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Researchers Submit Patent Application, "Nanoporous Gold Nanoparticles as High-Payload Molecular Cargos, Photothermal/Photodynamic Therapeutic Agents,...

May 8, 2014



Researchers Submit Patent Application, "Nanoporous Gold Nanoparticles as High-Payload Molecular Cargos, Photothermal/Photodynamic Therapeutic Agents, and Ultrahigh Surface-To-Volume Plasmonic Sensors"

By a News Reporter-Staff News Editor at Politics & Government Week -- From Washington, D.C., VerticalNews journalists report that a patent application by the inventor Shih, Wei-Chuan (Houston, TX), filed on March 12, 2013, was made available online on April 24, 2014.

No assignee for this patent application has been made.

News editors obtained the following quote from the background information supplied by the inventors: "A single living cell is a dynamic system constantly sensing and reacting to external stimuli, and can already be considered as a biological network itself. As the hierarchy upgrades, many cells can form a more complex biological network and demonstrate communication and collective behavior. To unravel the biological network even at the single cell level is still challenging because of its complexity and is a critical subject in fields such as system biology. One of the most important tricks in all experimental science is to effectively vary only one thing at a time. As such, the spatial and temporal precision of the delivery of controlled changes is critical.

"Recently, we have witnessed a paradigm shift from extracellular control of environmental stimuli to intracellular control of the actual internal connections themselves, which can potentially provide new insights of the living cellular machinery. As an obvious example, an external stimulus will most likely trigger a cascade of cell signaling via various pathways before its effect is actually received by the intended intracellular party. The response of interest may be completely masked or misinterpreted due to signal loss, attenuation or distortion within the long string of signaling cascade. Therefore, intracellular techniques have the potential to deliver the controlled effectors with much improved spatial, temporal and even molecular precision.

"Recent advances in nanoplasmonic technology have enabled new tools for light-gated drug delivery, photothermal therapy, DNA release, inducing protein aggregates, and nanometer scale direct interfacing with intracellular processes using oligonucleotides. A distinct advantage of gold nanoparticle-based approaches compared to lysosome vesicle or other metals is the much better control in coating, or functionalizing, them with thiolated ligands directly or through linker molecules, and its chemical inertness. Colloidal gold nanosphere has been first used as a photothermal agent for therapies and light-gated release of surface coated molecules. With plasmon resonance near 540 nm, in vivo applications were limited however by the strong scattering and absorption of skin, tissue, and hemoglobin at this wavelength. As a result, various colloidal gold nanoparticles of other geometry have been developed, e.g., nanoshell, nanorod, and nanocage, with two primary goals: shifting the resonance into the near-infrared transmission window and increasing the nanoparticle's cargo capacity.

"Plasmonic nanoparticles are generally characterized by scanning electron microcopy or dynamic light scattering for size distribution, absorption spectroscopy for both size and plasmonic resonance, and surface-sensitive techniques such as surface-enhanced Raman spectroscopy (SERS) using surface adsorbate or thiolated hydrocarbon as markers. Among these, SERS provides label-free adsorbate identification with the highest nanoparticle-molecule distance sensitivity because only the molecules within a few nanometers of the gold surface can be enhanced. In addition, SERS is arguably the most robust and sensitive technique for real biological applications because it is a background-free measurement assuming the photoluminescence from other interferents is negligible.

"Over the past decade, many types of colloidal nanoparticles of various shapes have been developed as shown and described below. All the existing nanoparticles share the same feature, that is, they are solid-core, with nanocage as the only exception, which features an empty void inside a 'porous' box. Therefore, only a small fraction, i.e., the molecules absorbed on nanocage walls, could be plasmonically enhanced, rendering single nanocage undetectable by SERS."

As a supplement to the background information on this patent application, VerticalNews correspondents also obtained the inventor's summary information for this patent application: "Surface-enhanced Raman spectroscopy has been widely used for high-sensitivity molecular detection and identification. However, as for most surface sensors, the performance of a SERS sensor is usually controlled by the delivery and binding of molecular analytes to the sensing surface. To address this challenge, we disclose a novel monolithic plasmonic nanofluidic architecture that exploits a 3-dimensional sensing volume inside nanoporous gold (NPG), as shown in FIG. 1(a). Unlike conventional sensors that only utilize an approximately flat sensing surface, our approach features an ultrahigh surface-to-volume ratio for collecting a large number of molecules inside the sensing volume that is matched to the optical focal volume. Further, once entering the sensing volume, these molecules are immersed in a plasmonic field that retains them and enables SERS acquisition over a prolonged period of time. The analytes can be released from the sensing volume after being measured by simply turning off the laser, and new analytes can be flowed in, trapped by the plasmonic field, and measured in a batch fashion, thereby enabling continuous monitoring. We envision that this approach will provide a powerful trapping mechanism to complement current surface binding strategies based on chemical or biochemical functionalization of the sensor surface. Moreover, this approach can become a versatile label- and surface functionalization-free technique for highly multiplexed sensing. Further, the proposed platform provides a unique opportunity to simultaneously exploit and study the synergy between nanofluidic confinement, plasmonic trapping and field enhancement.

