Gold Nanostars Obviate Limitations to Laser Interstitial Thermal Therapy (LITT) for the Treatment of Intracranial Tumors.

PURPOSE: Laser interstitial thermal therapy (LITT) is an effective minimally invasive treatment option for intracranial tumors. Our group produced plasmonics-active gold nanostars (GNS) designed to preferentially accumulate within intracranial tumors and amplify the ablative capacity of LITT. EXPERIMENTAL DESIGN: The impact of GNS on LITT coverage capacity was tested in ex vivo models using clinical LITT equipment and agarose gel-based phantoms of control and GNS-infused central "tumors." In vivo accumulation of GNS and amplification of ablation were tested in murine intracranial and extracranial tumor models followed by intravenous GNS injection, PET/CT, two-photon photoluminescence, inductively coupled plasma mass spectrometry (ICP-MS), histopathology, and laser ablation. RESULTS: Monte Carlo simulations demonstrated the potential of GNS to accelerate and specify thermal distributions. In ex vivo cuboid tumor phantoms, the GNS-infused phantom heated 5.5× faster than the control. In a split-cylinder tumor phantom, the GNS-infused border heated 2× faster and the surrounding area was exposed to 30% lower temperatures, with margin conformation observed in a model of irregular GNS distribution. In vivo, GNS preferentially accumulated within intracranial tumors on PET/CT, two-photon photoluminescence, and ICP-MS at 24 and 72 hours and significantly expedited and increased the maximal temperature achieved in laser ablation compared with control. CONCLUSIONS: Our results provide evidence for use of GNS to improve the efficiency and potentially safety of LITT. The in vivo data support selective accumulation within intracranial tumors and amplification of laser ablation, and the GNS-infused phantom experiments demonstrate increased rates of heating, heat contouring to tumor borders, and decreased heating of surrounding regions representing normal structures.

Plasmonic nanorod probes' journey inside plant cells for in vivo SERS sensing and multimodal imaging.

Nanoparticle-based platforms are gaining strong interest in plant biology and bioenergy research to monitor and control biological processes in whole plants. However, in vivo monitoring of biomolecules using nanoparticles inside plant cells remains challenging due to the impenetrability of the plant cell wall to nanoparticles beyond the exclusion limits (5-20 nm). To overcome this physical barrier, we have designed unique bimetallic silver-coated gold nanorods (AuNR@Ag) capable of entering plant cells, while conserving key plasmonic properties in the near-infrared (NIR). To demonstrate cellular internalization and tracking of the nanorods inside plant tissue, we used a comprehensive multimodal imaging approach that included transmission electron microscopy (TEM), confocal fluorescence microscopy, two-photon luminescence (TPL), X-ray fluorescence microscopy (XRF), and photoacoustics imaging (PAI). We successfully acquired SERS signals of nanorods in vivo inside plant cells of tobacco leaves. On the same leaf samples, we applied orthogonal imaging methods, TPL and PAI techniques for in vivo imaging of the nanorods. This study first demonstrates the intracellular internalization of AuNR@Ag inside whole plant systems for in vivo SERS analysis in tobacco cells. This work demonstrates the potential of this nanoplatform as a new nanotool for intracellular in vivo biosensing for plant biology.

Direct and Label-Free Detection of MicroRNA Cancer Biomarkers using SERS-Based Plasmonic Coupling Interference (PCI) Nanoprobes.

MicroRNAs (miRNAs), small noncoding endogenous RNA molecules, are emerging as promising biomarkers for early detection of various diseases and cancers. Practical screening tools and strategies to detect these small molecules are urgently needed to facilitate the translation of miRNA biomarkers into clinical practice. In this study, a label-free biosensing technique based on surface-enhanced Raman scattering (SERS), referred to as plasmonic coupling interference (PCI), was applied for the multiplex detection of miRNA biomarkers. The sensing mechanism of the PCI technique relies on the formation of a nanonetwork consisting of nanoparticles with Raman labels located between adjacent nanoparticles that are interconnected by DNA duplexes. Because of the plasmonic coupling effect of adjacent nanoparticles in the nanonetwork, the Raman labels exhibit intense SERS signals. Such effect can be modulated by the addition of miRNA targets of interest that act as inhibitors to interfere with the formation of this nanonetwork, resulting in a diminished SERS signal. In this study, the PCI technique is theoretically analyzed, and the multiplex capability for detection of multiple miRNA cancer biomarkers is demonstrated, establishing the great potential of PCI nanoprobes as a useful diagnostic tool for medical applications.

