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WO1999001766A1 - Particule metallique, sa preparation et son utilisation, et materiau ou dispositif comprenant cette particule metallique - Google Patents

Particule metallique, sa preparation et son utilisation, et materiau ou dispositif comprenant cette particule metallique Download PDF

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Publication number
WO1999001766A1
WO1999001766A1 PCT/NL1997/000381 NL9700381W WO9901766A1 WO 1999001766 A1 WO1999001766 A1 WO 1999001766A1 NL 9700381 W NL9700381 W NL 9700381W WO 9901766 A1 WO9901766 A1 WO 9901766A1
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Prior art keywords
alkyl
metal
residue
shell
silane
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PCT/NL1997/000381
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English (en)
Inventor
Paul Alexander Buining
Robertus Petrus Maria Van Gijlswijk
Bruno Martin Humbel
Johannes Leonardus Maria Leunissen
Adrianus Johannes Verkleij
Albert Pieter Philipse
Anton Klaas Raap
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Universiteit Utrecht
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Priority to PCT/NL1997/000381 priority Critical patent/WO1999001766A1/fr
Priority to AU33608/97A priority patent/AU3360897A/en
Publication of WO1999001766A1 publication Critical patent/WO1999001766A1/fr

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    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
    • G01N33/553—Metal or metal coated
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y10/00—Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09C—TREATMENT OF INORGANIC MATERIALS, OTHER THAN FIBROUS FILLERS, TO ENHANCE THEIR PIGMENTING OR FILLING PROPERTIES ; PREPARATION OF CARBON BLACK  ; PREPARATION OF INORGANIC MATERIALS WHICH ARE NO SINGLE CHEMICAL COMPOUNDS AND WHICH ARE MAINLY USED AS PIGMENTS OR FILLERS
    • C09C1/00—Treatment of specific inorganic materials other than fibrous fillers; Preparation of carbon black
    • C09C1/62—Metallic pigments or fillers
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/531—Production of immunochemical test materials
    • G01N33/532—Production of labelled immunochemicals
    • G01N33/533—Production of labelled immunochemicals with fluorescent label
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54346—Nanoparticles
    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54353—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals with ligand attached to the carrier via a chemical coupling agent
    • H—ELECTRICITY
    • H10—SEMICONDUCTOR DEVICES; ELECTRIC SOLID-STATE DEVICES NOT OTHERWISE PROVIDED FOR
    • H10K—ORGANIC ELECTRIC SOLID-STATE DEVICES
    • H10K10/00—Organic devices specially adapted for rectifying, amplifying, oscillating or switching; Organic capacitors or resistors having potential barriers
    • H10K10/701—Organic molecular electronic devices
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/01—Particle morphology depicted by an image
    • C01P2004/04—Particle morphology depicted by an image obtained by TEM, STEM, STM or AFM
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/60—Particles characterised by their size
    • C01P2004/64—Nanometer sized, i.e. from 1-100 nanometer
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2004/00—Particle morphology
    • C01P2004/80—Particles consisting of a mixture of two or more inorganic phases
    • C01P2004/82—Particles consisting of a mixture of two or more inorganic phases two phases having the same anion, e.g. both oxidic phases
    • C01P2004/84—Particles consisting of a mixture of two or more inorganic phases two phases having the same anion, e.g. both oxidic phases one phase coated with the other
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01P—INDEXING SCHEME RELATING TO STRUCTURAL AND PHYSICAL ASPECTS OF SOLID INORGANIC COMPOUNDS
    • C01P2006/00—Physical properties of inorganic compounds
    • C01P2006/22—Rheological behaviour as dispersion, e.g. viscosity, sedimentation stability

Definitions

  • a metal particle its preparation and use, and a material or device comprising the metal particle
  • This invention is in various technical fields, including chemistry involved in designing and making metal particles, in particular colloidal metal particles comprising Au, Pt, Pd and/or Ag having a size in the order of a few nanometers or less, and various fields in which such metal particles may be used, such as in nanoelectronic devices and methods involving the use of metal quantum dots, (photo) catalytic materials and methods, kits and methods for detecting or assaying (e.g. for diagnostic purposes) immunological substances or nucleic acids involving the use of a colloidal metal particle-labeled reagent, and the art of ceramic monoliths and coatings.
  • this invention relates to a metal particle, a material or device comprising same, a method for preparing said metal particle and use of said metal particle, wherein the metal is selected from the group consisting of gold, silver, platinum, palladium, rhodium, ruthenium, osmium and iridium.
  • colloidal metal sol preparation comprises the reduction of a molecular metal species (ionic metal salt or organometallic complex) in solution.
  • the stabilization of the metal particles is brought about by ligand molecules attached to their surface.
  • Effective ligand molecules are those that form strong bonds with the metal surface.
  • ligands containing triphenyl phosphine or thiol groups which show a strong chemisorption on metal surfaces.
  • ligands containing amine or ammonium groups are also adsorbing on metal, but to a lesser extent. ligands containing amine or ammonium groups. Using these types of ligands, extremely small metal clusters can be formed which contain only a few tens of metal atoms.
  • triphenyl-phosphine-stabilized gold clusters are the Au 55 [P (phenyl) 3 ] 12 C1 6 two-shell cluster having a core diameter of about 1.4 nm (G. Schmid (1992) Chem. Rev. 92: 1709) and the undecagold cluster Au u [ P (aryl) 3 ] 7 (CN) 3 which has a core diameter of 0.8 nm ⁇ P.
  • phosphine-stabilized bimetallic clusters are Au 13 Ag 12 [P(p-tolyl) 3 ] 10 Cl 8 + , Ni 34 Se 22 [P (phenyl) 3 ] 10 , Cu 36 Se 18 [P (t- Bu) 3 ] 12 , Pd 20 As 12 P (phenyl) 3 ] 12 , and Pd 9 Sb 6 [ P (phenyl) 3 ] 8 (G. Schmid (1992) Chem. Rev. 92:1709) .