"We disclose a novel class of nanoparticle, dubbed nanoporous gold nanoparticle (NPGN). As shown the figures and described below, NPGNs feature a fine porous network with pore size .about.20 nm in some embodiments throughout its entire volume, which is not seen in any existing gold nanoparticles including solid- or hollow-core nanosphere, nanorod, nanoshell, nanocrescent, and nanocage. The external shape of our first NPGN is similar to a nanodisk with a diameter of .about.400-500 nm and a thickness of .about.75 nm. Both the diameter and thickness can be easily tuned by slightly changing fabrication parameters. The high porosity is intriguing and critically important in several aspects.

"First, the increased surface area would permit NPGN to carry a much higher payload of surface adsorbates. This feature has significant implication in nanoparticle-based molecular cargo for the delivery of drugs, proteins, DNA and RNA into cells. It has a significant potential in improving current cancer treatment via chemotherapy, radiation therapy, or the combination of the two. Second, the NPGN is 'semitransparent' due to its porous nature. Thus, the internal surface adsorbates may in some cases be optically measured. In other words, the amount of internal payload can be quantified via optical methods. Third, with proper surface linkage, the entire 3-dimensional internal volume can be 'filled' and thus payload may be further increased without paying the price of size increase. Fourth, due to the fine pore structures, the majority of the 'filler' or surface adsorbate molecules are within the plasmonic field or 'hot spots.' We believe this is the fundamental mechanism giving rise to our recently observed intense Raman scattering from a benzenethiol self-assembled monolayer (SAM) coating. A heuristic argument similar to that in the discovery of SERS is that the increase of surface area (.about.10-30.times.) cannot account for the .about.4-5 orders of magnitude increase in SERS intensity by comparing solid-core gold nanodisk and NPGN. The porous nature must have modified the nanoplasmonic behavior dramatically.

"Another heuristic explanation can be applied to the red-shifted plasmon resonance peak. Colloidal gold nanosphere peaks at .about.540 nm and is relatively insensitive to size. Red-shifted plasmonic peak is known to be present in solid-core gold nanodisk (peak .about.700 nm) and un-patterned, i.e., continuous, NPG thin film (peak .about.650 nm). It appears that the combination of NPGN's shape and the fine porous network has further red-shifted the plasmonic peak into the near-infrared regime, at least to 785 nm employed in our experiments. This further red-shift provides a strong indication of synergistic coupling between external shape of a nanoparticle and its internal nanostructures.

"Fifth, the highly plasmonic nature of NPGN suggests that it is a good photothermal agent in the near-infrared, which is critical for deep tissue penetration in biomedical applications. Thus, the embedded molecules can be released by light activation. Sixth, the plasmonic heating on NPGN can become an effective light-gated delivery strategy of the internalized molecules at the cellular, tissue, organ and whole body level.

"Although NPGN has so many fascinating properties and potentials, it is not well understood. To the best of our knowledge, we are the first to pattern sub-100 nm thick continuous NPG film into 400-500 nm diameter NPGN.

"We have established a NPGN fabrication process. Starting with a continuous Au/Ag alloy film and followed by nanosphere lithography, etching and nitric acid leaching, we have repeatedly fabricated NPGN with consistent size and SERS resulting from a benzenethiol self-assembled monolayer coating throughout the NPGN's external and internal surfaces. In addition to ready-to-use dark-field microscope (DFM), localized surface plasmon resonance (LSPR) imager and a shared scanning electron microscope (SEM) we have developed two critical Raman instruments for NPGN characterization. A high-throughput line-scan Raman mapping system has been employed to characterize dense NPGN units over large area. The second Raman imager enables simultaneous random-access of 50 1-micron.sup.2 spots within a 100.times.100 micron.sup.2 sample area and has been employed to perform spatially-agile sampling of many individual NPGN units simultaneously. A novel SERS nanoparticle tracking and monitoring system enables the tracking, monitoring and heating of multiple selective NPGN floating in micro system such as biological cells, a critical milestone. This disclosure deepens our fundamental understanding of this new nanoplasmonic material and to guide future implementation of NPGN for modulation and measurement in biological networks.