Tailoring the Core-Satellite Nanoassembly Architectures by Tuning Internanoparticle Electrostatic Interactions.

The use of plasmonic nanoplatforms has received increasing interest in a wide variety of fields ranging from theranostics to environmental sensing to plant biology. In particular, the development of plasmonic nanoparticles into ordered nanoclusters has been of special interest due to the new chemical functionalities and optical responses that they can introduce. However, achieving predetermined nanocluster architectures from bottom-up approaches in the colloidal solution state still remains a great challenge. Herein, we report a one-pot assembly approach that provides flexibility in precise control of core-satellite nanocluster architectures in the colloidal solution state. We found that the pH of the assembly medium plays a vital role in the hierarchy of the nanoclusters. The architecture along with the size of the satellite gold nanoparticles determines the optical responses of nanoclusters. Using electron microscopy and optical spectroscopy, we introduce a set of design rules for the synthesis of distinct architectures of silica-core gold satellites nanoclusters in the colloidal solution state. Our findings provide insight into advancing the colloidal solution state nanoclusters formation with predictable architectures and optical properties.

Optical Fano resonances in a nonconcentric nanoshell.

The interaction of light with a metal nanoshell with an off-center core generates multipoles of all orders. We show here that the matrix elements used to compute the multipole expansion coefficients can be derived analytically and, with this result, we can show explicitly how the dipole and quadrupole terms in the expansion are coupled and give rise to a Fano resonance. We also show that the off-center core significantly increases the electric field enhancement at the shell surface compared to the concentric case, which can be exploited for surface-enhanced sensing. The multipole solutions are confirmed with finite-element calculations.

Tunable and amplified Raman gold nanoprobes for effective tracking (TARGET): in vivo sensing and imaging.

We describe the development of a highly tunable, physiologically stable, and ultra-bright Raman probe, named as TARGET (Tunable and Amplified Raman Gold Nanoprobes for Effective Tracking), for in vitro and in vivo surface-enhanced Raman scattering (SERS) applications. The TARGET structure consists of a gold core inside a larger gold shell with a tunable interstitial gap similar to a "nanorattle" structure. The combination of galvanic replacement and the seed mediated growth method was employed to load Raman reporter molecules and subsequently close the pores to prevent leaking and degradation of reporters under physiologically extreme conditions. Precise tuning of the core-shell gap width, core size, and shell thickness allows us to modulate the plasmonic effect and achieve a maximum electric-field (E-field) intensity. The interstitial gap of TARGET nanoprobes can be designed to exhibit a plasmon absorption band at 785 nm, which is in resonance with the dye absorption maximum and lies in the "tissue optical window", resulting in ultra-bright SERS signals for in vivo studies. The results of in vivo measurements of TARGETs in laboratory mice illustrated the usefulness of these nanoprobes for medical sensing and imaging.

In vivo detection of SERS-encoded plasmonic nanostars in human skin grafts and live animal models.

Surface-enhanced Raman scattering (SERS)-active plasmonic nanomaterials have become a promising agent for molecular imaging and multiplex detection. Among the wide variety of plasmonics-active nanoparticles, gold nanostars offer unique plasmon properties that efficiently induce strong SERS signals. Furthermore, nanostars, with their small core size and multiple long thin branches, exhibit high absorption cross sections that are tunable in the near-infrared region of the tissue optical window, rendering them efficient for in vivo spectroscopic detection. This study investigated the use of SERS-encoded gold nanostars for in vivo detection. Ex vivo measurements were performed using human skin grafts to investigate the detection of SERS-encoded nanostars through tissue. We also integrated gold nanostars into a biocompatible scaffold to aid in performing in vivo spectroscopic analyses. In this study, for the first time, we demonstrate in vivo SERS detection of gold nanostars using small animal (rat) as well as large animal (pig) models. The results of this study establish the usefulness and potential of SERS-encoded gold nanostars for future use in long-term in vivo analyte sensing.

