Gd2O3-mesoporous silica/gold nanoshells: A potential dual T1/T2 contrast agent for MRI-guided localized near-IR photothermal therapy.

A promising clinical trial utilizing gold-silica core-shell nanostructures coated with polyethylene glycol (PEG) has been reported for near-infrared (NIR) photothermal therapy (PTT) of prostate cancer. The next critical step for PTT is the visualization of therapeutically relevant nanoshell (NS) concentrations at the tumor site. Here we report the synthesis of PEGylated Gd2O3-mesoporous silica/gold core/shell NSs (Gd2O3-MS NSs) with NIR photothermal properties that also supply sufficient MRI contrast to be visualized at therapeutic doses (≥108 NSs per milliliter). The nanoparticles have r1 relaxivities more than three times larger than those of conventional T1 contrast agents, requiring less concentration of Gd3+ to observe an equivalent signal enhancement in T1-weighted MR images. Furthermore, Gd2O3-MS NS nanoparticles have r2 relaxivities comparable to those of existing T2 contrast agents, observed in agarose phantoms. This highly unusual combination of simultaneous T1 and T2 contrast allows for MRI enhancement through different approaches. As a rudimentary example, we demonstrate T1/T2 ratio MR images with sixfold contrast signal enhancement relative to its T1 MRI and induced temperature increases of 20 to 55 °C under clinical illumination conditions. These nanoparticles facilitate MRI-guided PTT while providing real-time temperature feedback through thermal MRI mapping.

Computational chromatography: A machine learning strategy for demixing individual chemical components in complex mixtures.

Surface-enhanced Raman spectroscopy (SERS) holds exceptional promise as a streamlined chemical detection strategy for biological and environmental contaminants compared with current laboratory methods. Priority pollutants such as polycyclic aromatic hydrocarbons (PAHs), detectable in water and soil worldwide and known to induce multiple adverse health effects upon human exposure, are typically found in multicomponent mixtures. By combining the molecular fingerprinting capabilities of SERS with the signal separation and detection capabilities of machine learning (ML), we examine whether individual PAHs can be identified through an analysis of the SERS spectra of multicomponent PAH mixtures. We have developed an unsupervised ML method we call Characteristic Peak Extraction, a dimensionality reduction algorithm that extracts characteristic SERS peaks based on counts of detected peaks of the mixture. By analyzing the SERS spectra of two-component and four-component PAH mixtures where the concentration ratios of the various components vary, this algorithm is able to extract the spectra of each unknown component in the mixture of unknowns, which is then subsequently identified against a SERS spectral library of PAHs. Combining the molecular fingerprinting capabilities of SERS with the signal separation and detection capabilities of ML, this effort is a step toward the computational demixing of unknown chemical components occurring in complex multicomponent mixtures.

Solar thermal desalination as a nonlinear optical process.

The ever-increasing global need for potable water requires practical, sustainable approaches for purifying abundant alternative sources such as seawater, high-salinity processed water, or underground reservoirs. Evaporation-based solutions are of particular interest for treating high salinity water, since conventional methods such as reverse osmosis have increasing energy requirements for higher concentrations of dissolved minerals. Demonstration of efficient water evaporation with heat localization in nanoparticle solutions under solar illumination has led to the recent rapid development of sustainable, solar-driven distillation methods. Given the amount of solar energy available per square meter at the Earth's surface, however, it is important to utilize these incident photons as efficiently as possible to maximize clean water output. Here we show that merely focusing incident sunlight into small "hot spots" on a photothermally active desalination membrane dramatically increases--by more than 50%--the flux of distilled water. This large boost in efficiency results from the nearly exponential dependence of water vapor saturation pressure on temperature, and therefore on incident light intensity. Exploiting this inherent but previously unrecognized optical nonlinearity should enable the design of substantially higher-throughput solar thermal desalination methods. This property provides a mechanism capable of enhancing a far wider range of photothermally driven processes with supralinear intensity dependence, such as light-driven chemical reactions and separation methods.

