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WO2011006002A2 - Nanostructures recouvertes de métal et procédés associés - Google Patents

Nanostructures recouvertes de métal et procédés associés Download PDF

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Publication number
WO2011006002A2
WO2011006002A2 PCT/US2010/041421 US2010041421W WO2011006002A2 WO 2011006002 A2 WO2011006002 A2 WO 2011006002A2 US 2010041421 W US2010041421 W US 2010041421W WO 2011006002 A2 WO2011006002 A2 WO 2011006002A2
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Prior art keywords
nanostructure
gold
shell
core
quantum dot
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Ceased
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WO2011006002A3 (fr
Inventor
Xiaohu Gao
Yongdong Jin
Matthew O'donnell
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University of Washington
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University of Washington
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Publication of WO2011006002A3 publication Critical patent/WO2011006002A3/fr
Priority to US13/273,095 priority Critical patent/US8701471B2/en
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A61K49/1827—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle
    • A61K49/1851—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule
    • A61K49/1854—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles having a (super)(para)magnetic core, being a solid MRI-active material, e.g. magnetite, or composed of a plurality of MRI-active, organic agents, e.g. Gd-chelates, or nuclei, e.g. Eu3+, encapsulated or entrapped in the core of the coated or functionalised nanoparticle having a (super)(para)magnetic core coated or functionalised with an organic macromolecular compound, i.e. oligomeric, polymeric, dendrimeric organic molecule the organic macromolecular compound being obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly(meth)acrylate, polyacrylamide, polyvinylpyrrolidone, polyvinylalcohol
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B22—CASTING; POWDER METALLURGY
    • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
    • B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
    • B22F1/17—Metallic particles coated with metal
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B22—CASTING; POWDER METALLURGY
    • B22F—WORKING METALLIC POWDER; MANUFACTURE OF ARTICLES FROM METALLIC POWDER; MAKING METALLIC POWDER; APPARATUS OR DEVICES SPECIALLY ADAPTED FOR METALLIC POWDER
    • B22F1/00—Metallic powder; Treatment of metallic powder, e.g. to facilitate working or to improve properties
    • B22F1/18—Non-metallic particles coated with metal
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/52—Use of compounds or compositions for colorimetric, spectrophotometric or fluorometric investigation, e.g. use of reagent paper and including single- and multilayer analytical elements
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors

Definitions

  • fluorophores such as semiconductor quantum dots
  • plasmonic materials such as gold
  • Plasmonic engineering of nanomaterials has the potential to revolutionize a variety of research fields ranging from optoelectronics and nanophotonics to nanomedicine.
  • deposition of silver nanoparticles on thin-film solar cells has resulted in greater than ten-fold enhancement in light absorption due to localized surface plasmons.
  • quantum dots QDs
  • MNPs have become an important contrast agent in T2-weighted magnetic resonance imaging (MRI) because MRI offers high-resolution and excellent tissue penetration depth.
  • MRI magnetic resonance imaging
  • MRI is not as sensitive as optical imaging or positron emission tomography, and is difficult to visualize in microscopic tissue examination.
  • gold NPs are often used in scattering based imaging and offer high sensitivity, high resolution, and multiplexing capability, tissue penetration depth of optical imaging is limited to millimeters.
  • Nanoprobes with integrated functionalities while maintaining compact size, remains a challenge.
  • Nanoprobes with coupled functionalities will enable new imaging modes not available from each individual component for enhanced contrast specificity.
  • MNPs Due to a number of desirable properties including magnetic attraction, near-infrared (NIR) absorption, photon scattering, and ease of biomolecular conjugation through the stable thiolate-gold interaction, noble metal (e.g., platinum, gold) coated MNPs with precisely controlled shell thickness and smooth surface are a long sought after coupled imaging probe.
  • NIR near-infrared
  • Au gold coated MNPs with precisely controlled shell thickness and smooth surface are a long sought after coupled imaging probe.
  • MNPs or MNP-silica composites utilizing the low dielectric permittivity of silica.
  • neither approach simultaneously provides nanoparticles with NIR response (critical for in vivo imaging and therapy) and while maintaining compact particle size (desirable for tissue penetration and plasma circulation).
  • gold coating on MNP-silica composites often results in large particles of 100-200 nm in diameter with uneven surfaces.
  • the present invention provides metal-coated nanostructures, methods for making the metal-coated nanostructures, methods for using the metal-coated nanostructures, and devices that include the metal-coated nanostructures.
  • a metal-coated nanostructure comprises (a) a nanostructure core, (b) a metal shell surrounding the core, and (c) a cationic polymer intermediate the core and the shell.
  • Representative nanostructures include quantum dots, magnetic nanoparticle, carbon nanotubes, and biological particles.
  • the shell comprises a template grown metal.
  • the shell is a gold shell.
  • the nanostructure further includes a material intermediate the core and polymer. The material may further include one or more polyelectrolyte bilayers.
  • the distance between the core and the shell is from about 0.1 to about 200 nm.
  • the shell has a thickness of from about 0.1 about 30 nm. In other embodiments, the shell has a thickness of from about 2 to about 3 nm.
  • nanostructure of the invention as an agent for hyperthermic treatment is also provided.
  • the invention provides a gold-coated quantum dot, comprising (a) a quantum dot core, (b) a gold shell surrounding the core, and (c) a cationic polymer intermediate the core and the shell.
  • a quantum dot of the invention for optical and/or fluorescent imaging is also provided.
  • the invention provides a gold-coated magnetic nanoparticle, comprising (a) a magnetic nanoparticle core, (b) a gold shell surrounding the core, and (c) a cationic polymer intermediate the core and the shell.
  • a magnetic nanoparticle of the invention as a contrast agent for magnet resonance imaging and for magnetomotive photoacoustic imaging are also provided.
  • the invention provides a method for making a metal-coated nano structure.
  • the method comprises:
  • step (c) adding a reducible metal ion complex to the plurality of nanostructures formed in step (b);
  • the method further comprises adding a polyamine to the plurality of individual nanostructures in water followed by adding a polyanionic material to provide a plurality of nanostructures comprising a polyelectrolyte bilayer, prior to adding the cationic polymer.
  • the method further comprises adding a polyamine to the plurality of nanostructures comprising a polyelectrolyte bilayer followed by adding a polyanionic material to provide a nanostructure comprising two polyelectrolyte bilayers, prior to adding the cationic polymer.
  • methods for imaging comprise administering to a subject or contacting a tissue with a nanostructure, a quantum dot, or a nanoparticle of the invention.
  • the nanostructure is a magnetic nanoparticle and imaging is magnetic resonance imaging.
  • the nanostructure is a magnetic nanoparticle and imaging is magnetomotive photoacoustic imaging.
  • the imaging is fluorescent imaging.
  • the imaging is based on light scattering.
  • the invention provides a method for sensing or detecting an analyte.
  • the method comprises contacting a sample containing an analyte with a nanostructure, a quantum dot, or a nanoparticle of the invention, and measuring a change in absorption and/or scattering of the nanostructure, quantum dot, or nanoparticle shell, wherein the change in absorption and/or scattering is indicative of the presence of the analyte in the sample.
  • a method for treating a condition comprises administering to a subject a therapeutically effective amount of a nanostructure of the invention, and irradiating the subject with a wavelength of light sufficient to cause the metal shell to generate heat effective for hyperthermic therapy.
  • the nanostructure further includes a targeting agent to direct the nanostructure to a site of interest.
  • the invention provides a photovoltaic device comprising an active layer comprising a quantum dot of the invention.
  • the invention provides a light-emitting device comprising an active layer comprising a quantum dot of the invention.
  • a metal-coated surface comprises (a) a continuous surface, (b) a metal coating, and (c) a cationic polymer intermediate the surface and the coating.
  • the invention provides a method for sensing or detecting an analyte.
  • the method comprises contacting a sample containing an analyte with a surface of the invention, and measuring a change in fluorescence, absorption, and/or scattering of the surface, wherein the change in fluorescence, absorption, and/or scattering is indicative of the presence of the analyte in the sample.
  • FIGURE IA is a schematic illustration of a method for producing a representative gold-coated nanostructure of the invention: a gold-coated quantum dot (QD).