Fano resonance in a gold nanosphere with a J-aggregate coating.

We present a facile method to induce J-aggregate formation on gold nanospheres in colloidal solution using polyvinylsulfate. The nanoparticle J-aggregate complex results in an absorption spectrum with a split lineshape due to plasmon-exciton coupling, i.e. via the formation of upper and lower plexcitonic branches. The use of nanoparticles with different plasmon resonances alters the position of the upper plexcitonic band while the lower band remains at the same wavelength. This splitting is investigated theoretically, and shown analytically to arise from Fano resonance between the plasmon of the gold nanoparticles and exciton of the J-aggregates. A theoretical simulation of a J-aggregate coated and uncoated gold nanosphere produces an absorption spectrum that shows good agreement with the experimentally measured spectra.

The three-dimensional inverse-scattering and inverse-source problems with a planar aperture.

When signals are recorded on a planar aperture with point emitters/detectors, from either a three-dimensional (3D) scattering potential or from a 3D spatially-incoherent source distribution, an integral equation arises containing the product of two Green's functions in the weak scattering limit (the Born approximation). This fundamental imaging equation for scatterers or sources is derived and solved analytically.

SERS nanosensors and nanoreporters: golden opportunities in biomedical applications.

This article provides an overview of recent developments and applications of surface-enhanced Raman scattering (SERS) nanosensors and nanoreporters in our laboratory for use in biochemical monitoring, medical diagnostics, and therapy. The design and fabrication of different types of plasmonics-active nanostructures are discussed. The SERS nanosensors can be used in various applications including pH sensing, protein detection, and gene diagnostics. For DNA detection the 'Molecular Sentinel' nanoprobe can be used as a homogenous bioassay in solution or on a chip platform. Gold nanostars provide an excellent multi-modality theranostic platform, combining Raman and SERS with two-photon luminescence (TPL) imaging as well as photodynamic therapy (PDT), and photothermal therapy (PTT). Plasmonics-enhanced and optically modulated delivery of nanostars into brain tumor in live animals was demonstrated; photothermal treatment of tumor vasculature may induce inflammasome activation, thus increasing the permeability of the blood brain-tumor barrier. The imaging method using TPL of gold nanostars provides an unprecedented spatial selectivity for enhanced targeted nanostar delivery to cortical tumor tissue. A quintuple-modality nanoreporter based on gold nanostars for SERS, TPL, magnetic resonance imaging (MRI), computed tomography (CT), and PTT has recently been developed. The possibility of combining spectral selectivity and high sensitivity of the SERS process with the inherent molecular specificity of bioreceptor-based nanoprobes provides a unique multiplex and selective diagnostic modality. Several examples of optical detection using SERS in combination with other detection and treatment modalities are discussed to illustrate the usefulness and potential of SERS nanosensors and nanoreporters for medical applications.

Plasmonic nanoprobes: from chemical sensing to medical diagnostics and therapy.

This article provides an overview of the development and applications of plasmonics-active nanoprobes in our laboratory for chemical sensing, medical diagnostics and therapy. Molecular Sentinel nanoprobes provide a unique tool for DNA/RNA biomarker detection both in a homogeneous solution or on a chip platform for medical diagnostics. The possibility of combining spectral selectivity and high sensitivity of the surface-enhanced Raman scattering (SERS) process with the inherent molecular specificity of nanoprobes provides an important multiplex diagnostic modality. Gold nanostars can provide an excellent multi-modality platform, combining two-photon luminescence with photothermal therapy as well as Raman imaging with photodynamic therapy. Several examples of optical detection using SERS and photonics-based treatments are presented to illustrate the usefulness and potential of the plasmonic nanoprobes for theranostics, which seamlessly combines diagnostics and therapy.