  • alkylammonium-stabilized metal clusters are the mono- and bimetallic 2 to 5 nm clusters of Pt, Pd, Rh, Ru, Os, Mo, Pt 50 Sn 50 , Cu 44 Pd 56 , and Pd 50 Pt 50 that have been (electrochemically) prepared by stabilizing with tetraalkyl- ammonium salt (a surfactant molecule) ⁇ M.T. Reetz and S.A.
  • phenanthroline a nitrogen-containing fused aromatic ring compound with sulfonate groups.
  • platinum and palladium are the phenanthroline-stabilized four-shell Pt 309 cluster (G. Schmid, B. Morun, J.-O. Malm
  • SET single- electron tunneling
  • Two quantum-sized metal particles separated by an insulating layer of about 2 nm thickness or smaller can be regarded as a tunnel junction, where single electrons can transfer due to Coulomb interaction generated by an external bias voltage.
  • the ligand-stabilized metal clusters e.g. the Au 55 (PPh 3 ) 12 C1 6 cluster with gold core diameter 1.4 nm and total diameter 2.1 nm (G. Schmid, R. Pfeil, R. Boese, F. Bandermann, S. Mayer, G.H.M. Calls, J.W.A.
  • the organic ligand shell stabilizes the metal core and prevents coalescence of the cores, thus preserving their identity as quantum dots.
  • the cores consist of geometric magic numbers of metal atoms, resulting from subsequently building up an n th shell of 10n 2 +2 atoms around the central atom (densest sphere packing). The amounts of atoms in the particles are: 13, 55, 147, etc. This way very narrow size distributions of clusters are obtained.
  • the electron-hopping behavior (tunnel resistance and capacitance) of the particles depends on (1) the size and monodispersity of the metal core, (2) the thickness of the ligand shell, and (3) the chemical nature of the ligand. Especially important is the particle monodispersity. In a polydisperse particle assembly, the precise electronic energy level structure will vary from particle to particle, resulting after assembly averaging in a distribution of energy levels. For application in nano-structured materials, it is essential for a controlled single-electron-hopping conductivity that the gold nanoparticles are kept apart at a constant distance. Electron-hopping conductivities were measured for gold particles stabilized by a ligand shell of alkanethiolate molecules by Terrill et al . (R.H.
  • Colloidal gold particles coupled to immunoreagents are used for detecting proteins, lipids, RNA and DNA in cell- biological electron-microscopy (EM) studies ⁇ Colloidal Gold: Principles , Methods and Applications , Hayat, M.A. Ed.; Academic Press: San Diego, CA, 1989, Vols. 1, 2 and 3) .
  • Faulk and Taylor were the first in preparing an immunoglobulin-colloidal gold complex, based on adsorption interaction, for cytochemistry at the transmission electron microscope (TEM) level. The method was further developed by Horisberger et al. (M. Horisberger and J. Rosset (1977) J.
  • the adsorption of macromolecules onto the gold surface is a complex phenomenon, depending on the stability of the colloid, concentration, shape, configuration and iso-electric point of the macromolecules, and ionic strength, pH and temperature of the suspending medium.
  • the monolayer of adsorbed macromolecules stabilizes the hydrophobic colloidal gold particles in aqueous solvent by electrosteric stabilization.
  • usually colloidal gold conjugation requires an extra stabilizer (e.g. bovine serum albumin) to minimize aggregation.
  • bovine serum albumin e.g. bovine serum albumin
  • Colloidal gold-antibody probes based on adsorption mostly suffer a certain degree of dissociation of the colloidal gold, leading to its aggregation.
  • the free IgG will then compete for labeling sites and reduce the number of antigens visualized by EM.
  • a covalent binding of an immunoreagent to colloidal gold will result, after purification, in a product without any free gold or free protein. Such a product will not show, as is the case for non-covalent gold-protein conjugates, a dissociation of gold due to the resetting of the adsorption equilibrium. Because of the lack of free gold particles, the labeling will show an improved reliability and a lower background. Because of the lack of free protein, the labeling will show an improved efficiency.
  • Colloidal gold conjugates having gold particle diameter of ⁇ 5-50 nm
  • Ultrasmall gold probes smaller than about 1.4 nm (ofter called gold clusters) penetrate more easily into cell structures (e.g. the cell nucleus) and reach antigen binding sites better. Therefore, they may approach the labeling efficiency of fluorescently labeled antibodies.
  • silver enhancement of the particles is necessary.
  • the on-growth of silver depends strongly on the cluster size. Therefore, to accomplish a homogeneous silver enhancement, it is important that the gold clusters have high monodispersity.
  • Cytochem . 40 : 1 77 Cytochem . 40 : 1 77
  • functional groups e.g. maleimide
  • the 1.4 nm core most probably represents a two-shell gold cluster consisting of 55 gold atoms, comparable to the Au 55 [P (phenyl ) 3 ] 12 C1 6 cluster prepared by Schmid (G. Schmid (1992) Chem . Rev. 92 : 1 709) .
  • the smallest gold label yet developed for covalent conjugation is the undecagold cluster Au [P (aryl) 3 ] -, (CN) 3 with a gold core diameter of 0.8 nm and a total diameter of ⁇ 2 nm ( P. A. Bartlet t , B .
  • This invention provides a metal particle comprising a metal core and a silane shell, wherein said core comprises a metal selected from the group consisting of gold, silver, platinum, palladium, rhodium, ruthenium, osmium, iridi ⁇ m and combinations thereof, and said shell comprises a mercaptosilane residue bound to said metal core.
  • said core comprises a metal selected from the group consisting of gold, silver, platinum, palladium, rhodium, ruthenium, osmium, iridi ⁇ m and combinations thereof
  • said shell comprises a mercaptosilane residue bound to said metal core.
  • said mercaptosilane residue is derived from a mercaptosilane compound of formula HS- (CH 2 ) m -Si (OR 1 ) n R 2 3 _ n , wherein m and n both are integers, m > 0, 0 ⁇ n ⁇ 3, each R 1 independent from any further R 1 ' s is a member of the group consisting of hydrogen, alkyl and trialkylsilyl, and each R 2 independent from any further R 2 ' s is a member of the group consisting of alkyl, haloalkyl, phenyl and halogen.