  • QD gold-coated quantum dot
  • hydrophobic QDs coated with trioctylphosphine oxide (TOPO) on QD surface were solubilized with a lipid-PEG-COOH conjugate to provide water-soluble QDs, which were then coated with poly-L-histidine (PLH) to facilitate immobilization of gold ions (Au 3+ ) ions at high density.
  • TOPO trioctylphosphine oxide
  • PH poly-L-histidine
  • Addition of a mild reducing agent (hydroxylamine) provided gold nucleation on the PLH template and formation of a thin gold shell.
  • FIGURE IB is a schematic illustration of a representative gold-coated nanostructure of the invention, a gold-coated quantum dot (QD), in which the distance between the QD core and the gold shell is tuned by coating QDs with polyelectrolyte bilayers (cationic polyallylamine (PAH) and anionic polystyrene sulfonate (PSS)) by layer-by-layer (LBL) assembly before PLH coating.
  • PHA cationic polyallylamine
  • PSS anionic polystyrene sulfonate
  • FIGURES 2A-2D presents transmission electron microscopy (TEM) images: FIGURE 2A is a TEM image of QD-gold hybrid nanoparticles in chloroform; FIGURE 2B is a TEM image of lipid-PEG-COOH conjugate-coated water-soluble QDs; FIGURES 2C and 2D are TEM images of representative gold-coated nanostructures of the invention, gold-coated QDs, shown at a magnification of 245 K and 340 K, respectively. These TEM images demonstrate that virtually every QD is encapsulated by a thin gold shell (2-3 nm) and having a gap between the shell and the nanop article core.
  • TEM transmission electron microscopy
  • FIGURES 3A and 3B illustrate optical properties of representative gold-coated nanostructures of the invention, gold-coated QDs.
  • FIGURE 3A compares the UV- Vis absorption spectra of QDs before and after gold encapsulation (QD/PLH is the water-soluble PLH-coated QD). After gold shell formation, the QD absorption was obscured by a strong surface plasmon resonance (SPR) band centered at 583 nm (QD/PLH/ Au).
  • SPR surface plasmon resonance
  • FIGURE 3B compares the fluorescence spectra of the original organic- soluble QDs (QD/CHCI 3 ), water-soluble QDs in the presence of Au 3+ ions (QD/PLH/Au 3+ ), and gold-shell-encapsulated QDs (QD/PLH/Au).
  • FIGURE 3C compares the quantum yield of fluorescence of representative gold- coated nanostructures of the invention, gold-coated QDs. Although the peak position did not change, the fluorescence intensity decreased 51.9% upon addition of Au 3+ salt, and decreased another 23.7% after gold shell formation.
  • polyelectrolyte bilayers composed of cationic PAH and anionic PSS were deposited onto the QD surface before PLH coating to increase the spacing between the QD core and the gold shell. Quantitative spectroscopic measurements indicated that the QD fluorescence was significantly improved with one to two layers of polyelectrolyte coating.
  • FIGURES 3D and 3E compare TEM images of representative gold-coated nanostructures of the invention, QD-gold core-shell nanoparticles with one and two layers of polyelectrolyte spacers, respectively.
  • FIGURE 3F1-3F3 are histograms comparing the core-shell separation distribution of representative particles of the invention having no polyelectrolyte bilayer (0-bilayer,
  • FIGURE 4A compares normalized photoluminescence (PL) intensity over time for a representative gold-coated nanostructure of the invention, gold-coated QDs
  • QD/organic water-soluble QDs
  • QD/PLH water-soluble QDs
  • QD/Au gold-coated QDs
  • the QD-gold nanoparticles are significantly more photostable than the lipid-PEG-coated water-soluble QDs, and slightly outperformed the original organic-soluble QDs.
  • FIGURES 4B-4G compare fluorescence and darkfield imaging of single representative nanoparticles of the invention spread between two glass coverslips.
  • QDs without gold shell coating FIGURES 4B-4D
  • FIGURES 4E-4G the encapsulated QDs
  • FIGURES 5A and 5B are TEM images of representative nanostructures of the invention: gold-coated iron oxide nanoparticles (FIGURE 5A) and gold-coated liposomes (FIGURES 5B).
  • the inset in FIGURE 5 A shows original iron oxide nanoparticles before gold shell encapsulation.
  • No TEM image of liposome before gold shell encapsulation is shown because liposomes are not electron-dense materials suitable for TEM visualization.
  • FIGURES 6A-6F present transmission electron microscopy (TEM) images: FIGURE 6A is a TEM image of QD-gold hybrid nanoparticles in chloroform; FIGURE 6B is a TEM image of lipid-PEG-COOH conjugate-coated water-soluble QDs; FIGURES 6C, 6D, and 6E are TEM images of representative gold-coated nanostructures of the invention, gold-coated QDs, shown at a magnification of 245 K, 340 K, and 1050 K, respectively. In FIGURE 6E, the crystal lattice fringe becomes visible. Due to the uneven shell thickness and the polycrystalline structure, some shell areas have low contrast.
  • TEM transmission electron microscopy
  • FIGURE 6F shows the signature crystal lattice of Au, confirming the existence of a thin shell.
  • the lattice spacing in CdSe core measured at 0.37 nm corresponds to CdSe (100) lattice planes, and 0.23 nm in the shell corresponds to the (111) planes of face-centered cubic (fee) Au.
  • FIGURE 7 is a schematic illustration of representative photovoltaic device incorporating a representative gold-coated nanostructure of the invention in the active layer.
  • FIGURE 8 is a schematic illustration of representative light-emitting device incorporating a representative gold-coated nanostructure of the invention in the active layer.
  • FIGURE 9A is a schematic of illustration of a method for producing a representative gold-coated nanostructure of the invention: a gold-coated magnetic nanoparticle (MNP-gold core-shell NPs).
  • MNP-gold core-shell NPs gold-coated magnetic nanoparticle
  • monodisperse hydrophobic MNPs coated with oleic acids are first solubilized using amphiphilic phospholipid (PL), PL-PEG-COOH.
  • PLH which is capable of chelating metal ions, is then adsorbed onto PL-PEG-COOH via electrostatic interaction.
  • gold ions and a reducing reagent thin gold shells form on the polypeptide template rather than directly on the core nanoparticles.
  • the molecular structures of oleic acid, PL-PEG-COOH, and PLH are shown.
  • FIGURE 9B is a schematic illustration of the response of a representative gold- coated nanostructure of the invention, MNP-gold core-shell NP, to a magnetic field, where the underlying curve represents field strength.
  • the coupled agents vibrate as the magnetic field is turned on and off.
  • FIGURE 9C is a schematic illustration of the mechanism of background suppression in magnetomotive photoacoustic (mmPA) imaging: mmPA imaging suppresses regions not susceptible to a controlled magnetic field while identifying regions with coupled agents responsive to a magnetic field.
  • mmPA imaging suppresses regions not susceptible to a controlled magnetic field while identifying regions with coupled agents responsive to a magnetic field.
  • FIGURES 10A- 1OD present transmission electron microscopy (TEM) images and FIGURES lOal-lOdl present size distribution histograms of PL-PEG-COOH / PLH coated MNPs (polymer layer not visible under TEM due to low electron density) (FIGURE 10A), and MNP-gold core-shell NPs with various shell thickness (FIGURE 1OB, about 1-2 nm; FIGURE 1OC, 2-3 nm; FIGURE 1OD, 4-5 nm).
  • the particle size histograms in FIGURE 1 OaI -FIGURE lOdl are plotted from analysis of > 150 particles for each sample.
  • FIGURES 1OE and 1OF are HR-TEM images of representative MNP-gold core-shell NPs with shell thickness of about 2-3 nm.
  • the lattice spacing of the MNP core measures at 0.48 nm corresponding to the (111) plane of Fe 3 O 4 ; whereas the (111) plane of face-centered cubic (fee) Au shows 0.23 nm lattice spacing
  • FIGURE HA compares extinction spectra of representative gold-coated nanostructures of the invention, MNP-gold core-shell NPs (MNP/ Au) successively coated with PL-PEG-COOH and PLH, and with gold nanoshells of various thickness, 1-2 nm, 2-3 nm, and 4-5 nm. As the gold nanoshell thickness increases, the spectral intensity increases and the peak center blue shifts.
