Pancreatic tumor microenvironmental acidosis and hypoxia transform gold nanorods into cell-penetrant particles for potent radiosensitization.

Coating nanoparticles with stealth epilayers increases circulation time by evading opsonization, macrophage phagocytosis, and reticuloendothelial sequestration. However, this also reduces internalization by cancer cells upon reaching the tumor. We designed gold nanorods (GNRs) with an epilayer that retains stealth properties in circulation but transforms spontaneously in the acidotic tumor microenvironment to a cell-penetrating particle. We used a customized stoichiometric ratio of l-glutamic acid and l-lysine within an amphiphilic polymer of poly(l-glutamic acid-co-l-lysine), or P(Glu-co-Lys), to effect this transformation in acidotic environments. P(Glu-co-Lys)-GNRs were internalized by cancer cells to facilitate potent in vitro radiosensitization. When administered intravenously in mice, they accumulate in the periphery and core of tumors without any signs of serum biochemical or hematological alterations, normal organ histopathological abnormalities, or overt deterioration in animal health. Furthermore, P(Glu-co-Lys)-GNRs penetrated the tumor microenvironment to accumulate in the hypoxic cores of tumors to potently radiosensitize heterotopic and orthotopic pancreatic cancers in vivo.

Self-Assembly of Nanocrystals into Ring-like Superstructures: When Shape, Size, and Material Do Not Matter.

This manuscript describes a universal method for the spontaneous self-assembly of nanostructures ranging from 2-4 nm spherical particles to ∼440 nm long anisotropic nanorods into ring-like superstructures. The nanostructures composed of Au, Pt, and Pd as surface materials were synthesized in an aqueous cetyltrimethyl ammonium bromide (CTAB) solution. The ligand exchange technique with 4-mercaptophenol was applied to replace CTAB from the surface of nanostructures with a functional thiol. The esterification reaction was carried out to covalently attach carboxy-terminated long-chain polystyrene (PS) molecules to the surface of nanostructures. The high grafting density of PS chains around nanocrystals made them highly soluble in a wide range of organic solvents. When a drop of nanostructure solution in a volatile nonpolar solvent was dried on a solid surface, the nanostructures spontaneously arranged themselves in the form of ring-like assemblies. The condensation of microscopic water droplets from the atmosphere on the surface of an evaporating solvent creates templates for the self-assembly of nanostructures into rings. We demonstrate that this self-assembly method is highly universal and can be extended to various nanostructures regardless of their shapes, sizes, and surface materials.

Synthesis of Asymmetric One-Dimensional Pd on Au Bimetallic Nanostructures.

Nanostructures composed of a gold nanorod (AuNR) core and a Pd/Pt shell are of great interest due to their potential application as plasmon resonance-enhanced catalysts. However, the synthesis of well-defined one-dimensional bimetallic nanostructures with precise control over shell thickness and length remains a challenge. In this study, we report a detailed and systematic study on the chemical synthesis of a uniform Pd shell on single crystalline and pentahedrally twinned (PHT) AuNRs of various lengths. AuNRs were used as a template, and the slow and controlled reduction of Pd(II) ions on preformed AuNRs was carried out for the formation of rectangular-shaped Au@Pd bimetallic nanorods. The Pd shell thickness around the AuNRs was controlled by the supply of Pd(II) ions in the growth solution. We were able to grow a ∼20 nm uniform Pd shell around the AuNR, keeping the rod-like morphology intact without local nucleation to form irregular shapes and randomly overgrown nanostructures. The formation of bimetallic nanorods was also extended beyond typical single crystalline nanorods to PHT high aspect ratio gold nanorods and nanowires, using them as templates. To our surprise, unusually curved asymmetric nanorods were formed when the Pd deposition was carried out on AuNRs longer than ∼800 nm which could be possibly due to a Pd and Au lattice mismatch at the interface and higher flexibility of the nanorods when they exceeded certain lengths.

Gold Nanowires from Nanorods.