Investigating the plasmonics of a dipole-excited silver nanoshell: Mie theory versus finite element method.

This report compares COMSOL's finite element method (FEM) algorithm with the Mie theory for solving the electromagnetic fields in the vicinity of a silica-silver core-shell nanoparticle when excited by a radiating dipole. The novelty of this investigation lies in the excitation source of the nanoshell system: an oscillating electric dipole is frequently used as a model for both molecular scattering and molecular fluorescence; moreover, a common classical model of atomic or molecular spontaneous emission is a decaying electric dipole. The radiated power spectra were evaluated both analytically and numerically by integrating the Poynting vector around 20, 60 and 100 nm nanoshells, thereby solving the total and scattered fields generated by a dipole positioned inside the core and in the surrounding air medium, respectively. The agreement was excellent in amplitude, plasmon resonance peak position and full width at half-maximum. The FEM algorithm also generates accurate solutions of the near-field electromagnetics in the spatial domain, where the E-field behavior as a function of polar angle theta for a fixed observation radius was evaluated. The quasistatic approximation, which is valid for small nanoparticles, is also employed to assess its limitations relative to the Mie and FEM algorithms.

Plasmonic Nanoparticles and Nanowires: Design, Fabrication and Application in Sensing.

This study involves two aspects of our investigations of plasmonics-active systems: (i) theoretical and simulation studies and (ii) experimental fabrication of plasmonics-active nanostructures. Two types of nanostructures are selected as the model systems for their unique plasmonics properties: (1) nanoparticles and (2) nanowires on substrate. Special focus is devoted to regions where the electromagnetic field is strongly concentrated by the metallic nanostructures or between nanostructures. The theoretical investigations deal with dimers of nanoparticles and nanoshells using a semi-analytical method based on a multipole expansion (ME) and the finite-element method (FEM) in order to determine the electromagnetic enhancement, especially at the interface areas of two adjacent nanoparticles. The experimental study involves the design of plasmonics-active nanowire arrays on substrates that can provide efficient electromagnetic enhancement in regions around and between the nanostructures. Fabrication of these nanowire structures over large chip-scale areas (from a few millimeters to a few centimeters) as well as FDTD simulations to estimate the EM fields between the nanowires are described. The application of these nanowire chips using surface-enhanced Raman scattering (SERS) for detection of chemicals and labeled DNA molecules is described to illustrate the potential of the plasmonics chips for sensing.

Plasmonics enhancement of a luminescent or Raman-active layer in a multilayered metallic nanoshell.

Expressions for the enhancement of the far-field scattering cross section of a luminescent or Raman-active compound contained within a multilayered nanosphere are derived, where the active compound resides between an outer metallic shell and a metallic core. The quasi-static approximation is assumed for silver and gold particles using a Lorentz-Drude model of the dielectric function. An attempt has also been made to account for the effect of electron scattering from the boundaries of the shell on the enhancement calculation.

Plasmonics of 3-D nanoshell dimers using multipole expansion and finite element method.

The spatial and spectral responses of the plasmonic fields induced in the gap of 3-D nanoshell dimers of gold and silver are comprehensively investigated and compared via theory and simulation using the multipole expansion (ME) and the finite element method (FEM) in COMSOL, respectively. The E-field in the dimer gap was evaluated and compared as a function of shell thickness, interparticle distance, and size. The E-field increased with decreasing shell thickness, decreasing interparticle distance, and increasing size, with the error between the two methods ranging from 1 to 10%, depending on the specific combination of these three variables. This error increases several fold with increasing dimer size, as the quasi-static approximation breaks down. A consistent overestimation of the plasmon's fwhm and red shifting of the plasmon peak occurs with FEM, relative to ME, and it increases with decreasing shell thickness and interparticle distance. The size effect that arises from surface scattering of electrons is addressed and shown to be especially prominent for thin shells, for which significant damping, broadening, and shifting of the plasmon band is observed; the size effect also affects large nanoshell dimers, depending on their relative shell thickness, but to a lesser extent. This study demonstrates that COMSOL is a promising simulation environment to quantitatively investigate nanoscale electromagnetics for the modeling and designing of surface-enhanced Raman scattering (SERS) substrates.