  • FIGURE HB compares magnetization as a function of magnetic field at room temperature for MNP and MNP/ Au (2-3 nm shell thickness).
  • the gold shell coating has negligible effect on MNPs' magnetic behavior.
  • the insets show the absence of magnetic hysteresis and magnetic separation of the MNP-gold NPs.
  • FIGURE I lC compares photothermal stability of MNP-gold NPs with gold nanocages and nanorods. Extinction peak shifts as a function of laser fluence indicate that nanocages and nanorods start to quickly degrade at 5 mJ/cm 2 , whereas the MNP-gold hybrid NPs remain stable against laser irradiation of approximately three times higher fluence.
  • TEM images of the nanocages and nanorods are shown as insets, scale bars are 50 and 100 nm for nanocages and nanorods, respectively.
  • FIGURES 12A-12E show multimodality imaging using MNP-gold hybrid NPs in accordance with an embodiment of the invention.
  • FIGURES 12A and 12B are dark-field imaging of single MNPs spread on glass coverslips before and after gold nanoshell coating. The coated MNPs are readily detectable under current experiment conditions (insets show corresponding TEM images).
  • FIGURE 12C shows T2- weighted MR images of the bare and gold-coated MNPs at various dilutions. The signal strength is indicated by the darkness of the images. At the same concentrations, the MR images are indistinguishable between the two series indicating unchanged magnetic properties before and after gold nanoshell coating.
  • FIGURES 12D-12E are cross-sectional photoacoustic (PA) images of a tube filled with 5 nm MNPs and 5 nm MNP-gold NPs on a dB scale. 0 dB corresponds to the maximum signal level among both images. Note that a different dynamic range was used for better visualization. Signal-to-noise ratio can be improved by 1 order of magnitude (20 dB) when MNP-gold NPs are used.
  • PA photoacoustic
  • FIGURES 13A-13G show data processing in magnetomotive photoacoustic
  • FIGURE 13A is a conventional PA image sequence acquired in synchrony with a magnetic pulse.
  • FIGURE 13B is an image showing the maximum displacement achieved at the end of the magnetic pulse tracked using this sequence with the magnetic pulse spanning the first 5 seconds.
  • FIGURE 13C compares three displacement courses and their fitted curves for pixels in different inclusions.
  • the maximum positive (FIGURE 13D) and maximum negative (FIGURE 13E) velocities were derived from fitted displacement curves, and used to create a weighting image (FIGURE 13F).
  • the product shown in FIGURE 13A and FIGURE 13F produced an mmPA image
  • FIGURE 13G where the gold nanorod inclusion is completely suppressed.
  • the display ranges are 40 dB dynamic range in FIGURE 13A and FIGURE 13 A, [0 (dark), 30 (light)] ⁇ m in (FIGURE 13B), [-20, 20] ⁇ m/s in FIGURE 13D and FIGURE 13E with -20 ⁇ m/s,
  • FIGURES 14A, 14B, 14D, and 14E show TEM images of representative gold- coated nanostructures of the invention, gold shell encapsulated MNPs, having 10 nm (FIGURES 14A and 14B) and 50 nm MNP core size (FIGURES 14D and 14E).
  • FIGURES 14C and 14F show extinction spectra of TEM images of representative gold-coated nanostructures of the invention, gold shell encapsulated MNPs, having 10 nm (FIGURE 14C) and 50 nm MNP core size (FIGURE 14E).
  • FIGURES 15A and 15B compare curves of magnetization versus temperature of 25 nm iron oxide NPs before (15A) and after (15B) coating of thin gold layers (about 2-3 nm) measured under ZFC and FC conditions (in a 500 Oe field), respectively.
  • FIGURE 16 compares lateral position displacements and velocities for a MNP inclusion and a MNP-gold NP inclusion.
  • FIGURE 17 is a TEM image of a representative gold-coated nanostructure of the invention, gold core (Au core) encapsulated with magnetic nanoparticles (MNP).
  • Au core gold core
  • MNP magnetic nanoparticles
  • the presence invention provides gold-coated nanostructures, methods for making the gold-coated nanostructures, methods for using the gold-coated nanostructures, and devices that include the gold-coated nanostructures.
  • the invention provides a metal-coated surface.
  • the metal-coated surface includes (a) a continuous surface, (b) a metal coating, and (c) a cationic polymer intermediate the surface and the coating.
  • the cationic polymer intermediate the surface and the coating provides a spacing or gap between the surface and the coating.
  • the invention provides a metal-coated nano structure.
  • the nanostructure includes (a) a nanostructure core, (b) a metal shell surrounding the core, and a cationic polymer intermediate the core and the shell.
  • the cationic polymer intermediate the core and the shell provides a spacing or gap between the core and the shell.
  • Nanostructures include quantum dots (i.e., semiconductor nanoparticles), metal nanoparticles, metal oxide nanoparticles, metalloid nanoparticles, metalloid oxide nanoparticles, polymer nanoparticles, silica nanoparticles, nanoscale micelles, nanoscale liposomes, and clusters and combinations thereof.
  • quantum dots i.e., semiconductor nanoparticles
  • metal nanoparticles metal oxide nanoparticles, metalloid nanoparticles, metalloid oxide nanoparticles, polymer nanoparticles, silica nanoparticles, nanoscale micelles, nanoscale liposomes, and clusters and combinations thereof.
  • nanoscale refers to a particle having at least on nanoscale (up to 1000 nm) dimension.
  • the nanoparticle is a magnetic nanoparticle.
  • Representative magnetic nanoparticles include metal nanoparticles, metal oxide nanoparticles, metalloid nanoparticles, metalloid oxide nanoparticles.
  • the metal and metal oxide nanoparticles are selected from the group consisting of gold, silver, copper, titanium, and oxides thereof.
  • the metal and metal oxide nanoparticles are lanthanide series metal nanoparticles.
  • Suitable magnetic nanoparticles include particles that are responsive to a magnetic field.
  • Representative magnetic nanoparticles include particles that include a suitable metal or metal oxide.
  • Suitable metals and metal oxides include iron, nickel, cobalt, iron platinum, zinc selenide, ferrous oxide, ferric oxide, cobalt oxide, aluminum oxide, germanium oxide, tin dioxide, titanium dioxide, gadolinium oxide, indium tin oxide, cobalt iron oxide, magnesium iron oxide, manganese iron oxide, and mixtures thereof.
  • the nanoparticle is a quantum dot.
  • the nanoparticle can be a single color quantum dot, a multicolor quantum dot, or a combination of quantum dots (multiple single color quantum dots), which can be used to provide a multicolor combination.
  • Suitable quantum dots include those known to those of skill in the art and include those that are commercially available.
  • Other suitable quantum dots include those described in U.S. Patent Nos. 5,906,670, 5,888,885, 5,229,320, 5,482,890, 6,468,808, 6,306,736, and 6,225,198, the description of these quantum dots and their preparations are incorporated herein by reference.
  • Representative nanostructures include nanoparticles such as quantum dots (e.g., CdSe/ZnS), carbon nanotubes (e.g., SWCNTs, MWCNTs), magnetic nanoparticles (e.g., iron oxide), and biological particles (e.g., liposome or cell).
  • quantum dots e.g., CdSe/ZnS
  • carbon nanotubes e.g., SWCNTs, MWCNTs
  • magnetic nanoparticles e.g., iron oxide
  • biological particles e.g., liposome or cell
  • the shell has a thickness of from about 2 to about 3 nm. In one embodiment, the shell is transmissive.
  • the nanostructure core is a quantum dot
  • the shell comprises a plasmonic metal
  • the nanoparticle is fluorescent
  • the invention provides a gold-coated quantum dot that includes (a) a quantum dot core, (b) a gold shell surrounding the core, and (c) a cationic polymer intermediate the organic material and the shell.
  • the invention provides a gold-coated magnetic nanoparticle that includes (a) a magnetic nanoparticle core, (b) a gold shell surrounding the core, and (c) a cationic polymer intermediate the organic material and the shell.