Gold nanowires (AuNWs) possess strong potential application in micro- and nanoelectronics as well as in plasmonic waveguides because of their low electrical resistance. However, the synthesis of pure solvent-dispersible AuNWs with full control over their length still remains a challenge. All the previously reported methods produce AuNWs with other impurities such as smaller nanorods, platelets, and spherical particles and are limited to a certain length (typically below 10 µm). This article describes a one-step synthesis of extremely long AuNWs (up to 25 µm) with great control over their dimensions by using pentahedrally twinned gold nanorods (AuNRs) as seed particles. To induce the AuNW growth, the reduction of Au(I) to Au(0) was carried out on the surface of AuNRs at a very low pH by introducing HCl into the growth solution. The slow conversion of Au(I) to Au(0) due to the increase in reduction potential at lower pH promoted the preferential deposition of metallic gold on the more reactive tips of AuNRs compared to their sides, resulting in the formation of AuNWs. In analogy to the "living" polymerization reaction, the length of the AuNWs was proportional to the amount of Au(I) added to the growth solution; thus, the desired length of AuNWs was achieved by controlling the supply of Au(I) ions in the reaction mixture. The AuNWs longer than 6 µm were found to be responsive to microwave radiation. When an aqueous solution of AuNWs was exposed to microwaves, the formation of sharp kinks was observed in several locations of AuNWs without their disintegration into smaller pieces.

Solution synthesis of anisotropic gold microcrystals.

Wet chemistry methods have proven to be successful for the synthesis of nanocrystals. However, the size and shape control is often lost when the dimensions of the particles exceed several hundred nanometers. Therefore, a synthetic transformation of nano- to microcrystals in solution remains to be a challenge. Here we report a very efficient chemical synthesis of anisotropic microcrystals of gold and the set of experimental conditions that enables precise control over their size and aspect ratio.

Gold Nanorod Synthesis with Small Thiolated Molecules.

Size and shape tunability have been widely demonstrated for gold nanorods (AuNRs), but reproducible and reliable protocols for the synthesis of small nanocrystals with high yield are still needed for potential biomedical applications. Here, we present novel seed-mediated and seedless protocols for gold nanorods by incorporating bioadditives or small thiolated molecules during the growth stage. The bioadditives glutathione (GSH), oxidized glutathione (GSSG), l-cysteine (l-cys), and l-methionine (l-met) are utilized in nanomolar and micromolar concentrations to modify the aspect ratio of AuNRs in a reproducible form. Overall, smaller aspect ratios are achieved for both synthetic approaches due to reduction in length or increment in length and width depending on the method, type of bioadditive and the strength of its interaction with the nanorod surface. For the seeded synthesis, only GSSG produces large nanorods in high yield, whereas for the seedless method GSH and GSSG form small nanorods with higher quality when compared to controls.

High yield synthesis and surface chemistry exchange of small gold hexagonal nanoprisms.

A new seed-mediated synthesis of AuHNPs in high yield is described using hydroquinone as a weak reductant and poly(vinylpyrrolidone) as a shape-directing additive. We obtain distinct and small edge lengths of AuHNPs with long-term shape stability. Also, PVP enhances the monodispersity and enables the higher stability of functionalized nanoprisms.

Improving the Shape Yield and Long-Term Stability of Gold Nanoprisms with Poly(vinylpyrrolidone).

Gold nanoprisms (AuNPRs) are anisotropic nanostructures that have gained great attention in recent years because of their interesting and unique optical properties that can be tailored for biomedical, energy, and sensing applications. At present, several protocols have reported the high yield synthesis of AuNPRs of different dimensions using a seed-mediated approach. However, there is a need to develop reproducible and scalable methods with the goal of a controllable synthesis. Here, we report an improved seed-mediated synthesis of small monodisperse AuNPRs of distinct sizes in high yield using poly(vinylpyrrolidone) (PVP) as an additive in nanomolar concentrations. We show optimal synthetic parameters for a blue-shifting of the surface plasmon resonance band which correlates with the reduction in the edge length (L) of AuNPRs from 75 to 35 nm. Using measured extinction coefficients for AuNPRs of different sizes, a linear equation is proposed to estimate the concentration of unknown samples by using Beer's law. Interestingly, the use of nanomolar amounts of PVP during the growth of AuNPRs significantly improves the shape yield. The surface chemistry properties of AuNPRs were measured by X-ray photoelectron spectroscopy and attenuated total reflectance infrared spectroscopy and revealed that PVP chains interact with AuNPRs through the carbonyl oxygen. This method is reproducible and scalable and enables the synthesis of AuNPRs with long-term shape stability (1 year) in aqueous solution.