  • R 1 is hydrogen, alkyl, preferably C j -C,, alkyl, most preferably methyl or ethyl, or C j - ⁇ trialkylsilyl, most preferably trimethylsilyl
  • R 2 is Ci-Cig alkyl, preferably C x -C 6 alkyl, halo (C ⁇ C ⁇ ) - alkyl, preferably halo (C j -C alkyl, phenyl, or halogen, wherein halo (gen) is selected from the group consisting of F, Cl, Br and I.
  • the metal particle will usually have a size of 5 nm or lower, preferably a size in the range of from about 0.8 nm to about 1.5 nm. References to sizes concern (number) averages. Usually, at least 70% of the particles will satisfy the size limitations, preferably at least 80%, more preferably, at least 90%.
  • the mercaptosilane residues in said shell are cross-linked with each other.
  • said silane shell is surrounded by a further shell, said further shell comprising a silane residue, a silicate residue, a titanate residue, a zirconate residue, an aluminate residue, or a borate residue.
  • said further shell comprises a silane residue derived from an organosilane compound of the formula X- (CH 2 ) m -Si (OR 1 ) ⁇ -, ⁇ , wherein m and n both are integers, m > 0, 0 ⁇ n ⁇ 3, each R 1 independent from any further R 1 ' s is a member of the group consisting of hydrogen, alkyl and trialkylsilyl, each R 2 independent from any further R 2 ' s is a member of the group consisting of alkyl, haloalkyl, fenyl and halogen, and X is a functional group.
  • X is selected from the group consisting of amino, thiol, carboxyl, aldehyde, dimethyl acetal, diethyl acetal, epoxy, cyano, isocyanate, acyl azide, anhydride, diazonium salt, sulfonate, hydroxyphenyl, aminophenoxy, halogen, acetate, acrylate, methacrylate and vinyl.
  • the metal particle of this invention preferably is a colloidal particle (i.e. capable of forming a stable sol or colloidal solution) .
  • the metal particle carries a foreign molecule covalently attached to a silane residue, preferably to a silane residue in said further shell.
  • Said foreign molecule is preferably selected from the group consisting of antibodies (immunoglobulines) , antigens, haptens, biotin, avidin, streptavidin, protein A, proteins, enzymes, lectins, hormones, nucleic acids (DNA, RNA, oligo- nucleotides) , fluorescent compounds (including fluoresceins and fluorochromes) and dyes.
  • This invention also provides a material or a device comprising a matrix or support having embedded therein or carrying a particle as defined herein, wherein said matrix or support is preferably selected from the group consisting of polymers, porous glass, colored glass, porous Ti0 2 , zeolites, silica, alumina, intercalated clay compositions, active carbon, graphite, ion-exchange resins, and semi-conductors such as p-GaAs, Ti0 2 , ZnO, CdS and Cd 3 P 2 .
  • this invention provides a method of making a metal particle comprising a metal core and a silane shell, wherein said core comprises a metal selected from the group consisting of gold, silver, platinum, palladium, rhodium, ruthenium, osmium, iridium and combinations thereof, and said shell comprises a mercaptosilane residue bound to said metal core, comprising treating a solution of a compound of the metal with a reducing agent in the presence of a mercaptosilane compound.
  • the metal compound may be selected from salts of the metal, preferably soluble salts, in particular chloride, nitrate or nitrite salts, such as a salt from the group consisting of HAuCl 4 , H 2 PtCl 6 , PdCl 2 , AgN0 3 , and similar Au, Pt, Pd and Ag salts. It is also possible to use two or more of such compounds together. Au, Pt, Pd and Ag are the preferred metals. It is preferred that in this method the metal compound is dissolved in a polar solvent, preferably a polar solvent having a dielectric constant of 15 or higher, most preferably methanol, ethanol, dimethylsulfoxide, or dimethylformamide . It is also preferred that the reaction is carried out in the presence of water, preferably from about 1 to about 10% by weight (based on total weight of water and organic solvent) .
  • a polar solvent preferably a polar solvent having a dielectric constant of 15 or higher, most preferably methanol,
  • Said reducing agent may, e.g., be a borohydride, such as sodium borohydride.
  • the reducing agent and the metal compound are used in a molar ratio of 7 or higher, and preferably the metal compound and the mercaptosilane compound are used in a molar ratio of 6 or lower.
  • this invention provides a method wherein the metal particle comprising said silane shell is subjected to a further reaction, to surround said silane shell by a further shell, said further shell comprising a silane residue, a silicate residue, a titanate residue, a zirconate residue, an aluminate residue, or a borate residue.
  • the reaction is carried out in a polar solvent, preferably a polar solvent having a dielectric constant of 15 or higher, most preferably methanol, ethanol, DMSO or DMF, in the presence of water, preferably from about 1 to about 10% by wt . (This weight percentage being based on the total weight of water and organic solvent.) Furthermore, it is preferred that the reaction is carried out in the presence of a catalyst for siloxane bond formation, such as an amine or ammonia.
  • a polar solvent preferably a polar solvent having a dielectric constant of 15 or higher, most preferably methanol, ethanol, DMSO or DMF
  • water preferably from about 1 to about 10% by wt .
  • a catalyst for siloxane bond formation such as an amine or ammonia.
  • This invention also provides a method which in addition comprises a reaction to covalently attach a foreign molecule to a silane residue, preferably a silane residue in said further shell.
  • This invention also provides various uses of a metal particle as defined herein, in particular in nanoelectronic devices and methods, in (photo) catalytic materials and methods, in monoliths and coatings, as a label or labeled reagent in immunoassay kits and immunoassay methods, or as a label or labeled probe in nucleic acid detection kits and methods .
  • FIGURE 1 shows a schematic illustration of the reaction sequence for the preparation of the mercaptosilane-stabilized metal particles and the coat ' ing of these with a secondary silane.
  • FIGURE 2 shows electron micrographs of ⁇ -mercaptopropyl- trimethoxysilane-stabilized gold particles.
  • the invention relates to the preparation and application of silane-stabilized metal particles of gold, platinum, palladium, silver, rhodium, ruthenium, osmium, iridium, or combinations thereof, which range in size from 5 nm colloids down to subnanometer clusters.