  • the distance between the core and the shell is from about 0.1 to about 200 nm. In certain embodiments, the shell has a thickness of from about 2 to about 3 nm. In one embodiment, the shell is transmissive.
  • the nanostructure core is a quantum dot
  • the shell comprises a plasmonic metal
  • the nanoparticle is fluorescent
  • the coating is a template grown metal coating.
  • Representative template grown metals include gold, silver, copper.
  • the coating includes a plasmonic metal.
  • the coating is a gold coating.
  • the surfaces or cores include a hydrophobic material.
  • the hydrophobic material provides a material on the surface or core that facilitates build up the surface or core and for receiving the cationic polymer.
  • R can be a C 1 to C 24 hydrocarbon, such as but not limited to, linear hydrocarbons, branched hydrocarbons, cyclic hydrocarbons, substituted hydrocarbons (e.g., halogenated), saturated hydrocarbons, unsaturated hydrocarbons, and combinations thereof.
  • a combination of R groups can be attached to P, N, or S.
  • the chemical compound can be selected from tri-octylphosphine oxide (TOPO), oleic acid, stearic acid, and octyldecyl amine.
  • TOPO tri-octylphosphine oxide
  • the surfaces or cores further comprise a material intermediate the surface or core and the polymer.
  • the material may be an organic material or an inorganic material.
  • the material comprises polyethylene glycol. Representative materials include lipid-polyethylene glycol conjugates (e.g., DSPE-PEG2000 CO 2 H).
  • the material comprises one or more polyelectrolyte bilayers (e.g., poly(allylamine) hydrochloride/polystyrene sulphonate bilayer).
  • the material comprises silica.
  • the cationic polymer is a polyamine (e.g., a polypeptide, such as polyhistidine or poly-L-histidine).
  • the cationic polymer is a metal chelator.
  • the metal coatings and shells do not directly contact the surfaces or cores.
  • the distance between the surface and the metal coating, or the core and the shell is from about 0.1 to about 200 nm.
  • the metal coating has a thickness of from about 0.1 about 30 nm. In certain embodiments, the shell has a thickness of from about 2 about 6 nm.
  • the invention provides a method for making a metal-coated nanostructure, comprising:
  • step (c) adding a reducible metal ion complex to the plurality of nanostructures formed in step (b);
  • the method further comprises adding a polyamine (e.g., PAH) to the plurality of individual nanostructures in water followed by adding a polyanionic material (e.g., PSS) to provide a plurality of nanostructures comprising a polyelectrolyte bilayer, prior to adding the cationic polymer.
  • a polyamine e.g., PAH
  • a polyanionic material e.g., PSS
  • the method further comprises adding a polyamine to the plurality of nanostructures comprising a polyelectrolyte bilayer followed by adding a polyanionic material to provide a nanostructure comprising two polyelectrolyte bilayers, prior to adding the cationic polymer.
  • the cationic polymer is a polyamine (e.g., a polypeptide, such as polyhistidine or poly-L-histidine).
  • the reducible metal ion complex is a gold complex (e.g., a gold (IV) complex, HAuCl 4 ).
  • the reducing agent is hydroxylamine.
  • the invention provides methods for imaging using the metal- coated nanostructures of the invention.
  • the method comprises administering to a subject or contacting a tissue with a nanostructure of the invention (e.g., gold-coated quantum dot or gold-coated magnetic particle).
  • the imaging is fluorescent imaging. In another embodiment, the imaging is based on light scattering.
  • the nanostructure is a magnetic nanoparticle and imaging is magnetic resonance imaging. In another embodiment, the nanostructure is a magnetic nanoparticle and imaging is magnetomotive photoacoustic imaging.
  • a method for sensing or detecting an analyte includes contacting a sample containing an analyte with a surface or a nanostructure of the invention, and measuring a change in absorption and/or scattering of the surface coating or nanoparticle shell, wherein the change in absorption and/or scattering is indicative of the presence of the analyte in the sample.
  • the sensing or detecting is measured by surface plasmon resonance.
  • the invention provides a method for treating a condition.
  • the method includes administering to a subject in need thereof a therapeutically effective amount of a nanostructure of the invention and irradiating the subject with a wavelength of light sufficient to cause the nano structure's metal shell to generate heat effective for hyperthermic therapy.
  • the nanostructure further includes a targeting agent to direct the nanoparticle to a site of interest.
  • targeting agent refers to a chemical moiety associated with (i.e., covalently coupled or otherwise stably associated with the complex that direct the complex to a specific site where the complex can then be imaged or where the complex delivers its associated therapeutic agent. Suitable targeting agents include those known in the art.
  • the targeting agent is an antibody or fragment thereof or its antigen.
  • the antigen can be a small molecule, peptide, protein, polynucleotide, or polysaccharide.
  • the targeting agent is a nucleic acid or its complement.
  • the nucleic acids can be DNAs and RNAs.
  • the targeting agent is an enzyme or its substrate.
  • the targeting agent is a receptor or its ligand.
  • the targeting agent is a nucleic acid or its partner protein.
  • the targeting agent is a ligand for a cell, a cell membrane, or an organelle.
  • the invention provides a composition containing a nanostructure of the invention and an acceptable carrier or diluent.
  • the composition includes a pharmaceutically acceptable carrier or diluent.
  • the composition can be administered parenterally, for example, orally, transdermally (e.g., patch) intravenously (injection), intraperitoneally (injection), and locally (injection).
  • devices that include a nanostructure of the invention are provided.
  • the invention provides a photovoltaic device having an active layer that includes a nanostructure of the invention.
  • a schematic illustration of a representative photovoltaic device is shown in FIGURE 7.
  • photovoltaic device 150 includes a first electrode 105', a photovoltaic layer 110', and a second electrode 115'.
  • one of the electrodes 105' or 115' is a transparent conductor, such as indium-tin oxide (ITO), and the other electrode is a metal, such as aluminum.
  • ITO indium-tin oxide
  • the photovoltaic layer 110' comprises a nanostructure of the invention that utilizes the energy from incident electromagnetic radiation (e.g., visible light) to form free carriers, such as holes and electrons.
  • the work functions of the electrodes 105' and 115' create an energetic state of the device 150 such that holes will flow to a hole-collecting electrode (e.g., 115'), and electrons will flow to an electron-collecting electrode (e.g., 105').
  • the holes and electrons generated in the photovoltaic layer 110' migrate towards their respective electrodes for collection, and electrical current is generated.
  • a device e.g., a battery or electrical circuit
  • the optional electron-transporting layer 106 forms an intermediary layer between the photovoltaic layer 110' and the electron-collecting electrode 105', such that electrons are allowed to pass favorably through the electron-transporting layer 106 and holes are blocked.
  • a hole-transporting layer 111 is also optional in the device 150 and forms an intermediary layer between the photovoltaic layer 110' and the hole-collecting electrode 115' such that holes are favorably passed through the hole-transporting layer 111 and electrons are blocked.
  • an optional substrate 120 is illustrated abutting the hole-collecting electrode 115'. It will be appreciated that in another embodiment, a substrate can alternatively abut the electron-collecting electrode 105' instead of the hole-collecting electrode 115'.
  • a typical photovoltaic device 150 is fabricated on a substrate 120 of plastic- or glass-coated indium- tin oxide (ITO). Because ITO is typically sold pre-coated on glass or plastic substrates, the hole-collecting electrode (ITO) is essentially tied to the substrate when fabricating devices. Thus, the substrate 120 also acts as the hole-collecting electrode 115' when an ITO-coated glass or plastic substrate is used for device fabrication.
  • ITO indium- tin oxide
  • the invention provides a light-emitting device having an active layer that includes a nanostructure of the invention.
  • a schematic illustration of a representative light-emitting device is shown in FIGURE 8.
  • representative device 200 includes first substrate layer 210, indium-tin oxide (ITO) anode layer 220, emissive layer 230 comprising a nanostructure of the invention, electron transporting and protective layer 240, anode 201, and cathode 202.
  • ITO indium-tin oxide
  • emissive layer 230 comprising a nanostructure of the invention
  • electron transporting and protective layer 240 anode 201
  • cathode 202 cathode
  • the invention provides a gold-coated fluorescent nanoparticle having fluorescent and plasmonic activities. The combined functionality in a single nanoparticle is achieved by controlling the spacing (e.g., gap) between the nanoparticle (e.g., quantum dot) core and the thin gold shell.
