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.

Understanding Resonant Light-Triggered DNA Release from Plasmonic Nanoparticles.

Nanoparticle-based platforms for gene therapy and drug delivery are gaining popularity for cancer treatment. To improve therapeutic selectivity, one important strategy is to remotely trigger the release of a therapeutic cargo from a specially designed gene- or drug-laden near-infrared (NIR) absorbing gold nanoparticle complex with NIR light. While there have been multiple demonstrations of NIR nanoparticle-based release platforms, our understanding of how light-triggered release works in such complexes is still limited. Here, we investigate the specific mechanisms of DNA release from plasmonic nanoparticle complexes using continuous wave (CW) and femtosecond pulsed lasers. We find that the characteristics of nanoparticle-based DNA release vary profoundly from the same nanoparticle complex, depending on the type of laser excitation. CW laser illumination drives the photothermal release of dehybridized single-stranded DNA, while pulsed-laser excitation results in double-stranded DNA release by cleavage of the Au-S bond, with negligible local heating. This dramatic difference in DNA release from the same DNA-nanoparticle complex has very important implications in the development of NIR-triggered gene or drug delivery nanocomplexes.

Near real-time determination of metabolic parameters for unquenched 6-mercaptopurine and xanthine oxidase samples using capillary electrophoresis.

The enzyme activity of xanthine oxidase (XO) is influenced by several environmental factors including solution conditions, storage conditions, inhibitors, other enzymes, and activators. For instance, the metabolic reaction involving XO and the pro-drug 6-mercaptopurine, a drug used in the treatment maintenance of acute lymphatic leukemia, Crohn's disease, and ulcerative colitis, is often modified through the use of inhibitors, which varies the kinetic parameters associated with this reaction. Methods that provide fast and accurate determination of these kinetic constants can help in understanding the mechanism of these reactions. Herein, sequential and time-delayed electrokinetic injections of unpurified and unquenched samples containing xanthine oxidase, 6-mercaptopurine, and the inhibitor allopurinol are evaluated using capillary electrophoresis (CE). Using progress curve analysis, the Michaelis constant, apparent Michaelis constant, and inhibition constant are estimated to be 43.8 ± 2.0 µM, 143.0 ± 3.7 µM and 13.2 ± 1.4 µM, respectively. In addition, a turnover number of 7.9 ± 0.2 min(-1) is quantified. These values are consistent with some previously published values but were obtained without user intervention for reaction monitoring. This unique application of CE enzyme assays offers substantial advantages over traditional methods by determining kinetic parameters for enzymatic reactions with minimal (nL) sample volumes, short (<30 min) reaction analysis times, without any sample quenching or purification, and minimal user intervention.

Au nanomatryoshkas as efficient near-infrared photothermal transducers for cancer treatment: benchmarking against nanoshells.

Au nanoparticles with plasmon resonances in the near-infrared (NIR) region of the spectrum efficiently convert light into heat, a property useful for the photothermal ablation of cancerous tumors subsequent to nanoparticle uptake at the tumor site. A critical aspect of this process is nanoparticle size, which influences both tumor uptake and photothermal efficiency. Here, we report a direct comparative study of ∼90 nm diameter Au nanomatryoshkas (Au/SiO2/Au) and ∼150 nm diameter Au nanoshells for photothermal therapeutic efficacy in highly aggressive triple negative breast cancer (TNBC) tumors in mice. Au nanomatryoshkas are strong light absorbers with 77% absorption efficiency, while the nanoshells are weaker absorbers with only 15% absorption efficiency. After an intravenous injection of Au nanomatryoshkas followed by a single NIR laser dose of 2 W/cm(2) for 5 min, 83% of the TNBC tumor-bearing mice appeared healthy and tumor free >60 days later, while only 33% of mice treated with nanoshells survived the same period. The smaller size and larger absorption cross section of Au nanomatryoshkas combine to make this nanoparticle more effective than Au nanoshells for photothermal cancer therapy.