BRIEF DESCRIPTION OF THE DRAWINGS

"The features, nature, and advantages of the disclosed subject matter will become more apparent from the detailed description set forth below when taken in conjunction with the drawings, wherein:

"FIG. 1(a) shows an Au nanofluidic architecture;

"FIG. 1(b) shows 300 nm thick NPG thin film;

"FIG. 1© shows patterned NPGD with diameter 500 nm and thickness 75 nm;

"FIG. 1(d) shows benzenethiol SERS from NPGD with SERS EF.about.10.sup.8-9;

"FIGS. 2(a)-© show SEM images of Au nanoparticles, a nanotip, and nanostructured SERS substrates;

"FIGS. 3(a)-(d) show SEM images of Ag nanoparticle decorated anodized alumina, Ag-coated porous silicon, immobilized Au nanoparticle, and a nanorod array;

"FIG. 4(a) shows a SEM image of sputtered gold nanodots;

"FIG. 4(b) shows a large-area, high-resolution SERS map of benzenethiol self-assembled monolayer (SAM);

"FIG. 4© shows a benzenethiol SERS spectrum;

"FIGS. 5(a)-© show SERS integrated with microfluidics;

"FIGS. 5(d)-(f) show SERS integrated with nanofluidics;

"FIG. 6(a) shows LSPR spectrum vs. pore size in NPG films;

"FIG. 6(b) shows LSPR peak position vs. pore size in NPG films;

"FIG. 6© shows SEM of mechanically wrinkled NPG films;

"FIG. 6(d) shows mechanically densified NPG film;

"FIG. 7 shows a model for FDTD analysis, including a 3-D model and a refractive index profile of Au disk with ten 10 nm through-holes;

"FIGS. 8(a)-(d) show a fabrication process flow for NPG or NPGD plasmonic nanofluidics and a microfluidic enclosure for sample delivery;

"FIG. 9(a) shows E-field distribution near a solid Au disk;

"FIG. 9(b) shows a plasmon resonance peak for Au and Ag disks;

"FIG. 10 shows FDTD results from three Au disks with ten 10-nm through-holes;

"FIG. 11(a) shows a SEM image of monolithic NPG thin films on a silicon substrate

"FIG. 11(b) shows a SEM image of a NPG thin films lift off from the substrate to reveal cross-section;

"FIG. 12(a) shows a SEM image of patterned NPGD with PS beads on top;

"FIG. 12(b) shows a SEM image of patterned NPGD with PS beads removed;

"FIG. 13(a) shows normalized benzenethiol SAM SERS from nanoshell, NPGD and NPG;

"FIG. 13(b) shows SERS from different thiolated ligands;

"FIGS. 14(a)-(f) show a comparison of sparse and dense NPGD samples, with bright-field white light images in (a) and (d), SERS maps in (b) and (e), and SERS spectra from five different locations in © and (f);

"FIG. 15(a) shows etched Au/Ag alloy disks on Au bases;

"FIG. 15(b) shows an enlarged image of NPGD sides to show visible boundary between Au/Ag alloy and the Au base;

"FIG. 15© shows a top view of NPGD;

"FIG. 15(d) shows unpatterned NPG thin film;

"FIG. 16(a) shows normalized SERS from NPGD, unpatterned NPG thin films, and Au@SiO.sub.2 nanoshells;

"FIG. 16(b) shows SERS from a single NPGD at various detector temperatures;

"FIG. 17(a) shows a released NPGN;

"FIG. 17(b) shows high-density NPGN prior to release with polystyrene beads in place;

"FIG. 17© shows released NPGN with polystyrene still attached;

"FIG. 18(a) shows an FDTD electric field distribution;

"FIG. 18(b) shows extinction spectra for gold and silver;

"FIG. 18© shows a continuous NPG film;

"FIG. 18(d) shows NPGN;

"FIG. 18(e) shows a SERS map vs. bright-field;

"FIG. 19(a) shows a 300 nm thick NPG film;

"FIG. 19(b) shows un-released NPGNs;

"FIG. 20(a) shows a SERS map of un-released NPGN using benzenethiol Raman peak @ 1575 cm.sup.-1;

"FIG. 20(b) shows benzenethiol SERS;

"FIG. 20© shows ABL patterned photoresist;

"FIG. 21 shows 11-point random access SERS imaging of nanoshells coated with benzenethiol SAM;

"FIGS. 22(a)-(e) show an adaptive SERS based tracking scheme, with motion sensor configuration, tracking experiments, SERS intensity, and single vs. dimer nanoshells benzenethiol SERS;

"FIGS. 23(a)-© show ABL resist pattern of 60 nm circles, 11-spot SERS tracking, and 50-spot Si Raman; and

"FIGS. 24(a)-(l) show various types of plasmon-resonant nanoparticles: spheres; rods; bipyramids; rods @ Ag shells; rice; shells; bowls; spiky shells; nanostars, tetrahedra, octahedra, and cuboctahedra; cube; cages; and crescents."

For additional information on this patent application, see: Shih, Wei-Chuan. Nanoporous Gold Nanoparticles as High-Payload Molecular Cargos, Photothermal/Photodynamic Therapeutic Agents, and Ultrahigh Surface-To-Volume Plasmonic Sensors. Filed March 12, 2013 and posted April 24, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=4673&p=94&f=G&l=50&d=PG01&S1=20140417.PD.&OS=PD/20140417&RS=PD/20140417

Keywords for this news article include: Patents, Nanoporous, Nanotechnology, Emerging Technologies.

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