  • the spacing is controlled with nanometer precision through layer-by-layer assembly.
  • the invention provides a method for the deposition of an ultrathin gold layer onto virtually any discrete nanostructure or continuous surface.
  • the method provides nanostructures useful for multimodal bioimaging, interfacing with biological systems, reducing nanotoxicity, modulating electromagnetic fields, and contacting nanostructures.
  • Example 1 The preparation and characteristics of a representative nanostructure of the invention, a gold-coated quantum dot, are described in Example 1.
  • the nanostructures are produced from a homogeneous solution-based method that provides an ultrathin gold coating on both isolated nanostructures and continuous surfaces, and has direct relevance to problems frequently encountered in engineering sophisticated electronic devices and bioimaging probes, such as connecting molecules with electric sources in molecular electronics, producing multimodality imaging probes, and creating anchor points for simple biomolecule conjugation.
  • encapsulation of QDs made from toxic chemical elements (for example, CdSe) with a thin layer of gold which is biocompatible and highly stable, may address concerns regarding QD toxicity, which is the determining factor for translational and clinical applications of QDs.
  • gold nanostructures are known fluorescence quenchers for both organic fluorophores and QDs;
  • a thick surrounding gold shell will block QD fluorescence transmittance;
  • the gold precursor, chloroauric acid (HAUCI 4 ) is highly acidic and corrosive, and can irreversibly damage QDs;
  • the QD structural scaffold for gold shell growth is small (a few nanometers); and
  • the space between the QD core and the gold shell must be precisely controlled.
  • the present invention provides fluorescent gold-coated nanostructures using biomolecules as the structural scaffold.
  • lipid- stabilized water-soluble QDs are coated with a layer of polyamine (e.g., peptide such as poly-L-histidine (PLH)), which serves as the gold deposition template.
  • PLL poly-L-histidine
  • an important feature of PLH is that its histidine groups are capable of immobilizing Au 3+ ions at very high packing density for deposition of thin and smooth gold shells.
  • HAUCI 4 is highly acidic, the pH of the reaction solution was adjusted to 9-10 with NaOH to avoid QD damage.
  • the separation between the QD core and the gold shell is determined by the size of the polyethylene glycol (PEG) chains and can be increased with nanometer precision by adding alternating polyelectrolyte monolayers, such as polyallylamine hydrochloride (PAH, cationic) and sodium polystyrene sulphonate (PSS, anionic), a process also known as layer-by-layer (LBL) assembly (see FIGURE IB).
  • PEG polyethylene glycol
  • PES polystyrene sulphonate
  • FIGURES 2A-2D show representative transmission electron microscopy (TEM) images of the QD-gold core- shell nanoparticles (FIGURES 2C and 2D) and the original organic- soluble QDs (FIGURE 2A) and water-soluble QDs (FIGURE 2B) coated with lipids and PLH.
  • TEM transmission electron microscopy
  • Commercial QDs with narrow emission peaks full-width at half-maximum (FWHM), 32 nm) centered at 655 nm were used as the starting materials, which were insoluble in water.
  • the lipid-based QD surface-coating method was highly efficient in transferring QDs into aqueous solutions yielding well dispersed particles (FIGURE 2B).
  • the soluble QDs remained single with successive adsorption of PLH and gold ions.
  • the core-shell structure was revealed by TEM (FIGURES 2C and 2D).
  • the shell thickness was about 2-3 nm, with a transparent gap of 3 nm observed between the core and shell because the sandwiched organic materials are not electron-dense enough for TEM visualization. This separation unambiguously shows that the gold deposition was not directly on (i.e., contacting) the core particle surface, but was templated by the polymer outer layer.
  • the optical properties of the QD-gold nanoparticles were characterized.
  • the QDs absorbed over a broad spectrum with increasing molar extinction coefficient towards shorter wavelengths and a first quantum confinement peak of 646 nm (FIGURE 3A).
  • the QD absorption was obscured by the strong gold surface plasmon resonance (SPR) peak centered at 583 nm.
  • SPR gold surface plasmon resonance
  • Quantitative spectroscopy measurements revealed that the original organic-soluble QDs and the lipid coated water-soluble QDs shared a similar quantum yield (QY) of 75%, whereas that of the QD-gold nanoparticles decreased to 18% (FIGURE 3C). Despite this fluorescence intensity decrease, the emission peak position did not shift. Detailed stepwise investigation of the synthesis revealed that the quenching occurred instantaneously upon the introduction of Au 3+ ions, and this process accounted for approximately half of the total quenching effect. Although the exact mechanism is unclear at this time, likely a small number of Au 3+ ions penetrated through the PEG layer and directly interacted with the QD surface. Several lines of evidence support this observation.
  • the quenching effect was also observed for the control experiment without the PLH coating layer, indicating that the quenching was not due to the Au 3+ ions adsorbed on the polymer.
  • the fluorescence was completely quenched due to the higher accessibility of Au 3+ to the QD surface.
  • a similar effect has been observed previously with Ag+, Pb 2+ and Cu 2+ ions and has been attributed to cation exchange in the nanocrystals' lattice.
  • the thickness of the gold shell Another factor that could affect the fluorescence is the thickness of the gold shell. The thicker the shell, the more fluorescence will be blocked. Based on the peptide templated gold deposition, a 2-3 nm thin gold layer was achieved. Under the experiment conditions (excitation 400 nm and emission 655 nm), the light transmittance values for excitation and emission were 86% and 92% through the thin gold shell, collectively resulting in about 20% fluorescence attenuation. The QD fluorescence decreased gradually with slight increase of the gold shell thickness and was significantly quenched when this was greater than 5 nm.
  • a further factor that affects the QD fluorescence is the gold shell SPR, which can simultaneously quench and enhance the QD fluorescence (competing processes) depending on the spacing between the two materials and the spectral overlap between the QD fluorescence and the gold SPR.
  • the quenching effect dominates, whereas long distance and spectral overlap of QD absorption and gold SPR result in more pronounced field enhancement.
  • the QD core and gold shell separation was increased with successive adsorption of cationic and anionic polymers by means of LBL assembly, which is capable of reducing Au 3+ diffusion to the QD surface and tuning the distance between the QD and gold with nanometer precision.
  • LBL on nanometer- sized particles requires multiple rounds of centrifuge -based purification for every layer of polyelectrolyte deposition (experiments described herein use three rounds for every polymer coating layer), which consequently results in an overall low QD recovery. From the TEM images, small but statistically meaningful increments of the gap between the two electron-dense materials were measured.
  • FIGURE 13F shows the histograms of the gap distribution obtained from more than 100 particles with zero, one and two bilayers.
  • the average separations are 3.0+0.5, 3.9+0.6 and 4.6+0.6 nm, respectively, which are smaller than the previously reported PAH/PSS bilayer thickness (about 1.2 nm) and could originate from the limited TEM image resolution and slight gold shell infiltration into the polyelectrolyte bilayers. Nevertheless, reproducible and quantitative fluorescence spectroscopy shows that the QD quantum yield increased to 33% with one additional bilayer of polyelectrolyte coating and 39% for two bilayers.
  • This new class of multimodality nanoprobe will allow imaging with both fluorescence and scattering as well as light-triggered photo thermal treatment (particularly when the surface plasmon band is tuned to the NIR region). These modes of imaging and therapy cannot be achieved simultaneously with the traditional small molecule-, amphiphilic polymer-, and silica-coated QDs.
  • the present invention provides gold-shell encapsulated QDs prepared by peptide-templated shell growth.
  • gold nanoparticles have been demonstrated as efficient fluorescence quenchers, the spacing between the QD core and the gold shell in the gold-coated nanostructures of the invention resulted in QDs with a quantum yield of 39%.
  • the thin gold shell also exhibits strong surface plasmon scattering, which makes the QD-gold nanoparticles an excellent dual-modality imaging probe.
  • monodisperse nanostructures often have a similar surface chemistry as QDs (for example, monolayer of hydrophobic ligands)
  • this technology can serve as a general route for encapsulating a variety of discrete nanomaterials and modulating their surrounding electromagnetic field.