Chemical Transformation of Nanorods to Nanowires: Reversible Growth and Dissolution of Anisotropic Gold Nanostructures.

This manuscript describes a reversible wet chemical process for the tip-selective one-dimensional (1D) growth and dissolution of gold nanorods (AuNRs) and gold nanowires (AuNWs). Tip-selective dissolution was achieved by oxidation of AuNRs with a Au(III)/CTAB complex, whereas the growth of AuNRs was carried out by the reduction of Au(I) ions on the AuNR surface with a mild reducing agent, ascorbic acid (AA). Both the dissolution and growth processes are highly tip selective and proceed exclusively in one dimension. A decrease in the aspect ratio (AR) of AuNRs during the dissolution resulted in a blue shift in the longitudinal plasmon band (LPB) position, and red shifts in the LPB position were achieved by increasing the AR by 1D growth of AuNRs. Both growth and dissolution processes are fully controllable and can be stopped and resumed at any given time when the desired AR and/or LPB position is achieved. In addition, the tip-selective 1D growth of AuNRs can be continued with the additional supply of Au(I)/CTAB/AA solution to produce extremely long AuNWs.

Gram-Scale Synthesis of Isolated Monodisperse Gold Nanorods.

Although gold nanorods (AuNRs) have strong potential applications in nanotechnology, plasmonics, and sensing, the scale-up synthesis of isolated AuNRs in gram quantities remains a challenge. Nearly all previously reported methods produce aqueous solutions of cetyltrimethylammonium bromide (CTAB)-coated AuNRs in milligram quantities with yields of approximately 20-30 % in terms of AuI to Au0 conversion. In addition, it is difficult to remove the CTAB bilayer from the surface of AuNRs and yet make them soluble and functionalized for further processing and chemical modification. This report describes the synthesis of monodisperse functionalized AuNRs (standard deviation, σ≈5 %) in gram quantities. Our approach involved increasing the concentration of HAuCl4 ⋅3 H2 O in the growth solution to produce larger quantities of starting AuNRs and further reducing the remaining AuI ions onto the surface of AuNRs. The slow and controlled addition of ascorbic acid as a reducing agent continued the conversion of AuI into Au0 (through a disproportionation reaction) onto the surface of the nanorods, which maintained their uniform morphology without creating any unwanted impurities of various shapes. In addition, this approach significantly narrowed the size distribution owing to continuous growth of the partially grown AuNRs during the initial stage of the synthesis. To isolate a 1 g quantity of the AuNRs and to make them functionalized for further chemical reactions, a ligand-exchange approach was utilized, in which the CTAB surfactant was replaced with 4-mercaptophenol. The thiol group from 4-mercaptophenol formed a covalent bond with the surface of the AuNRs, leaving free functional OH groups available for further chemical coupling reactions. For the ligand-exchange process, a concentrated solution of 4-mercaptophenol in tetrahydrofuran solution was introduced into the AuNRs solution. Pure AuNRs functionalized with 4-mercaptophenol were isolated by dispersion and rinsing with an excess amount of THF, followed by centrifugation.

Accelerating Gold Nanorod Synthesis with Nanomolar Concentrations of Poly(vinylpyrrolidone).

A novel modification for the seedless synthesis of gold nanorods (AuNRs) has been developed. Nanomolar concentrations of 10 kDa poly(vinylpyrrolidone) (PVP) can be introduced to a growth solution containing 25, 50, or 100 mM cetyltrimethylammonium bromide (CTAB) to significantly reduce the dimensions of AuNRs. We found that PVP accelerates the growth rate of AuNRs by more than two times that of nanorods grown in 50 and 100 mM CTAB solutions. Additionally, there is a time-dependent effect of adding PVP to the nanorod growth solution that can be utilized to tune their aspect ratio. Because the concentration of PVP is far below the concentration of HAuCl4 in the reaction mixture, PVP primarily functions not as a reducing agent, but as a capping or templating ligand to stabilize the growing nanorods. Our reproducible protocol enables the synthesis of AuNRs in high yield with tunable sizes: 45 × 6.7, 28 × 5.5, and 12 × 4.5 nm for 100, 50, and 25 mM CTAB, respectively. We estimated the number of PVP chains per nanorod in growth solutions to be around 30, which suggests that the effect on the aspect ratio is caused by a direct interaction between the AuNR surface and the PVP.