UV-Resonant Al Nanocrystals: Synthesis, Silica Coating, and Broadband Photothermal Response.

The field of plasmonics has largely been inspired by the properties of Au and Ag nanoparticles, leading to applications in sensing, photocatalysis, nanomedicine, and solar water treatment. Recently the quest for new plasmonic materials has focused on earth-abundant elements, where aluminum is a sustainable, low-cost potential alternative. Here we report the chemical synthesis of sub-50 nm diameter Al nanocrystals with a plasmon-resonant absorption in the UV region of the spectrum. We observe a transition from a UV-resonant response, that is, a colorless solution, to a broadband absorptive response, that is, a completely black solution, as the nanocrystal concentration is increased. The strong absorptive interband transition in Al provides the dominant mechanism responsible for this effect. We developed a robust method to functionalize Al nanocrystals with silica to increase their stability in H2O from hours to weeks enabling us to observe efficient broadband photothermal heating with these nanoparticles.

Near-infrared remotely triggered drug-release strategies for cancer treatment.

Remotely controlled, localized drug delivery is highly desirable for potentially minimizing the systemic toxicity induced by the administration of typically hydrophobic chemotherapy drugs by conventional means. Nanoparticle-based drug delivery systems provide a highly promising approach for localized drug delivery, and are an emerging field of interest in cancer treatment. Here, we demonstrate near-IR light-triggered release of two drug molecules from both DNA-based and protein-based hosts that have been conjugated to near-infrared-absorbing Au nanoshells (SiO2 core, Au shell), each forming a light-responsive drug delivery complex. We show that, depending upon the drug molecule, the type of host molecule, and the laser illumination method (continuous wave or pulsed laser), in vitro light-triggered release can be achieved with both types of nanoparticle-based complexes. Two breast cancer drugs, docetaxel and HER2-targeted lapatinib, were delivered to MDA-MB-231 and SKBR3 (overexpressing HER2) breast cancer cells and compared with release in noncancerous RAW 264.7 macrophage cells. Continuous wave laser-induced release of docetaxel from a nanoshell-based DNA host complex showed increased cell death, which also coincided with nonspecific cell death from photothermal heating. Using a femtosecond pulsed laser, lapatinib release from a nanoshell-based human serum albumin protein host complex resulted in increased cancerous cell death while noncancerous control cells were unaffected. Both methods provide spatially and temporally localized drug-release strategies that can facilitate high local concentrations of chemotherapy drugs deliverable at a specific treatment site over a specific time window, with the potential for greatly minimized side effects.

Nanophotonics-enabled solar membrane distillation for off-grid water purification.

With more than a billion people lacking accessible drinking water, there is a critical need to convert nonpotable sources such as seawater to water suitable for human use. However, energy requirements of desalination plants account for half their operating costs, so alternative, lower energy approaches are equally critical. Membrane distillation (MD) has shown potential due to its low operating temperature and pressure requirements, but the requirement of heating the input water makes it energy intensive. Here, we demonstrate nanophotonics-enabled solar membrane distillation (NESMD), where highly localized photothermal heating induced by solar illumination alone drives the distillation process, entirely eliminating the requirement of heating the input water. Unlike MD, NESMD can be scaled to larger systems and shows increased efficiencies with decreased input flow velocities. Along with its increased efficiency at higher ambient temperatures, these properties all point to NESMD as a promising solution for household- or community-scale desalination.

Enhancing T1 magnetic resonance imaging contrast with internalized gadolinium(III) in a multilayer nanoparticle.