  • the gold-coating methodology described herein can prevent toxic chemicals from being released into the biological environment. This improved stability represents a potential solution to converting toxic nanomaterials into biocompatible materials, a critical step towards translational nanotechnology.
  • the present invention provides compact, uniform, NIR- responsive MNP-gold core-shell nanostructures having a gap between the particle core and shell.
  • the nanostructures of the invention are magnetically- sensitive having with strong NIR and MR responses, and enable a new modality, magnetomotive photoacoustic (mmPA) imaging.
  • mmPA imaging with a coupled agent provides the same sensitivity, but with markedly improved contrast specificity. Indeed, all PA signals not created by the coupled NP potentially can be suppressed to the electronic noise limit of the imaging system.
  • the core and shell of the nanostructures of the present invention are spatially separated with a dielectric polymer layer.
  • This method allows formation of uniform MNP-gold particles simultaneously being compact in size and responsive in the NIR spectrum, which have not been achieved previously.
  • the resulting NPs show highly integrated properties including electronic, magnetic, optical, acoustic, and thermal responses, which allow multimodality imaging.
  • conventional NP based imaging modalities such as TEM, optical imaging, MRI, and photoacoustic (PA) imaging
  • coupling of magnetic motion with photothermal conversion enables magnetomotive photoacoustic (mmPA) imaging, a new modality with remarkable contrast enhancement compared to conventional PA imaging.
  • the gold-coated nanostructures have a surface that allows simple conjugation with biomolecular targeting ligands to develop all-in-one nanostructures for noninvasive imaging, molecular diagnosis, and hyperthermia-based treatment of complex diseases.
  • Example 2 The preparation and characteristics of a representative nanostructure of the invention, a gold-coated magnetic nanoparticle, are described in Example 2.
  • MNP-gold NPs can be manipulated for mmPA imaging.
  • a pulsed magnetic field can be applied wherein voxels within the imaging region experience a force induced by the local field and magnetization.
  • MNP-gold NPs move as a result of their strong magnetization, creating a moving source within a PA image.
  • the magnetic field can be pulsed on and off such that a shaking motion is achieved.
  • Non-magnetic PA sources do not move coherently with the applied field during this entire interval. Consequently, coherent motion processing of a PA image sequence can identify sources related to MNP-gold NPs and reject all background signals whether from diffuse or localized sources. Such processing can greatly enhance the contrast specificity of the NP (e.g., by suppressing background signal in molecular imaging.
  • FIGURE 9A A schematic illustration of the preparation of a representative gold-coated magnetic nanoparticle of the invention (MNP-gold NP) is shown in FIGURE 9A.
  • monodisperse MNPs with hydrophobic surface ligands e.g., oleic acid
  • PL-PEG-COOH phospholipids-polyethylene glycol terminated with carboxylic acid
  • the hydrophobic PL segment interdigitates with oleic acids through hydrophobic interactions, and the PEG block facing outward renders the MNPs water-soluble and negatively charged due to the terminal carboxylic acids.
  • a layer of positively charged peptide, poly-L-histidine (PLH) is adsorbed onto the outer surface of MNP-PEG via charge-charge interaction at pH 5-6.
  • Zeta potentials of the PEG solubilized MNPs before and after coating with PLH were -15.5 and +9.1 mV, respectively. This surface charge inversion suggests a successful layer-by-layer surface coating of polyelectrolytes (ionic polymers) on the NP surfaces.
  • the histidine groups in PLH are capable of immobilizing Au 3+ ions on QD surfaces at high packing density.
  • the multilayer organic molecules coated on the MNP surface act as an effective barrier preventing gold ions from direct growth on the iron oxide core. Further reduction of Au 3+ with a reducing reagent leads to the formation of multifunctional MNP-gold core-shell particles with clear separation and only small size increase over the original MNPs.
  • the resulting MNP-gold nanoprobe provides contrast not only for conventional modalities such as TEM, optical imaging, PA imaging, MRI, but also for the new modality of mmPA imaging.
  • FIGURE 9B illustrates how MNP-gold NPs can be manipulated for mmPA imaging.
  • a pulsed magnetic field is applied. Voxels within the imaging region experience a force induced by the local field and magnetization.
  • MNP-gold NPs move as a result of their strong magnetization, creating a moving source within a PA image.
  • the field is turned off, MNP-gold NPs return to their original positions.
  • Non-magnetic PA sources do not move coherently with the applied field during this entire interval. Consequently, coherent motion processing of a PA image sequence (FIGURE 9C) can identify sources related to MNP-gold NPs and reject all background signals whether from diffuse or localized sources.
  • bare MNPs are not a suitable contrast agent for PA or mmPA imaging even though they can respond to magnetic field. Bare MNPs do not absorb efficiently in the NIR and, consequently, exhibit poor PA efficiency. Large NIR absorption per particle is required for all PA applications.
  • MNP-gold NPs of the invention apply to MNPs of various sizes, the synthesis, characterization, and applications of the coupled nanoprobe discussed below are focused on one representative MNP having a 25 nm diameter (FIGURE 10A).
  • TEM images show MNP-gold core-shell NPs with different shell thickness and a gap of about 3 nm between core and shell due to the low electron density of the embedded organic molecules.
  • PLH templated gold deposition can be controlled with nanometer precision to form an ultrathin and relatively smooth shell layer.
  • a gold nanoshell less than 3-4 nm thick enabled direct observation of the internal structure of the MNP-gold core-shell NPs (FIGURES 1OB and 10C).
  • the shell thickness was slightly increased to 4-5 nm, the core-shell internal structure disappeared and manifested as solid dark dots (FIGURE 10D).
  • the 4-5 nm shell thickness was not directly measured (not visible under TEM), but was derived from the overall particle size increase compared with original MNPs and MNPs coated with thin gold layers (FIGURES 1OD and 1 OdI).
  • FIGURE HA shows the extinction spectra of MNP-gold core- shell hybrid particles corresponding to the TEM images shown in FIGURES 10A- 10D.
  • SPR surface plasmon resonance
  • the elevated curves are part of the extinction signals instead of noise, which is commonly seen in shell-type plasmonic materials.
  • the SPR band centered around 900 nm.
  • SPR extinction peak blue-shifted to 760 nm and 660 nm, respectively, following a similar trend to that of silica-gold nanoshells.
  • This spectroscopic measurement confirms the electron microscopy results of FIGURE 10 showing that the gold shell is separated from the iron oxide core (red-shift in the visible spectrum with increasing shell thickness would be expected otherwise).
  • the extinction peaks of hybrid NPs are broader than theoretical values. This kind of line broadening is commonly seen in virtually all gold shell nanostructures and has been attributed to the combination of a number of factors including phase retardation effects, size distribution of both cores and shells, and electron scattering at the shell interfaces.
  • the magnetization of the hybrid NPs (2-3 nm gold shell) was measured using superconducting quantum interference device (SQUID) magnetometry.
  • the temperature dependence of the zero-field-cooled/field-cooled (ZFC/FC) magnetization is shown in FIGURE 15. The two curves overlap at high temperature and quickly depart from each other as the temperature decreases.
  • the ZFC curves show maxima at 275 K and 270 K (blocking temperature, T b ) for MNPs before and after coating with thin Au shells, which is characteristic behavior of superparamagnetism.
  • T b S of MNPs are well below room temperature and the slight decrease after surface coating has been previously observed as well.
  • the MNP-gold NPs tested with conventional modalities, including dark field, and PA and MR imaging.
  • MNP and gold have highly complementary features for other imaging modes.
  • FIGURES 12A and 12B the strong scattering property of gold nanoshell makes the NPs an excellent optical imaging probe. Samples of dilute uncoated and gold shell encapsulated MNPs were spread on glass coverslips, resulting in spatially isolated single NPs on the surface. Under dark field imaging conditions, the MNP-gold NPs are easily detectable while the original MNPs are not.
  • the second feature unique to the gold nanoshell is the strong NIR absorption, and companion energy release in the form of heat, which can be utilized for photo thermal therapy and PA imaging.