  • the particles can be easily prepared at room temperature by the chemical reduction of an ionic metal species, e.g. Au, Pt, Pd or Ag species (e.g.
  • HAuCl 4 , H 2 PtCl 6 preferably in a polar solvent of dielectric constant in excess of 15, such as in particular ethanol, methanol, dimethylsulfoxide (DMSO) and dimethylformamide (DMF), in the presence of a mercaptosilane compound like:
  • R 1 H, alkyl, or trialkylsilyl
  • R 2 alkyl, halogen, haloalkyl, or phenyl
  • m a positive integer including zero
  • n 0, 1, 2 or 3.
  • R 1 is alkyl, it may be straight chain or branched chain alkyl.
  • each alkyl group is a lower alkyl, which may contain from 1 up to 6, preferably from 1 to 4, most preferably 1 or 2 carbon atoms.
  • R 1 is trialkylsilyl
  • each alkyl preferably is a lower alkyl, such as C x -C 4 alkyl. Most preferably, when R 1 represents trialkylsilyl, it is trimethylsilyl .
  • each alkyl group may be straight chain or branched chain alkyl and may contain from 1 up to 18 or more carbon atoms, preferably 1 to ⁇ carbon atoms, most preferably 1 to 4 carbon atoms.
  • Halogen comprises F, Cl, Br and I.
  • Haloalkyl may be fluoroalkyl, chloroalkyl, bromoalkyl and iodoalkyl.
  • the presence of at least one alkoxy substituent facilitates subsequent binding of further chemicals.
  • R 2 is halogen, this halogen atom facilitates further reactions.
  • the integer m may be 0 (zero), up to about 18 or higher.
  • m will be from 1 up to 6, and most preferably m is about 3.
  • the reaction is carried out in a polar solvent.
  • a sufficiently polar solvent By using a sufficiently polar solvent, the formation of colloidally stable mercaptosilane- stabilized metal particles is facilitated.
  • a solvent of too low polarity say with dielectric constant below 12
  • the metal particles will form, but they will not retain their colloidal stability and will form floes. This may be due to charge and/or solvation effects of the silane surface groups. For certain applications, however, it may not be detrimental or even be desirable that the particles lack colloidal stability.
  • the thiol group of the mercaptosilane has a high affinity for the metal, leading to a stabilizing chemisorbed mercaptosilane monolayer on the metal particle surface.
  • the metal particle size is determined by the amount of metal surface formed by the self-assembling process of the mercaptosilane molecules on that surface at a certain metal- to-mercaptosilane ratio during the preparation. This way, the particle size can be controlled by the metal/mercaptosilane ratio; the smaller this ratio, the smaller the particles.
  • the mercaptosilane stabilizes the metal nuclei in a manner which resembles the role of the surfactant in the spontaneous formation of a water-in-oil microemulsion.
  • R 1 H, alkyl, or trialkylsilyl
  • R 2 alkyl, halogen, haloalkyl, or phenyl
  • R R 2 , m and n are the same as for the mercaptosilane compound.
  • the actual meaning of R 1 , R 2 , m and n in this secondary silane compound may be the same as, or different from the actual meaning of the same symbols in the mercaptosilane compound used.
  • a cage-like siloxane-network structure is formed which wraps up the metal core (see Figure 1, illustrating monolayer coverage of both ⁇ -mercaptopropyltrimethoxysilane and ⁇ -aminopropyltriethoxysilane) .
  • This cross-linked-silane coat prevents the mercaptosilane molecules from being liberated from the metal core by for example high temperature or a strongly reducing (thio) reagent applied during processing of the metal particles.
  • the functional groups of the secondary silane molecules at the particle periphery can serve as the substrate for further covalent reaction with foreign molecules.
  • first the secondary silane is coupled to the silane part of the mercaptosilane on the metal particle surface, after which a foreign molecule is bound to the functional group of the secondary silane.
  • the coupling of foreign molecules onto the metal particles can be accomplished indirectly by first binding the foreign molecule to the functional group of the secondary silane, after which the silane part of this molecule provides the coupling to the silane part of the mercaptosilane on the metal particle surface.
  • This procedure illustrates the potentiality for binding organic and inorganic species to the metal particles. Abundant possibilities can be imagined, taking into account the large amount of (commercially) available organosilanes, which can be combined with the metal colloids to form hybrid organic-inorganic materials.
  • amino- silanes Compared to other organosilane coupling agents, amino- silanes show a higher binding reactivity towards silica surfaces owing to the ⁇ -amine group, which catalyzes the formation of siloxane bonds ⁇ E . P. Pl ueddemann , Silane Coupling Agents ; Plenum : New York, 1982) . Therefore they are of special interest to be used as the functional secondary silane compound.
  • siloxane-bond formation sufficient water needs to be present to protonate the amine and hydrolyze the alkoxy groups. Excess water, however, stimulates the formation of aminosilane multilayers.
  • the reaction should be performed in the presence of a small percentage of water. Usually, this percentage will be in the range of from 1 to 10% by weight.
  • siloxane-bond formation that takes place in the coupling of functional secondary silanes, but also in the silane-cage formation of neighbouring silanes already present on the particle surface, is effectively catalyzed by amines, such as ethylamine, diethylamine, triethylamine, and ammonia ( J. P. Bli tz, R . S. Shreedhara Murthy, and D. E. Leyden (1988) J. Colloid Interfa ce Sci . 126: 387) .
  • amines such as ethylamine, diethylamine, triethylamine, and ammonia
  • Other secondary compounds that can be attached to the mercaptosilane-stabilized metal particle are silicates, aluminates, titanates, zirconates, or borates, like:
  • R 1 alkyl group or H
  • R 2 alkyl group with or without a functional group, or halogen
  • m a positive integer of from 0 to 4 (in case of Si, Ti and Zr compounds) or from 0 to 3 (in case of Al and B compounds) .
  • nanoelectronic devices such as single- electron tunneling transistors, switches in the nanometer range, tunnel resonance resistors, non-linear optical devices, opto-electronic switches, and quantum lasers.
  • the use of ultrasmall metal particles instead of semiconductor material is of great advantage with respect to the miniaturization of such devices.
