfide shells that include Ag, Zn, Ni, Co, and Cd.38 Final Frontier: What Faces Do Gold Nanorods Present to Their Local Environment? The quaternary ammonium head groups of CTAB in the outer leaflet face the solvent for assynthesized gold nanorods. We have just seen that it is possible to overcoat the CTAB bilayer with polyelectrolytes and thus have amine, carboxylate, sulfonate, or other groups facing the solvent, available for surface chemistry. In biological experiments, as we and others have argued before, cells and organisms reside in complex aqueous media, and components of the media overcoat the nanorods.42,50-52 Qualitatively, the zeta potential (effective surface charge) of the nanorods will change; in fact, for as-made cationic and anionic nanorods, five minutes of exposure to a standard cell media is enough to flip the surface charges of all nanorods to the same value that corresponds to the zeta potential of the main protein in the media.42 Thus, what molecules in the


The anisotropic nature of the rod shape suggests that different chemistry can be operative on the ends of the nanorods compared to those on the sides. There is evidence in the literature that gold nanorods can be selectively functionalized at the ends, leaving the CTAB bilayer on the sides (presumably). In our own group, we incubated long gold nanorods with biotin disulfides, added streptavidin (a protein which can tightly bind up to four biotins), and showed, at appropriate concentrations, that the nanorods were linked end-to-end with high statistical significance, as judged by transmission electron microscopy.55 These nanorods' longitudinal plasmon bands were too far into the near-infrared to be able to take supporting spectra, which were predicted to show a characteristic red shift and broadening. As streptavidin is a ∼5 nm object, we were also able to measure the rod-rod spacings that were 5-7 nm, highly suggestive of the presence of the protein connector. Since then, many other groups have reported end-to-end linkages of shorter gold nanorods,and, in some cases, showed red-shifting longitudinal plasmon bands; dynamic light scattering is another tool for supporting the notion of aggregation.56-61 Many of these papers use TEM as the primary method to establish end-to-end connections for small molecule linkers.56-61 As it is possible to randomly find end-to-end

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nanorods on a TEM grid when no linkers are present, good statistics and control experiments are essential to support the contention that true end-to-end behavior is observed. One recent Science paper reports that hydrophobic polymers at the ends of CTAB-capped gold nanorods can be lead to rational assembly of chains and small rings of nanorods.62 Again, TEM is the primary characterization tool. Less examined as a method to infer the existence of multiple faces of nanorods are etching reactions in which CTAB-coated gold nanorods preferentially are “eaten” from the ends, suggesting that the ends are more available for reaction either because CTAB is not present or because the crystallographic faces of the exposed metal are differentially reactive.63,64

community to quantitatively reach their goals on a large, reproducible scale.

AUTHOR INFORMATION Corresponding Author: *To whom correspondence should be addressed. E-mail: murphycj@ illinois.edu.

Biographies Catherine J. Murphy is the Peter C. and Gretchen Miller Markunas Professor of Chemistry at the University of Illinois at UrbanaChampaign. She was educated at Illinois (B.S. 1986), Wisconsin (Ph.D. 1990), and Caltech (postdoc, 1990-1993) and was a faculty member at the University of South Carolina from 1993 to 2009. Her coauthors, listed in order of seniority, are current members of her research group and hail from the midwestern United States (L. Thompson, D. Chernak), the southeastern United States (P. Sisco), Jordan (A. Alkilany), Haiti (S. Boulos), the United Kingdom (S. Sivapalan), Singapore ( J. Yang), and China ( J. Huang).

FUTURE DIRECTIONS AND CHALLENGES The questions that we set out to answer ; what is the surface of gold nanorods, how can we manipulate the surface chemistry, and what faces to the gold nanorods show to the outside environment ; have been partially answered. We identify several key challenges that need to be addressed for more progress on these questions:

ACKNOWLEDGMENT We thank the National Science Foundation and the Air Force Office of Scientific Research for funding, and our collaborators and past group members for their wonderful contributions.

(1) New tools are needed to quantitatively characterize the local chemical environment of nanoparticles in situ with high spatial resolution. “Local” means both the outer corona of physisorbed molecules and the chemical identity of metal-bound ligands. (2) The perennial issue of biofouling, which plagues most conventional biosensors, is operative for nanoparticles in complex aqueous systems as well. Surface chemistry functionalization strategies such as using PEG to resist protein adsorption should help, but more work needs to be done to actually quantify the degree of PEGylation and the degree of protein desorption on these surfaces.65 (3) The design rules for growing nanorods and chemical functionalization of their surfaces, especially if more than one surface group is desired to face the solvent, are emerging, but for the most part, a priori predictions of what nanoparticle shape would result from a given synthetic protocol are few; rationalization of the product shape after the fact is the norm. Improved computational simulations that explicitly include ions and solvent molecules may be able to guide synthetic work more effectively.

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Rationalization of the product shape after the fact is the norm.

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The tendency of the “user community” for gold nanorods is to conjugate the nanorods for an application and demonstrate that the nanorods made it to the target/destroyed a cancer cell/assembled into the proper macrostructure. A more in-depth understanding of the faces that gold nanorods show to their environment will improve the ability of the user


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The Many Faces of Gold Nanorods - The Journal of Physical

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