  • PA imaging can sample optical phenomena within tissue to a depth of several centimeters. It is also significantly less expensive to operate and more portable than MRI.
  • Absorption of pulsed NIR laser light creates acoustic sources within tissue, where the source strength is proportional to the local absorption of the optical pulse.
  • An image is formed using conventional ultrasound technology, where PA contrast is directly related to optical absorption.
  • FIGURES 12D and 12E show cross- sectional PA images of the tube corresponding to the different solutions on a decibel (dB) scale, with 0 dB corresponding to the maximum signal level across all images.
  • MNP-gold of the same concentration improved image signal-to-noise ratio by nearly 1 order of magnitude (i.e., 20 dB) due to the strong gold-shell SPR absorption.
  • MNP-gold NPs' strong magnetization and NIR absorption were demonstrated to enable mmPA imaging with significantly improved contrast specificity compared with conventional PA imaging.
  • a 3-mm thick, 10% polyvinyl alcohol (PVA) disk was constructed as an imaging phantom. It contained three 2-mm diameter cylindrical inclusions made of 10% PVA mixed with 8% 15-um polymer beads.
  • the first, containing gold nanorods with comparable absorption coefficient as 3 nm MNP-gold hybrid NPs serves as a magnetic reference, i.e., a localized "background" region to be suppressed in mmPA imaging.
  • the second, containing 3 nm MNP-gold hybrid NPs serves as an object of interest.
  • Third, containing 3 nm MNPs serves as an optical reference.
  • FIGURE 13A shows a cross- sectional PA image on a dB scale of the PVA phantom at 720 nm optical wavelength with 0 dB corresponding to the maximum signal level across all images.
  • the inclusion with MNP-gold hybrid NPs (middle) is one order of magnitude (i.e., 20 dB) brighter than the one with MNPs (right), in agreement with FIGURE HA. While the inclusion with gold nanorods (left) has comparable PA strength to that with MNP-gold hybrid NPs, it is suppressed in the mmPA image shown in FIGURE 13G.
  • An mmPA image can be derived from a series of PA images in a variety of ways.
  • FIGURE 13 illustrates the current signal processing scheme.
  • a conventional PA image (FIGURE 13A) sequence was acquired in synchrony with a magnetic pulse. The displacement of each pixel in a PA image from its initial position was tracked using a conventional speckle tracking algorithm over the entire 10 second interval, with the magnetic pulse spanning the first 5 seconds.
  • FIGURE 13B shows the maximum displacement at the end of the magnetic pulse. For each pixel, the displacement was fitted as linear functions of time over the two 5-second intervals when the field was on/off. A pixel with positive slope in the first half and negative slope in the second half was subsequently fitted to two cascaded exponential functions using nonlinear least squares curve fitting. Three representative fitted curves are shown in FIGURE 13C for three pixels within the inclusions.
  • FIGURE 13G shows the mmPA image produced from the product of FIGURE 13A and FIGURE 13F, where the gold nanorod inclusion is almost completely suppressed.
  • mmPA imaging the induced motion depends not only on the magnetic field, but also on tissue elastic properties. Therefore, in biomedical applications, it is hard to quantitate the contrast agent concentration based on motion alone. For example, displacements and velocities in the MNP inclusion were slightly greater than those in the MNP-gold hybrid NP inclusion primarily because of differences in the elasticity of the inclusions (FIGURE 16).
  • the induced motion regardless of scale, is coherent with the applied magnetic field. By detecting motion in response to a time-varying magnetic field, contrast can be greatly improved. The ability to enhance regions with targeted contrast agents makes mmPA imaging an attractive modality for molecular diagnostics.
  • tissue elastic properties e.g., after the magnetic field is turned off, displaced tissue moves back to its original position subject only to intrinsic elastic properties such as relaxation
  • mmPA imaging can potentially also be used for elasticity imaging.
  • Oleic acid-capped monodisperse superparamagnetic iron oxide nanocrystals of different sizes were a gift from Oceannanotech LLC.
  • a UV-2450 spectrophotometer (Shimadzu) and a Fluoromax4 fluorometer (Horiba Jobin Yvon) were used to characterize the absorption and emission spectra.
  • a table-top ultracentrifuge (Beckman TL120) was used for nanoparticle purification and isolation. Particle size was measured on a CMlOO transmission electron microscope (Philips EO, Netherlands). HRTEM analysis was performed on a FEI TECNAI G2 F20 S-TWIN electron microscope.
  • Fluorescence and dark-field images were obtained with an IX-71 inverted microscope (Olympus, San Diego, CA) and a Q-color5 digital color camera (Olympus).
  • broadband excitation in the blue range (460-500 nm) was provided by a mercury lamp.
  • a long-pass dichroic filter (505 nm) and emission filter (510 nm, Chroma Technologies) were used to reject the scattered light and to pass the Stokes-shifted fluorescence signals.
  • SQUID magnetometry was measured at 300K on a Quantum Design MPMS-5S SQUID Magnetometer (Quantum Design, San Diego, CA).
  • Gold-Coated Nanostructures Gold-Coated Quantum Dots
  • Organic- soluble QD 655 nanoparticles (1 ⁇ M solution in decane, 100 ⁇ l) were first flocculated by using a 4x methanol/isopropanol mixture (v/v 75/25), and resuspended in chloroform (1 ml). Lipid- PEG-COOH (3 mg) was added to the solution and sonicated for
  • the purified nanoparticles were redispersed in DI water (3 ml), to which PLH (1.5 mg) was added.
  • the QDs and PLH were incubated at room temperature for about 1 h to allow PLH to adsorb onto the QD surface by electrostatic interaction. Excess PLH molecules were again removed by ultracentrifugation.
  • the purified QD-PLH with a final concentration of 5.2 nM was dispersed in DI water and stored for use.
  • PAH and PSS stock solutions (10 mg ml" 1 in 1 mM NaCl solution) were used for the LBL polyelectrolyte deposition onto the lipid-PEG-coated QDs before deposition of PLH and gold.
  • PAH solution 0.5 ml of PAH solution was added and mixed with 3 ml of the above synthesized water-soluble QDs suspended in 1 mM NaCl. After 30 min incubation, unbound PAH was removed by ultracentrifugation (three rounds). The same procedure was repeated for additional layers of polyelectrolytes and finally capped with a layer of PLH for gold nucleation and growth.
  • the QD quantum yield (QY) was determined relative to rhodamine 101, as its QY is well documented. During each step of polyelectrolyte coating, the QY of the QD-polymer complex can be easily determined in the same manner. However, after gold shell formation on the surface of the QDs, the QD first extinction peak was buried by the strong gold plasmon peak, and as a consequence the QD concentration can no longer be determined using UV absorbance. Fortunately, due to the high reaction yield, virtually all QDs are encapsulated with a gold shell (confirmed with many randomly selected TEM images). Because the concentration of QDs before and after gold shell formation remained the same, the QY values of QD-gold can be calculated using QD-PLH as a reference in fluorescence spectroscopy measurements.
  • Gold-Coated Magnetic Nanoparticles Gold-Coated Magnetic Nanoparticles
  • preparation and characteristics of a representative gold-coated nanostructure of the invention, gold-coated magnetic nanoparticles, are described.
  • Solubilization of MNPs with PL-PEG-COOH was performed by first mixing 1.0 mg of the oleic acid coated MNPs with 1.4 mg of PL-PEG-COOH in 1 mL of chloroform followed by slow evaporation of chloroform. The residual solid was heated to 80 0 C for 5 min to completely removed chloroform. The MNPs became soluble after adding deionized (DI) water (1 ml) and brief sonication. Excess lipids were purified out from the solubilized MNPs with repeated ultracentrifugation (25,000 rpm for Ih X 3 times). The purified MNPs were redispersed in 4 mL of DI water, to which 1.1 mg of PLH was added. The pH of the solution was adjusted to 5-6 using 0.1 N HCl. After incubation of 60 min, MNPs coated with PLH were again purified with ultracentrifugation and dispersed in 5 mL DI water.
  • DI dei
  • PA imaging particle samples were injected into a polycarbonate tube (CTPC167-200-5, Paradigm Optics, Vancouver, WA; 167 and 200 ⁇ m inner and outer diameters, respectively).