Comparison of FDTD numerical computations and analytical multipole expansion method for plasmonics-active nanosphere dimers.

This paper describes a comparative study of finite-difference time-domain (FDTD) and analytical evaluations of electromagnetic fields in the vicinity of dimers of metallic nanospheres of plasmonics-active metals. The results of these two computational methods, to determine electromagnetic field enhancement in the region often referred to as "hot spots" between the two nanospheres forming the dimer, were compared and a strong correlation observed for gold dimers. The analytical evaluation involved the use of the spherical-harmonic addition theorem to relate the multipole expansion coefficients between the two nanospheres. In these evaluations, the spacing between two nanospheres forming the dimer was varied to obtain the effect of nanoparticle spacing on the electromagnetic fields in the regions between the nanostructures. Gold and silver were the metals investigated in our work as they exhibit substantial plasmon resonance properties in the ultraviolet, visible, and near-infrared spectral regimes. The results indicate excellent correlation between the two computational methods, especially for gold nanosphere dimers with only a 5-10% difference between the two methods. The effect of varying the diameters of the nanospheres forming the dimer, on the electromagnetic field enhancement, was also studied.

Optical response of linear chains of metal nanospheres and nanospheroids.

A semi-analytical method for computing the electric field surrounding a finite linear chain of metal nanospheres and nanospheroids is described. In treating chains or clusters of spheres, a common approach is to use the spherical-harmonic addition theorem to relate the multipole expansion coefficients between different spheres. A method is described here that avoids the use of spherical-harmonic addition theorems, which are not applicable to spheroidal chains. Simulations are given that illustrate the large field enhancements that can occur in the gaps between silver nanoparticles arising from plasmon resonances.

Spectral bounds on plasmon resonances for Ag and Au prolate and oblate nanospheroids.

Analytical expressions for the plasmon resonance frequencies of prolate and oblate spheroids and their dependence on ellipticity have been derived, and approximate bounds on these frequencies established. These formulas may be useful in tuning the plasmon resonance within certain limits. With increasing aspect ratio, the prolate spheroid resonance is red shifted relative to a sphere with no lower limit under the assumptions of a Drude dispersion model. On the other hand, the oblate resonances are blue shifted as the spheroid becomes increasingly flat, but up to a limit.

Noise propagation in linear and nonlinear inverse scattering.

The propagation of noise from the data to the reconstructed speed of sound image by inverse scattering within the framework of the Lippmann-Schwinger integral equation of scattering is discussed. The inversion algorithm that was used consisted in minimizing a Tikhonov functional in the unknown speed of sound. The gradient of the objective functional was computed by the method of the adjoint fields. An analytical expression for the inverse scattering covariance matrix of the image noise was derived. It was shown that the covariance matrix in the linear x-ray computed tomography is a special case of the inverse scattering matrix derived in this paper. The matrix was also analyzed in the limit of the linearized Born approximation, and the results were found to be in qualitative agreement with those recently reported in the literature for Born inversion using filtered backpropagation algorithm. Finally, the applicability of the analysis reported here to the obstacle problem and the physical optics approximation was discussed.

Imaging the distribution of magnetic nanoparticles with ultrasound.

Magnetic nanoparticles can be caused to oscillate under the influence of an incident ultrasonic wave. If the particles are momentarily aligned with a magnetizing pulse creating a macroscopic magnetization, this oscillation will result in a time-varying magnetic moment which should be detectable as an induced voltage in a nearby pickup coil. In this way, focused ultrasound can be used to map, or image, the spatial distribution of the magnetic particles after these particles have been introduced into the body. The magnetic particles could be antibody-labeled to target tumor cells or used as a cardiovascular contrast agent, among other applications. The magnitude of the induced signal is estimated for one micron particles with a Fe/tissue volume fraction of 10(-6), which is about the limit of detectability for MRI superparamagnetic contrast agents consisting of single domain iron-oxide particles. One advantage of this method compared to conventional MRI is potentially greater sensitivity due to the absence of a large background signal.