Multifunctional nanoparticles for biomedical applications have shown extraordinary potential as contrast agents in various bioimaging modalities, near-IR photothermal therapy, and for light-triggered therapeutic release processes. Over the past several years, numerous studies have been performed to synthesize and enhance MRI contrast with nanoparticles. However, understanding the MRI enhancement mechanism in a multishell nanoparticle geometry, and controlling its properties, remains a challenge. To systematically examine MRI enhancement in a nanoparticle geometry, we have synthesized MRI-active Au nanomatryoshkas. These are Au core-silica layer-Au shell nanoparticles, where Gd(III) ions are encapsulated within the silica layer between the inner core and outer Au layer of the nanoparticle (Gd-NM). This multifunctional nanoparticle retains its strong near-IR Fano-resonant optical absorption properties essential for photothermal or other near-IR light-triggered therapy, while simultaneously providing increased T1 contrast in MR imaging by concentrating Gd(III) within the nanoparticle. Measurements of Gd-NM revealed a strongly enhanced T1 relaxivity (r1 ∼ 24 mM-1⋅s-1) even at 4.7 T, substantially surpassing conventional Gd(III) chelating agents (r1 ∼ 3 mM-1⋅s-1 at 4.7 T) currently in clinical use. By varying the thickness of the outer gold layer of the nanoparticle, we show that the observed relaxivities are consistent with Solomon-Bloembergen-Morgan (SBM) theory, which takes into account the longer-range interactions between the encapsulated Gd(III) and the protons of the H2O molecules outside the nanoparticle. This nanoparticle complex and its MRI T1-enhancing properties open the door for future studies on quantitative tracking of therapeutic nanoparticles in vivo, an essential step for optimizing light-induced, nanoparticle-based therapies.

Aluminum Nanocrystals: A Sustainable Substrate for Quantitative SERS-Based DNA Detection.

Since its discovery in the 1970s, surface-enhanced Raman scattering (SERS) has been primarily associated with substrates composed of nanostructured noble metals. Here we investigate chemically synthesized nanocrystal aggregates of aluminum, an inexpensive, highly abundant, and sustainable metal, as SERS substrates. Al nanocrystal aggregates are capable of substantial near-infrared SERS enhancements, similar to Au nanoparticles. The intrinsic nanoscale surface oxide of Al nanocrystals supports molecule-substrate interactions that differ dramatically from noble metal substrates. The preferential affinity of the single-stranded DNA (ssDNA) phosphate backbone for the Al oxide surface preserves both the spectral features and nucleic acid cross sections relative to conventional Raman spectroscopy, enabling quantitative ssDNA detection and analysis.

Compact solar autoclave based on steam generation using broadband light-harvesting nanoparticles.

The lack of readily available sterilization processes for medicine and dentistry practices in the developing world is a major risk factor for the propagation of disease. Modern medical facilities in the developed world often use autoclave systems to sterilize medical instruments and equipment and process waste that could contain harmful contagions. Here, we show the use of broadband light-absorbing nanoparticles as solar photothermal heaters, which generate high-temperature steam for a standalone, efficient solar autoclave useful for sanitation of instruments or materials in resource-limited, remote locations. Sterilization was verified using a standard Geobacillus stearothermophilus-based biological indicator.

Nanoparticle-Mediated, Light-Induced Phase Separations.

Nanoparticles that both absorb and scatter light, when dispersed in a liquid, absorb optical energy and heat a reduced fluid volume due to the combination of multiple scattering and optical absorption. This can induce a localized liquid-vapor phase change within the reduced volume without the requirement of heating the entire fluid. For binary liquid mixtures, this process results in vaporization of the more volatile component of the mixture. When subsequently condensed, these two steps of vaporization and condensation constitute a distillation process mediated by nanoparticles and driven by optical illumination. Because it does not require the heating of a large volume of fluid, this process requires substantially less energy than traditional distillation using thermal sources. We investigated nanoparticle-mediated, light-induced distillation of ethanol-H2O and 1-propanol-H2O mixtures, using Au-SiO2 nanoshells as the absorber-scatterer nanoparticle and nanoparticle-resonant laser irradiation to drive the process. For ethanol-H2O mixtures, the mole fraction of ethanol obtained in the light-induced process is substantially higher than that obtained by conventional thermal distillation, essentially removing the ethanol-H2O azeotrope that limits conventional distillation. In contrast, for 1-propanol-H2O mixtures the distillate properties resulting from light-induced distillation were very similar to those obtained by thermal distillation. In the 1-propanol-H2O system, a nanoparticle-mediated, light-induced liquid-liquid phase separation was also observed.