  • a frequency doubled YAG pulsed laser (Surelite 1-20, Continuum, Santa Clara, CA) with 5-ns pulse width pumped an optical parametric oscillator (Surelite OPO Plus, Continuum) to illuminate the tube at 750 nm wavelength and 3.3 mJ/cm 2 fluence.
  • PA signals were received by the central 32 elements of an ultrasound linear array (L 14-5/38, Ultrasonix, Burnaby, BC, Canada) and recorded by an ultrasound scanner (Sonix RP, Ultrasonix).
  • a delay-and-sum beam forming algorithm was used for image reconstruction.
  • samples were subjected to 30-min continuous irradiation at wavelengths close to the SPR peaks of each particle sample at fixed laser fluence.
  • a phantom of 10% polyvinyl alcohol (PVA) disk with 3-mm thickness was constructed using three short freeze-thaw cycles.
  • Three 2-mm diameter cylindrical inclusions made of 10% PVA mixed with 8% 15-um polymer beads were placed within the phantom: the first one contained gold nanorods with about the same absorption coefficient as 3 nm MNP-gold hybrid NPs, the second contained 3 nm MNP-gold hybrid NPs, and the third contained 3 nm MNPs.
  • a frequency doubled YAG pulsed laser (Surelite 1-20, Continuum, Santa Clara, CA) with 5-ns pulse width pumped an optical parametric oscillator (Surelite OPO Plus, Continuum) to illuminate the PVA phantom at 720 nm wavelength and 2.3 mJ/cm 2 fluence.
  • a 15-MHz single element transducer (Olympus, Waltham, MA) was translated to scan ID PA images.
  • the RF signal was acquired using an amplifier (AM- 1300, MITEQ, Hauppauge, NY) and a digital oscilloscope (LeCroy, Chestnut Ridge, NY).
  • MR images were obtained using a 2D multi-slice-multi-echo spin echo (SE) sequence with various echo times.
  • SE spin echo
  • the imaging parameters were as following: repetition time, 2500 ms; echo times, 10/30/50/70/100 ms; field of view, 10 cm; matrix, 256x256; and thickness, 2 mm.

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Abstract

La présente invention se rapporte à des nanostructures recouvertes de métal, à des procédés de fabrication de nanostructures recouvertes de métal, à des procédés d'utilisation de nanostructures recouvertes de métal et à des dispositifs qui comprennent des nanostructures recouvertes de métal.
PCT/US2010/041421 2009-07-08 2010-07-08 Nanostructures recouvertes de métal et procédés associés Ceased WO2011006002A2 (fr)

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WO2013136167A1 (fr) * 2012-03-16 2013-09-19 Nanosensing Technologies, Inc. Cellules solaires métalliques composites
US8701471B2 (en) 2009-07-08 2014-04-22 University of Washington through its Center for Commercialiation Method and system for background suppression in magneto-motive photoacoustic imaging of magnetic contrast agents
WO2014107055A1 (fr) * 2013-01-04 2014-07-10 연세대학교 산학협력단 Agent de contraste irm comprenant un matériau de contraste t1 revêtu sur la surface d'un support de nanoparticules
ITVR20130034A1 (it) * 2013-02-07 2014-08-08 Trentino Sviluppo Spa Nanoparticella magnetica e metodo di sintesi di detta nanoparticella.
EP2772271A1 (fr) * 2013-02-27 2014-09-03 National Cheng Kung University Nanostructure, dispositif appliqué et son procédé de préparation
WO2015136226A3 (fr) * 2014-03-13 2015-10-29 Chromalys Nanoparticules pour leur utilisation dans la detection de tumeurs mobiles
WO2017015531A1 (fr) * 2015-07-22 2017-01-26 University Of Maryland, Baltimore County Revêtements hydrophiles de métaux plasmoniques permettant une fluorescence améliorée par faible volume de métal
WO2017156402A1 (fr) * 2016-03-11 2017-09-14 The Government Of The United States Of America, As Represented By The Secretary Of The Navy Assemblage et soudage programmables de nanoparticules métalliques en nanostructures discrètes
CN107238575A (zh) * 2017-06-08 2017-10-10 深圳大学 一种基于完美涡旋光激发spr的光声显微系统
US10330600B2 (en) * 2013-06-04 2019-06-25 Board Of Regents, The University Of Texas System Plasmonic-magnetic bifunctional nanotubes for biological applications
US10809195B2 (en) 2015-12-23 2020-10-20 Koninklijke Philips N.V. Optical detection of particles in a fluid
WO2022261530A1 (fr) * 2021-06-11 2022-12-15 The Regents Of The University Of California Système et procédé d'enregistrement sans fil d'activité cérébrale

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US20060140868A1 (en) * 2002-12-19 2006-06-29 Stephanie Grancharov Method of preparation of biomagnetic nanoparticles coated with a noble metal layer
US7226636B2 (en) * 2003-07-31 2007-06-05 Los Alamos National Security, Llc Gold-coated nanoparticles for use in biotechnology applications
US20060057384A1 (en) * 2004-04-01 2006-03-16 Benoit Simard Methods for the fabrication of gold-covered magnetic nanoparticles
US7597959B2 (en) * 2006-12-19 2009-10-06 Bridgestone Corporation Core-shell fluorescent nanoparticles

Cited By (16)

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US8701471B2 (en) 2009-07-08 2014-04-22 University of Washington through its Center for Commercialiation Method and system for background suppression in magneto-motive photoacoustic imaging of magnetic contrast agents
WO2013136167A1 (fr) * 2012-03-16 2013-09-19 Nanosensing Technologies, Inc. Cellules solaires métalliques composites
WO2014107055A1 (fr) * 2013-01-04 2014-07-10 연세대학교 산학협력단 Agent de contraste irm comprenant un matériau de contraste t1 revêtu sur la surface d'un support de nanoparticules
EP2942064B1 (fr) * 2013-01-04 2022-09-07 Inventera Pharmaceuticals Inc. Agent de contraste irm comprenant un matériau de contraste t1 revêtu sur la surface d'un support de nanoparticules
ITVR20130034A1 (it) * 2013-02-07 2014-08-08 Trentino Sviluppo Spa Nanoparticella magnetica e metodo di sintesi di detta nanoparticella.
WO2014122608A1 (fr) 2013-02-07 2014-08-14 Trentino Sviluppo S.P.A. Nanoparticule à noyau magnétique, enrobage polymère et une enveloppe en or, et procédé de synthèse correspondante
EP2772271A1 (fr) * 2013-02-27 2014-09-03 National Cheng Kung University Nanostructure, dispositif appliqué et son procédé de préparation
TWI511918B (zh) * 2013-02-27 2015-12-11 Univ Nat Cheng Kung 奈米結構、其應用裝置及其製備方法
US10330600B2 (en) * 2013-06-04 2019-06-25 Board Of Regents, The University Of Texas System Plasmonic-magnetic bifunctional nanotubes for biological applications
WO2015136226A3 (fr) * 2014-03-13 2015-10-29 Chromalys Nanoparticules pour leur utilisation dans la detection de tumeurs mobiles
WO2017015531A1 (fr) * 2015-07-22 2017-01-26 University Of Maryland, Baltimore County Revêtements hydrophiles de métaux plasmoniques permettant une fluorescence améliorée par faible volume de métal
US10809195B2 (en) 2015-12-23 2020-10-20 Koninklijke Philips N.V. Optical detection of particles in a fluid
US10464169B2 (en) 2016-03-11 2019-11-05 The Government Of The United States Of America, As Represented By The Secretary Of The Navy Programmable assembly and welding of metallic nanoparticles into discrete nanostructures
WO2017156402A1 (fr) * 2016-03-11 2017-09-14 The Government Of The United States Of America, As Represented By The Secretary Of The Navy Assemblage et soudage programmables de nanoparticules métalliques en nanostructures discrètes
CN107238575A (zh) * 2017-06-08 2017-10-10 深圳大学 一种基于完美涡旋光激发spr的光声显微系统
WO2022261530A1 (fr) * 2021-06-11 2022-12-15 The Regents Of The University Of California Système et procédé d'enregistrement sans fil d'activité cérébrale

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