  • nonconducting host lattices e.g. polymers, porous glasses, or zeolites ( R . Pelster, P. Marquardt , G. Nimtz , A . Enders , H. Eifert , K. Friedrich , F. Petzold (1992) Phys . Rev.
  • lattices in which the metal particles have an ordered distribution with identical inter-particle distances are of special interest.
  • the silane coat around the metal particles of the invention will show a high compatibility towards the inorganic lattices like zeolites and porous glasses and also will form covalent links to them, preventing particle coalescence.
  • Another option for fabrication is to press the ligand- stabilized particles into e.g. disks of quantum dots, or arrange them in one-dimensional arrays as quantum wires, where it is important that the ligands are not destroyed (causing particle coalescence) and that a constant inter- particle distance (smaller than about 2 nm) is maintained ( Schmid et al . (1994) US Pa ten t no . 5 , 350 , 930) .
  • the mercaptosilane- functional silane coat (of controllable thickness) will keep the gold nanoparticles of the invention at a constant distance apart, being essential for a controlled single- electron-hopping conductivity.
  • the rigidness of the siloxane cages around the metal particles of the invention will prevent the pressure forces to compress or even destroy the ligand shells, thereby changing ligand thickness.
  • the superlattices may well be suitable for another type of application, that is photonic crystals ⁇ J. D . Joannopoulos , P. P . Villeneuve, S . Fan (1991) Na ture 386 : 143) .
  • photonic crystals ⁇ J. D . Joannopoulos , P. P . Villeneuve, S . Fan (1991) Na ture 386 : 143) .
  • dielectric constant the lattice constant of the photonoic crystal being comparable to the wavelength of light
  • a photonic bandgap exists of frequencies which are forbidden.
  • this line can be used as a waveguide for light that propagates with a frequency within the bandgap (thus forbidden outside the waveguide in the perfect crystal) .
  • a new approach is the design of a 3D periodic lattice of isolated metallic regions within a dielectric host.
  • the particles of the invention are of special interest because they can be incorporated chemically bound into a silica polymer network or colloidal crystal of highly mono- dispersed silica spheres.
  • An interesting application may be in energy-producing solar cells based on dye sensitization of large-bandgap semiconductor electrodes as described by Gratzel and co- workers ( B 0' Regan and M. Gra tzel (1991 ) Na ture 353 : 131) .
  • the metal particles of the invention may be combined with semiconductor particles to form covalently-attached sandwich colloids, that can be deposited in a porous electrode.
  • the metal particles of the invention may be combined with semiconductor particles to form covalently-attached sandwich colloids, that can be deposited in a porous electrode.
  • the metal particles of the invention may be combined with semiconductor particles to form covalently-attached sandwich colloids, that can be deposited in a porous electrode.
  • the metal particles of the invention may be combined with semiconductor particles to form covalently-attached sandwich colloids, that can be deposited in a porous electrode.
  • nanocolloids of catalytic metal is expressed by their high surface area and special (photo) - electronic properties at their surface. It has been found that e.g. by using Karstedt's catalyst
  • Pt 100 _ x Au x colloidal alloys interesting behavior has been observed towards hydrogenolysis arid isomerization of, e.g., n-butane.
  • Finely divided Pt supported on zeolites are very good isomerization catalysts, but also colloidal noble metal catalyst nanoparticles have been supported on ion-exchange resins, active carbon, intercalated clay compositions, colloidal graphite, alumina, and porous glasses.
  • the silane- coated metal particles of the invention can be strongly anchored to the internal surface of the zeolite (alumino) silicate structure or a porous glass medium.
  • the anchoring can be performed already during the synthesis of the zeolite or glass medium. The anchoring prevents the metal particles from aggregating, so that their catalytic activity is preserved.
  • Another application would be in photoelectrochemical solar cells e.g. for the production of hydrogen gas. Reactions are driven by minority charge carriers produced upon illumination. Instead of the classical procedures of metallizing semiconductor surfaces, electrocatalytic metal nanoparticles (e.g. Pt) could be deposited onto the semi- conductor (e.g. p-GaAs particles) from a colloidal solution (A . Meier, I . Uhlendorf, D. Meissner (1995) Electrochim . Acta 40 : 1523) . This leads to the formation of multiple nano- contacts (MNCs), at the semiconductor/ electrolyte interface.
  • MNCs nano- contacts
  • the metal nanoparticles of the invention with colloidal semiconductor particles (e.g. large-bandgap materials like Ti0 2 and ZnO, or small-bandgap materials like CdS and Cd 3 P 2 ) into sandwich colloids may well give even better results. Visible light excitation leads to an electron-hole pair in the small- bandgap particle of which the electron will immediately (picosecond range) transfer to the particle with the lowest conduction-band energy level. This may lead to charge-carrier separation, useful for photocatalysis .
  • the particle size and surface properties of the metal particles of the invention may be tailored for this purpose easily and with a rich variety of both organic and inorganic compounds.
  • Particles of this invention which comprise Pt, Pd, Ag, Rh, Ru, Os, Ir are preferred, and especially Pt, Pd and/or Ag, more especially Pt and/or Pd, most of all Pt, are most preferred for these (photo) catalytic uses.
  • the metal particles of the invention can be incorporated in colored glass.
  • An optical glass can be prepared with con- trolled absorption properties, depending on the metal type, size, and uniformity of the incorporated metal particles. Especially important for a well-defined absorption spectrum of the glass is that the metal particles are non-aggregated.
  • the particles may be added to the melt.
  • the silane coat around the particles will bind to the silane polymers and the particles will be incorporated without aggregation.
  • the silane coat of the particles will covalently attach to the silane (and/or titanate and/or zirconate and/or hybrid inorganic/organic) network.
  • the particles will not coalesce.
  • the metal particles could be deposited on glass as a coating with certain reflection and absorption properties. Concerning coatings, also paints and lacquers can be loaded with the metal particles.
  • the metal nanoparticles can then be covalently attached to e.g. titania colloids before incorporating these in the paint.
  • Another option is to use methacrylate-coated metal particles (see Example 6) to incorporate them in a metha- crylate polymer network.
  • the metal nanoparticles can be cross-linked to plastic monomers in the production of e.g. polyethylene, polystyrene, PVC, polycarbonate, etc.