Evolution of light-induced vapor generation at a liquid-immersed metallic nanoparticle.

When an Au nanoparticle in a liquid medium is illuminated with resonant light of sufficient intensity, a nanometer scale envelope of vapor-a "nanobubble"-surrounding the particle, is formed. This is the nanoscale onset of the well-known process of liquid boiling, occurring at a single nanoparticle nucleation site, resulting from the photothermal response of the nanoparticle. Here we examine bubble formation at an individual metallic nanoparticle in detail. Incipient nanobubble formation is observed by monitoring the plasmon resonance shift of an individual, illuminated Au nanoparticle, when its local environment changes from liquid to vapor. The temperature on the nanoparticle surface is monitored during this process, where a dramatic temperature jump is observed as the nanoscale vapor layer thermally decouples the nanoparticle from the surrounding liquid. By increasing the intensity of the incident light or decreasing the interparticle separation, we observe the formation of micrometer-sized bubbles resulting from the coalescence of nanoparticle-"bound" vapor envelopes. These studies provide the first direct and quantitative analysis of the evolution of light-induced steam generation by nanoparticles from the nanoscale to the macroscale, a process that is of fundamental interest for a growing number of applications.

Hot electrons do the impossible: plasmon-induced dissociation of H2 on Au.

Heterogeneous catalysis is of paramount importance in chemistry and energy applications. Catalysts that couple light energy into chemical reactions in a directed, orbital-specific manner would greatly reduce the energy input requirements of chemical transformations, revolutionizing catalysis-driven chemistry. Here we report the room temperature dissociation of H(2) on gold nanoparticles using visible light. Surface plasmons excited in the Au nanoparticle decay into hot electrons with energies between the vacuum level and the work function of the metal. In this transient state, hot electrons can transfer into a Feshbach resonance of an H(2) molecule adsorbed on the Au nanoparticle surface, triggering dissociation. We probe this process by detecting the formation of HD molecules from the dissociations of H(2) and D(2) and investigate the effect of Au nanoparticle size and wavelength of incident light on the rate of HD formation. This work opens a new pathway for controlling chemical reactions on metallic catalysts.

Identifying Surface-Enhanced Raman Spectra with a Raman Library Using Machine Learning.

Since its discovery, surface-enhanced Raman spectroscopy (SERS) has shown outstanding promise of identifying trace amounts of unknown molecules in rapid, portable formats. However, the many different types of nanoparticles or nanostructured metallic SERS substrates created over the past few decades show substantial variability in the SERS spectra they provide. These inconsistencies have even raised speculation that substrate-specific SERS spectral libraries must be compiled for practical use of this type of spectroscopy. Here, we report a machine learning (ML) algorithm that can identify chemicals by matching their SERS spectra to those of a standard Raman spectral library. We use an approach analogous to facial recognition that utilizes feature extraction in the presence of multiple nuisance variables for spectral recognition. The key element is a metric we call "Characteristic Peak Similarity" (CaPSim) that focuses on the characteristic peaks in the SERS spectra. It has the flexibility to accommodate substrate-specific variability when quantifying the degree of similarity to a Raman spectrum. Analysis shows that CaPSim substantially outperforms existing spectral matching algorithms in terms of accuracy. This ML-based approach could greatly facilitate the spectroscopic identification of molecules in fieldable SERS applications.

Combined Surface-Enhanced Raman and Infrared Absorption Spectroscopies for Streamlined Chemical Detection of Polycyclic Aromatic Hydrocarbon-Derived Compounds.