Optimization of Spectral and Spatial Conditions to Improve Super-Resolution Imaging of Plasmonic Nanoparticles.

Interactions between fluorophores and plasmonic nanoparticles modify the fluorescence intensity, shape, and position of the observed emission pattern, thus inhibiting efforts to optically super-resolve plasmonic nanoparticles. Herein, we investigate the accuracy of localizing dye fluorescence as a function of the spectral and spatial separations between fluorophores (Alexa 647) and gold nanorods (NRs). The distance at which Alexa 647 interacts with NRs is varied by layer-by-layer polyelectrolyte deposition while the spectral separation is tuned by using NRs with varying localized surface plasmon resonance (LSPR) maxima. For resonantly coupled Alexa 647 and NRs, emission to the far field through the NR plasmon is highly prominent, resulting in underestimation of NR sizes. However, we demonstrate that it is possible to improve the accuracy of the emission localization when both the spectral and spatial separations between Alexa 647 and the LSPR are optimized.

Adsorption and Unfolding of a Single Protein Triggers Nanoparticle Aggregation.

The response of living systems to nanoparticles is thought to depend on the protein corona, which forms shortly after exposure to physiological fluids and which is linked to a wide array of pathophysiologies. A mechanistic understanding of the dynamic interaction between proteins and nanoparticles and thus the biological fate of nanoparticles and associated proteins is, however, often missing mainly due to the inadequacies in current ensemble experimental approaches. Through the application of a variety of single molecule and single particle spectroscopic techniques in combination with ensemble level characterization tools, we identified different interaction pathways between gold nanorods and bovine serum albumin depending on the protein concentration. Overall, we found that local changes in protein concentration influence everything from cancer cell uptake to nanoparticle stability and even protein secondary structure. We envision that our findings and methods will lead to strategies to control the associated pathophysiology of nanoparticle exposure in vivo.

Influence of cross sectional geometry on surface plasmon polariton propagation in gold nanowires.

We investigated the effects of cross sectional geometry on surface plasmon polariton propagation in gold nanowires (NWs) using bleach-imaged plasmon propagation and electromagnetic simulations. Chemically synthesized NWs have pentagonally twinned crystal structures, but recent advances in synthesis have made it possible to amplify this pentagonal shape to yield NWs with a five-pointed-star cross section and sharp end tips. We found experimentally that NWs with a five-pointed-star cross section, referred to as SNWs, had a shorter propagation length for surface plasmon polaritons at 785 nm, but a higher effective incoupling efficiency compared to smooth NWs with a pentagonal cross section, labeled as PNWs. Electromagnetic simulations revealed that the electric fields were localized at the sharp ridges of the SNWs, leading to higher absorptive losses and hence shorter propagation lengths compared to PNWs. On the other hand, scattering losses were found to be relatively uncorrelated with cross sectional geometry, but were strongly dependent on the plasmon mode excited. Our results provide insight into the shape-dependent waveguiding properties of chemically synthesized metal NWs and the mode-dependent loss mechanisms that govern surface plasmon polariton propagation.

Why single-beam optical tweezers trap gold nanowires in three dimensions.

Understanding whether noble-metal nanostructures can be trapped optically and under what conditions will enable a range of applications that exploit their plasmonic properties. However, there are several nontrivial issues that first need to be resolved. A major one is that metal particles experience strong radiation pressure in optical beams, while stable optical trapping requires an attractive force greater than this radiation pressure. Therefore, it has generally been considered impossible to obtain sufficiently strong gradient forces using single-beam optical tweezers to trap relatively large metal nanostructures in three dimensions. Here we demonstrate that a single, tightly focused laser beam with a wavelength of 800 nm can achieve three-dimensional optical trapping of individual gold (Au) nanowires with lengths over 2 µm. Nanowires can be trapped by the beam at one of their ends, in which case they undergo significant angular fluctuations due to Brownian motion of the untrapped end. They can also be trapped close to their midpoints, in which case they are oriented approximately perpendicular to the light polarization direction. The behavior is markedly different from that of Ag nanowires with similar length and diameter, which cannot be trapped in three dimensions by a single focused Gaussian beam. Our results, including electrodynamics simulations that help to explain our experimental findings, suggest that the conventional wisdom, which holds that larger metal particles cannot be trapped, needs to be replaced with an understanding based on the details of plasmon resonances in the particles.