  • the metal particles described in this paper can be conjugated to immunoreactive bioreagents such as antibodies, (strept ) avidin and protein-A.
  • immunoreactive bioreagents such as antibodies, (strept ) avidin and protein-A.
  • gold is the most beneficial biochemical probe for many reasons, this application section will further deal particularly with gold instead of the other metals.
  • the main advantage of these conjugates over traditionally prepared immuno-gold reagents is that the coupling between gold and immunoreactive reagent is chemical instead of adsorptive. This means the stability is better and labeling better defined.
  • the method to couple these gold particles relies on chemistry that is generally used to modify immunoreactive reagents with other proteins such as enzymes or avidin ⁇ van Gijlswijk et . al . (1996) J. Imm . Meth .
  • the gold particles of the invention can be covalently coated with groups that are chemically reactive towards bioreagents. These groups are e.g. sulfhydryls, maleimides, and iodoacetamides .
  • the procedure is that first a molecule containing the bioreagent-reactive group (e.g. an N-hydroxy- succinimide ester of maleimide or iodoacetamide) is bound to the secondary silane compound (e.g.
  • Bioreagent-functional gold particles that are most used in the examples are those coated with S-acetylthio- acetate groups, which have a protected sulfhydryl group ( Duncan et al . (1983) Anal . Biochem . 132 : 68- 14 ) . These particles are deprotected prior to use, after which the sulfhydryl activity remains unchanged during long-time storage of the particles.
  • the protein Upon coupling of the (deprotected) gold particles to the protein, the protein must contain a sulfhydryl-reactive group.
  • Either maleimides or iodoacetamides are used for this purpose in the examples, implying that the gold particles are labeled to the proteins by virtue of a thiolether bond.
  • Maleimides or iodoacetamides can be introduced to immunoreactive proteins by incubating these proteins with N-hydroxysuccinimide esters of maleimide or iodoacetamide. A fraction of the lysine aminoacid residues of the protein react with the ester and the maleimide or iodoacetamide is bound through a stable amide bond.
  • Similar chemistry can be applied to couple the gold particles of the invention to amino-labeled oligonucleotides and nucleotides. Because of the relative inertness of the particles described here, they allow applications such as in- situ hybridization with probes directly labeled with gold particles.
  • the silane cage-like coat of the gold particles of the invention gives them a high chemical and temperature stability.
  • Other chemically-reactive gold particles e.g. those stabilized with triphenylphosphine groups ( Hainfeld et al . (1994) US Pa ten t no . 5 , 360, 895) ) are less heat stable and consist of chemically less stable bonds between the gold particle and its functional group.
  • silane-stabilized gold particles Another advantage of these silane-stabilized gold particles is the easy ability to bind more than one molecule simultaneously to the mercaptosilane shell of each gold particle. For instance, besides protected sulfhydryl groups for the bioreagent coupling, also fluoresceins and/or biotin molecules can be attached to the same particle, rendering a multi-functional gold probe.
  • the fluorochrome-labeled gold particles serve as easily detectable labels to check their conjugation to high molecular weight biomolecules, but they can also be used for immunocytochemical analysis. Immuno- chemical labeling prepared for electron microscopy can first easily be confirmed by fluorescence microscopy to obtain information at the cellular level before EM is applied for information at the sub-cellular level.
  • the siloxane cage has an insulating effect on the electronic interaction between the energy levels of the gold (quantum-) particle and those of the fluorescent molecules. This way, quenching of the fluorescence signal is reduced, a problem especially serious for non-covalently bound gold probes .
  • Hapten-labeled gold particles can be used for similar experiments and furthermore the hapten can function as a tool in the separation of gold-labeled immunoreagents from non- gold-labeled counterparts. It is also possible to introduce more than two labels on the surface of the gold particle, allowing a combination of reactive groups for conjugation, chemically-cleavable haptens for purification (see Examples 14 and 15) , and fluorochromes for the easy and sensitive confirmation of protein labeling and immunochemistry . Generally, one can use the gold labels of the invention bound to immunoglobulins, lectins, hormones, etc. for immuno- labeling and effector-labeling in high-resolution (electron microscopic) localization studies.
  • RNA For localization of DNA or RNA one can apply hybridization of gold-labeled oligo- nucleotides for high-resolution gene (transcript) mapping on chromosomes or DNA spreads.
  • radioactive gold conjugates can be targeted to cancer cells. Non-radioactive gold particles, targeted to cancer cells, can then be activated, e.g. by heating them with an appropriate energy beam.
  • the gold sols were prepared in absolute ethanol (Nedalco) at room temperature by the reduction of hydrogen tetrachloroaurate (III) (prepared with HAuCl 4 • (H 2 0) y , Janssen, 49 wt . % Au) with sodium borohydrate (NaBH 4 , dissolved in twice-distilled water) in the presence of ⁇ -mercaptopropyl- trimethoxysilane (MPS, Fluka, >97% purity) as a particle stabilizer (see Figure la) .
  • To 10.0 ml of ethanol were successively added 1.00 mL of a x g/L MPS solution in ethanol and 200 ⁇ L 13.5 mM aqueous HAuCl 4 solution.
  • 200 ⁇ L of a 100 M NaBH 4 aqueous solution was added in one portion under vigorous stirring.
  • a NaBH 4 :HAuCl 4 molar ratio beyond seven ensured complete and fast reduction.
  • a colouring appeared which depended on the HAuCl 4 :MPS ratio. This ratio and an identification of the solvent used are incorporated in brackets in the sol codes Au(Et,6.62) to Au (Et , 0.053 ) .
  • aqueous HAuCl 4 stock solution remained (visibly) unchanged upon storage at room temperature during several months.
  • Gold sols prepared with a three months old HAuCl 4 stock solution did not show any difference in comparison to sols prepared with a fresh solution with respect to sol colour, absorption spectra, and electron micrographs.
  • a Sephadex LH-20 (Pharmacia Biotech) column was used with ethanol as the eluent.
  • Sephadex LH-20 in ethanol shows a void volume percentage of 32% and, for polyethylene glycol, an exclusion limit at a molecular weight of about 4000 g/mol.