Polycyclic aromatic hydrocarbons (PAHs) constitute a class of universally prevalent carcinogenic environmental contaminants. It is increasingly recognized, however, that PAHs derivatized with oxygen, sulfur, or nitrogen functional groups are frequently more dangerous than their unfunctionalized counterparts. This much larger family of chemicals─polycyclic aromatic compounds─PACs─is far less well characterized than PAHs. Using surface-enhanced Raman and IR Absorption spectroscopies (SERS + SEIRA) combined on a single substrate, along with density functional theoretical (DFT) calculations, we show that direct chemical detection and identification of PACs at sub-parts-per-billion concentration can be achieved. Focusing our studies on 9,10-anthraquinone, 5,12-tetracenequinone, 9-nitroanthracene, and 1-nitropyrene as model PAC contaminants, detection is made possible by incorporating a hydroxy-functionalized self-assembled monolayer that facilitates hydrogen bonding between analytes and the SERS + SEIRA substrate. 5,12-Tetracenequinone was detected at 0.3 ppb, and the limit of detection was determined to be 0.1 ppb using SEIRA alone. This approach is straightforwardly extendable to other families of analytes and will ultimately facilitate fieldable chemical detection of these dangerous yet largely overlooked environmental contaminants.

Plasmonic gadolinium oxide nanomatryoshkas: bifunctional magnetic resonance imaging enhancers for photothermal cancer therapy.

Nanoparticle-assisted laser-induced photothermal therapy (PTT) is a promising method for cancer treatment; yet, visualization of nanoparticle uptake and photothermal response remain a critical challenge. Here, we report a magnetic resonance imaging-active nanomatryoshka (Gd2O3-NM), a multilayered (Au core/Gd2O3 shell/Au shell) sub-100 nm nanoparticle capable of combining T1 MRI contrast with PTT. This bifunctional nanoparticle demonstrates an r1 of 1.28 × 108 mM-1 s-1, an MRI contrast enhancement per nanoparticle sufficient for T1 imaging in addition to tumor ablation. Gd2O3-NM also shows excellent stability in an acidic environment, retaining 99% of the internal Gd(3). This report details the synthesis and characterization of a promising system for combined theranostic nanoparticle tracking and PTT.

Visualizing light-triggered release of molecules inside living cells.

The light-triggered release of deoxyribonucleic acid (DNA) from gold nanoparticle-based, plasmon resonant vectors, such as nanoshells, shows great promise for gene delivery in living cells. Here we show that intracellular light-triggered release can be performed on molecules that associate with the DNA in a DNA host-guest complex bound to nanoshells. DAPI (4',6-diamidino-2-phenylindole), a bright blue fluorescent molecule that binds reversibly to double-stranded DNA, was chosen to visualize this intracellular light-induced release process. Illumination of nanoshell-dsDNA-DAPI complexes at their plasmon resonance wavelength dehybridizes the DNA, releasing the DAPI molecules within living cells, where they diffuse to the nucleus and associate with the cell's endogenous DNA. The low laser power and irradiation times required for molecular release do not compromise cell viability. This highly controlled co-release of nonbiological molecules accompanying the oligonucleotides could have broad applications in the study of cellular processes and in the development of intracellular targeted therapies.

A 3D Plasmonic Antenna-Reactor for Nanoscale Thermal Hotspots and Gradients.

Plasmonic nanoantennas focus light below the diffraction limit, creating strong field enhancements, typically within a nanoscale junction. Placing a nanostructure within the junction can greatly enhance the nanostructure's innate optical absorption, resulting in intense photothermal heating that could ultimately compromise both the nanostructure and the nanoantenna. Here, we demonstrate a three-dimensional "antenna-reactor" geometry that results in large nanoscale thermal gradients, inducing large local temperature increases in the confined nanostructure reactor while minimizing the temperature increase of the surrounding antenna. The nanostructure is supported on an insulating substrate within the antenna gap, while the antenna maintains direct contact with an underlying thermal conductor. Elevated local temperatures are quantified, and high local temperature gradients that thermally reshape only the internal reactor element within each antenna-reactor structure are observed. We also show that high local temperature increases of nominally 200 °C are achievable within antenna-reactors patterned into large extended arrays. This simple strategy can facilitate standoff optical generation of high-temperature hotspots, which may be useful in applications such as small-volume, high-throughput chemical processes, where reaction efficiencies depend exponentially on local temperature.