The surprising in vivo instability of near-IR-absorbing hollow Au-Ag nanoshells.

Photothermal ablation based on resonant illumination of near-infrared-absorbing noble metal nanoparticles that have accumulated in tumors is a highly promising cancer therapy, currently in multiple clinical trials. A crucial aspect of this therapy is the nanoparticle size for optimal tumor uptake. A class of nanoparticles known as hollow Au (or Au-Ag) nanoshells (HGNS) is appealing because near-IR resonances are achievable in this system with diameters less than 100 nm. However, in this study, we report a surprising finding that in vivo HGNS are unstable, fragmenting with the Au and the remnants of the sacrificial Ag core accumulating differently in various organs. We synthesized 43, 62, and 82 nm diameter HGNS through a galvanic replacement reaction, with nanoparticles of all sizes showing virtually identical NIR resonances at ∼800 nm. A theoretical model indicated that alloying, residual Ag in the nanoparticle core, nanoparticle porosity, and surface defects all contribute to the presence of the plasmon resonance at the observed wavelength, with the major contributing factor being the residual Ag. While PEG functionalization resulted in stable nanoparticles under laser irradiation in solution, an anomalous, strongly element-specific biodistribution observed in tumor-bearing mice suggests that an avid fragmentation of all three sizes of nanoparticles occurred in vivo. Stability studies across a wide range of pH environments and in serum confirmed HGNS fragmentation. These results show that NIR resonant HGNS contain residual Ag, which does not stay contained within the HGNS in vivo. This demonstrates the importance of tracking both materials of a galvanic replacement nanoparticle in biodistribution studies and of performing thorough nanoparticle stability studies prior to any intended in vivo trial application.

Hot-electron-induced dissociation of H2 on gold nanoparticles supported on SiO2.

Hot-electron-induced photodissociation of H2 was demonstrated on small Au nanoparticles (AuNPs) supported on SiO2. The rate of dissociation of H2 was found to be almost 2 orders of magnitude higher than that observed on equivalently prepared AuNPs on TiO2. The rate of H2 dissociation was found to be linearly dependent on illumination intensity with a wavelength dependence resembling the absorption spectrum of the plasmon of the AuNPs. This result provides strong additional support for the hot-electron-induced mechanism for H2 dissociation in this photocatalytic system.

Orienting nanoantennas in three dimensions to control light scattering across a dielectric interface.

The light scattering properties of hemispherical resonant nanoantennas can be used to redirect normal incidence light to propagate within a thin film or thin film-based device, such as a solar cell, for enhanced efficiency. While planar nanoantennas are typically fabricated as simple nanoparticles or nanostructures in the film plane, here we show that a hemispherical nanoantenna with its symmetry axis tilted out of the plane accomplishes this task with far greater efficacy. The amount of light scattered into an underlying dielectric by the electric and magnetic dipole response of oriented nanocups can be more than three times that achieved using symmetric antenna structures.

Salt-mediated self-assembly of thioctic acid on gold nanoparticles.

Self-assembled monolayer (SAM) modification is a widely used method to improve the functionality and stability of bulk and nanoscale materials. For instance, the chemical compatibility and utility of solution-phase nanoparticles are often improved using covalently bound SAMs. Herein, solution-phase gold nanoparticles are modified with thioctic acid SAMs in the presence and absence of salt. Molecular packing density on the nanoparticle surfaces is estimated using X-ray photoelectron spectroscopy and increases by ∼20% when molecular self-assembly occurs in the presence versus the absence of salt. We hypothesize that as the ionic strength of the solution increases, pinhole and collapsed-site defects in the SAM are more easily accessible as the electrostatic interaction energy between adjacent molecules decreases, thereby facilitating the subsequent assembly of additional thioctic acid molecules. Significantly, increased SAM packing densities increase the stability of functionalized gold nanoparticles by a factor of 2 relative to nanoparticles functionalized in the absence of salt. These results are expected to improve the reproducible functionalization of solution-phase nanomaterials for various applications.