  • the sol coded Au(Et, 0.529) migrated as a narrow brown band of constant width.
  • the relative elution volume of ethanol needed for the particles to migrate through the column was roughly in the order of 30% of total column volume, implying that the MPS-stabilized gold particles elude at void volume.
  • Table 1 shows the results of the reduction by NaBH 4 of a series of HAuCl 4 -MPS mixtures with varying HAuCl 4 :MPS ratio.
  • Upon adding little MPS corresponding to a HAuCl 4 :MPS ratio higher than about six, all the gold immediately flocculated and formed a (purple-) black sediment.
  • Upon adding more MPS stable sols were formed which showed a trend in their colour from wine-red for sol Au(Et,5.29) to yellow-brown for sol Au(Et, 0.106) .
  • Table 1 Alcosols of MPS-stabilized gold particles X Sample Code b Appearance D TEM (nm)
  • sol Au (Et , 0.106)
  • the NaBH 4 was not added immediately after mixing the MPS and HAuCl 4 .
  • a stable gold sol was only obtained after the HAuCl 4 -MPS mixture first had been stirred for about ten minutes until it had changed from yellow to colourless. This colour change also took place for the other HAuCl 4 :MPS ratios and took more time for increasing HAuCl 4 :MPS ratio.
  • the absorption spectrum was recorded in time for a HAuCl 4 -MPS mixture of HAuCl 4 :MPS ratio 0.529.
  • the absorption band at 320 nm being characteristic for AuCl 4 ⁇
  • the absorption band at 320 nm gradually decreased in intensity (without shifting its position) until it completely disappeared after hundred minutes.
  • the solution then was colourless.
  • the AuCl 4 ⁇ complex gradually changed into a MPS-gold complex. It may be possible that the thiol group of MPS, by oxidizing to a disufide, reduces the Au(III) from the tetrachloroaurate to Au ( I ) which complexes with MPS.
  • High-angle-annular-dark-field images were made with a Philips CM-200 scanning-transmission electron microscope (HAADF-STEM) equipped with a field emission gun and operated at 200 kV.
  • Sample preparation for TEM and STEM was performed by dipping a carbon-supported 400-mesh copper electron-microscopy grid in the alcosol, draining the excess alcosol from the grid, and drying in the air.
  • the particle size determinations by electron microscopy reveal that a decrease of the HAuCl 4 :MPS ratio causes a decrease of the particle diameter from about 3-5 nm for sol Au(Et,5.29) to about 1 nm or even smaller for sol Au(Et, 0.106) .
  • the gold particles of sol Au(Et,5.29), visualized by TEM are quite non-isometric and non-uniform in size.
  • the aggregates of these particles on the micrograph are due to drying effects on the EM grid.
  • the TEM micrograph of Au(Et, 0.529) ( Figure 2b) shows nanometer-sized gold particles in an aggregate structure in which the indivi- dual particles cannot be identified anymore.
  • FT-IR Fourier-transform infrared
  • fluorescein isothiocyanate (FITC, Sigma) was first coupled to the APS (FITC forms an isothiourea linkage with the APS amine) by bringing 50 mM of each in ethanol and stirring for two hours (APS-FITC) .
  • APS-FITC fluorescein isothiocyanate
  • this sol was transferred to water and purified from ammonia and excess APS-FITC by dialysis in a cellulose tube against demineralized water for one week until no FITC could be visually observed in the supernatant. It showed a dominant yellow-green fluorescent colouring of the FITC.
  • Au sols EtOH, MeOH, H 2 0, DMSO, DMF, aceton / HAuCl 4 (dissolved in H 2 0, EtOH, or DMSO) ; After 20 h of stirring, the aceton sol showed some flocculated material but still contained a stable sol above it.
  • the sols were purified with a Sephadex LH-20 column with eluent EtOH, MeOH, DMSO, DMF, or aceton.
  • the metal particles traveled in the void volume (exclusion limit of Sephahex LH- 20 is ⁇ MW 4000) .
  • the sols in H 2 0 or DMSO could be purified with Sephadex G-50, Sephadex G-75, or Sephadex G-100 with H 2 0 or DMSO eluent. In the Sephadex G-series the metal particles should be separated on size.
  • Sol Au 50 Ag n (Et, 7.56) : To 11.0 ml of ethanol were subsequently added 1.0 ml of a 0.01% (w/v) MPS solution in ethanol, 200 ⁇ l of a 0.01 M HAuCl 4 solution in H 2 0, and 100 ⁇ l of a 0.02 M AgN0 3 solution in H 2 0. After 1 min of stirring, the metal was reduced with 200 ⁇ l of a 0.10 M NaBH 4 solution in H 2 0. Sol Au 50 Ag sn (Et, 0.756) : as above but applying a 0.1% (w/v) MPS solution in ethanol. Results
  • Au fi0 Ag R0 ( Et , 7 . 56 ) was a dark purple-red sol of estimated particle size 5 nm and Au 50 Ag 50 ( Et , 0 . 756 ) was a dark brown-red sol of estimated particle size 2 nm .
  • Bimetallic particles can be stabilized with MPS and their size can be controlled by the MPS-to-total metal ion ratio.
  • Sol Au(Et, 0.378) -TPM was prepared as follows. To 10.0 ml of ethanol were subsequently added 1.0 ml of a 0.1% (w/v) MPS solution in ethanol, and 200 ⁇ l of a 0.01 M HAuCl 4 solution in H 2 0. After 1 min of stirring, the metal was reduced with 200 ⁇ l of a 0.10 M NaBH 4 solution in H 2 0. Then were added 500 ⁇ l of ammonia (25% NH 3 ) and 1.0 ml of a 0.1% (w/v) solution of ⁇ -trimethoxysilyl propyl methacrylate (TPM) in ethanol. The mixture was stirred for 24 h at RT .
  • TPM ⁇ -trimethoxysilyl propyl methacrylate
  • the ethanolic solvent was slowly evaporated by drying in air at 70°C until a dry brown solid remained sticking to the bottom of the glass container.
  • ethanol about 5 ml
  • Methacrylate-coated ultrasmall-gold particles can be processed in powder form without irreversible particle coalescence. This may have important benefits for their application .