Direct optical detection of aptamer conformational changes induced by target molecules.

Aptamers are single-stranded DNA/RNA oligomers that fold into three-dimensional conformations in the presence of specific molecular targets. Surface-enhanced Raman spectroscopy (SERS) of thiol-bound DNA aptamer self-assembled monolayers on Au nanoshell surfaces provides a direct, label-free detection method for the interaction of DNA aptamers with target molecules. A spectral cross-correlation function, Gamma, is shown to be a useful metric to quantify complex changes in the SERS spectra resulting from conformational changes in the aptamer induced by target analytes. While the pristine, unexposed anti-PDGF (PDGF = platelet-derived growth factor) aptamer yields highly reproducible spectra with Gamma = 0.91 +/- 0.01, following incubation with PDGF, the reproducibility of the SERS spectra is dramatically reduced, yielding Gamma = 0.67 +/- 0.02. This approach also allows us to discriminate the response of a cocaine aptamer to its target from its weaker response to nonspecific analyte molecules.

Routes to Potentially Safer T1 Magnetic Resonance Imaging Contrast in a Compact Plasmonic Nanoparticle with Enhanced Fluorescence.

Engineering a compact, near-infrared plasmonic nanostructure with integrated image-enhancing agents for combined imaging and therapy is an important nanomedical challenge. Recently, we showed that Au@SiO2@Au nanomatryoshkas (NM) are a highly promising nanostructure for hosting either T1 MRI or fluorescent contrast agents with a photothermal therapeutic response in a compact geometry. Here, we show that a near-infrared-resonant NM can provide simultaneous contrast enhancement for both T1 magnetic resonance imaging (MRI) and fluorescence optical imaging (FOI) by encapsulating both types of contrast agents in the internal silica layer between the Au core and shell. We also show that this method of T1 enhancement is even more effective for Fe(III), a potentially safer contrast agent compared to Gd(III). Fe-NM-based contrast agents are found to have relaxivities 2× greater than those found in the widely used gadolinium chelate, Gd(III) DOTA, providing a practical alternative that would eliminate Gd(III) patient exposure entirely. This dual-modality nanostructure can enable not only tissue visualization with MRI but also fluorescence-based nanoparticle tracking for quantifying nanoparticle distributions in vivo, in addition to a near-infrared photothermal therapeutic response.

Coherent anti-Stokes Raman scattering with single-molecule sensitivity using a plasmonic Fano resonance.

Plasmonic nanostructures are of particular interest as substrates for the spectroscopic detection and identification of individual molecules. Single-molecule sensitivity Raman detection has been achieved by combining resonant molecular excitation with large electromagnetic field enhancements experienced by a molecule associated with an interparticle junction. Detection of molecules with extremely small Raman cross-sections (~10(-30) cm(2) sr(-1)), however, has remained elusive. Here we show that coherent anti-Stokes Raman spectroscopy (CARS), a nonlinear spectroscopy of great utility and potential for molecular sensing, can be used to obtain single-molecule detection sensitivity, by exploiting the unique light harvesting properties of plasmonic Fano resonances. The CARS signal is enhanced by ~11 orders of magnitude relative to spontaneous Raman scattering, enabling the detection of single molecules, which is verified using a statistically rigorous bi-analyte method. This approach combines unprecedented single-molecule spectral sensitivity with plasmonic substrates that can be fabricated using top-down lithographic strategies.