An atomistic view of the interfacial structures of AuRh and AuPd nanorods.

In this work we address the challenge of furthering our understanding of the driving forces responsible for the metal-metal interactions in industrially relevant bimetallic nanocatalysts, by taking a comparative approach to the atomic scale characterization of two core-shell nanorod systems (AuPd and AuRh). Using aberration-corrected scanning transmission electron microscopy, we show the existence of a randomly mixed alloy layer some 4-5 atomic layers thick between completely bulk immiscible Au and Rh, which facilitates fully epitaxial overgrowth for the first few atomic layers. In marked contrast in AuPd nanorods, we find atomically sharp segregation resulting in a quasi-epitaxial, strained interface between bulk miscible metals. By comparing the two systems, including molecular dynamics simulations, we are able to gain insights into the factors that may have influenced their structure and chemical ordering, which cannot be explained by the key structural and energetic parameters of either system in isolation, thus demonstrating the advantage of taking a comparative approach to the characterization of complex binary systems. This work highlights the importance of achieving a fundamental understanding of reaction kinetics in realizing the atomically controlled synthesis of bimetallic nanocatalysts.

Therapeutic platforms based on gold nanoparticles and their covalent conjugates with drug molecules.

This review will first look at the various covalent strategies that have been developed to attach drugs to gold nanoparticles as well as the strengths and limitations of such strategies. After examining general strategies for the synthesis of gold nanoparticles and their subsequent covalent functionalization, this review will focus on nanoparticle conjugates for gene therapy, antibacterial, and anticancer applications including the use of gold nanoparticles with intrinsically therapeutic properties. The effects of targeting and cellular uptake of gold nanoparticles will also be discussed.

Identification of higher order long-propagation-length surface plasmon polariton modes in chemically prepared gold nanowires.

A comprehensive understanding of the type of modes and their propagation length for surface plasmon polaritons (SPPs) in gold nanowires is essential for potential applications of these materials as nanoscale optical waveguides. We have studied chemically synthesized single gold nanowires by a novel technique called bleach-imaged plasmon propagation (BlIPP), which relies on the plasmonic near-field induced photobleaching of a dye to report the SPP propagation in nanowires. We observed a much longer propagation length of 7.5 ± 2.0 µm at 785 nm compared to earlier reports, which found propagation lengths of ~2.5 µm. Finite difference time domain simulations revealed that the bleach-imaged SPP is a higher order m = 1 mode and that the lowest order m = 0 mode is strongly quenched due to the loss to the dye layer and cannot be resolved by BlIPP. A comparative assessment of BlIPP with direct fluorescence imaging furthermore showed that the significant difference in propagation lengths obtained by these two techniques can be attributed to the difference in their experimental conditions, especially to the difference in thickness of the dye layer coating on the nanowire. In addition to identifying a higher order SPP mode with long propagation length, our study infers that caution must be taken in selecting indirect measurement techniques for probing SPP propagation in nanoscale metallic waveguides.

Functional gold nanorods: synthesis, self-assembly, and sensing applications.

Gold nanorods have received much attention due to their unique optical and electronic properties which are dependent on their shape, size, and aspect ratio. This article covers in detail the synthesis, functionalization, self-assembly, and sensing applications of gold nanorods. The synthesis of three major types of rods is discussed: single-crystalline and pentahedrally-twinned rods, which are synthesized by wet chemistry methods, and polycrystalline rods, which are synthesized by templated deposition. Functionalization of these rods is usually necessary for their applications, but can often be problematic due to their surfactant coating. Thus, general strategies are provided for the covalent and noncovalent functionalization of gold nanorods. The review will then examine the significant progress that has been made in controllable assembly of nanorods into various arrangements. This assembly can have a large effect on measurable properties of rods, making it particularly applicable towards sensing of a variety of analytes. Other types of sensing not dependent on nanorod assembly, such as refractive-index based sensing, are also discussed.