  • a gold sol was prepared in DMSO as follows: To 11.0 ml of DMSO under stirring were subsequently added: 200 ⁇ l of a 0.10% MPS solution in ethanol, and 400 ⁇ l of a 10 mM HAuCl 4 solution in ethanol. This light green-yellow solution was stirred for 1 min, after which gold reduction was achieved by adding 400 ⁇ L of a 100 mM NaBH 4 solution in H 2 0 (twice distilled) . The sol color turned brown (sol code Au ( Dm, 3.78 ) ) .
  • the G ⁇ R IgG / SMCC mixture was concentrated to 200 ⁇ L using a c30-filter (Amicon) and further purified using a 2 ml Sephadex G-50 Fine column with lxMEI buffer as the eluent. The fraction eluting at 0.6-1.2 ml was pooled and divided over 3 fractions of 0.2 ml of maleimide-functional G ⁇ R IgG each (G ⁇ R-MEI) .
  • IgG solution (coded G ⁇ R-Au) .
  • SIAB 10 mg/ml SIAB (Pierce) solution in DMSO (50 ⁇ g SIAB) . This mixture was incubated for 1 h at RT .
  • the G ⁇ R-to-gold conjugate provided specific staining of Mouse IgG, with a detection limit of ⁇ 15 ng Mouse IgG.
  • HRP method was found to detect ⁇ 30 pg Mouse IgG.
  • the example shows that iodoacetate-activated IgG can be used in combination with APS-SATA and MPS-functionalized gold particles to prepare IgG-to-gold conjugates.
  • HRP-SATA horseradish peroxidase
  • the filters were incubated with 2 ⁇ g/ml of a biotinylated Goat IgG anti Mouse IgG (G ⁇ M-Biotin, Sigma) in TNB buffer. After 30 min at RT, the filters were washed 3 times for 5 min in TNT buffer and finally one in twice- distilled H 2 0.
  • a biotinylated Goat IgG anti Mouse IgG G ⁇ M-Biotin, Sigma
  • the avidin-D-to-gold conjugate provided specific staining of Mouse IgG, with a detection limit of ⁇ 3 ng Mouse IgG.
  • the HRP method was found to detect ⁇ 10 pg Mouse IgG.
  • the example shows that iodoacetate-activated avidin-D can be used in combination with APS-SATA and MPS-functionalized gold particles to prepare avidin-D-to-gold conjugates.
  • a filter was incubated with AvidinD-FITC-Au, l:50x diluted to 50 ⁇ g/ml avidin-D in TNB buffer.
  • the second filter was incubated with AvidinD-HRP. After 30 min at RT, the filters were washed 3 times for 5 min in TNT buffer and finally once in twice-distilled H 2 0.
  • the FITC-and-avidin-D-to-gold conjugate showed a Mouse-IgG-specific fluorescence signal
  • Metaphase probes (1) Standard metaphase probes were cultivated on glass slides (colcemid, methanol/acetic acid (3 : 1 ) -fixed) . After 24 h drying kept in 70 % ethanol at 4°C.
  • the glass slides were dried for ⁇ 10 min at RT . Then they were incubated with a 100 ⁇ g/ml Rnase solution in 2xSSPE buffer for 20 min at RT to break down cytoplasmic RNA. Then, the glasses were washed three times 3 min in PBS buffer and after that 2 min in twice- distilled water. Then, incubation with 0.05% pepsine in 0.01 M HC1 for 10 min at 37°C to increase accessibility of the nucleus. Then, washing two times 3 min in PBS buffer.
  • the metaphases were denaturated in 70% formamide in 2xSSC buffer for 10 min at 80°C. Then, they were dehydrated in an alcohol concentration series and dried in the air. The metaphases were hybridized left with Iql2-HRP (l:200 ⁇ diluted in ureum hybmix) , and right with Yql2-HRP (l:400x diluted in ureum hybmix), for 16 h at 37°C. The glass slides were washed three times 5 min in 3 M ureum/lxSSTE buffer/0.1% Tween 20 and after that 5 min in PBS buffer.
  • the oligo-probe hybridization showed a specific silver staining, especially for the lql2 probe.
  • the gold particles are used that have been coated with both SATA and biotin ss .
  • the SATA groups are used to couple the gold particles to Goat IgG anti dinitrophenol (G ⁇ DNP) , using the SMCC method (described in Example 8).
  • the disulfide- containing biotins on the gold particles serve to extract the IgG-gold conjugates from the solution.
  • free gold particles were removed by gel filtration (fraction 1), streptavidin-coated magnetic beads were added. Only immunoglobulin-gold conjugates can bind to the streptavidin beads. These beads were collected using a magnet and the supernatant, containing unlabeled immunoglobulins, was removed (fraction 2). Immunoglobulin-gold conjugates were separated from the beads by an incubation with DTT which cleaves the sulfhydryl bridge between the biotin and the (immunoglobulin bound) gold particle (fraction 3).
  • Fraction 1 could be stained by any method. This proves that fraction 1 contained immunoglobulins and that the labeling with the biotinated gold particles was, at least partly, successful. Fraction 2 could only be stained with the anti-goat IgG antibody, thus consisted of free immunoglobulins .
  • fraction 3 showed staining by the anti-goat IgG antibody and the silver enhancement but not with streptavidin-alkaline phosphatase. Thus, fraction 3 contained immunoglobulin-gold conjugates, free of biotin labels.
  • SATA N-succinimidyl S-acetyl thioacetate
  • SIAB N-succinimidyl (4-iodoacetyl) aminobenzoate
  • SMCC succinimidyl 4- (N-maleimidomethyl) cyclohexane 1-carboxylate
  • MPS ⁇ -mercaptopropyl trimethoxysilane APS: ⁇ -aminopropyl triethoxysilane APMS : ⁇ -aminopropyl methyl diethoxysilane TEA: triethyl amine TPM: ⁇ -trimethoxysilyl propyl methacrylate
  • 5xNHS buffer 250 mM (Na) phosphate pH8.0/500 mM NaCl/25 mM EDTA.
  • 5xSATA buffer 250 mM (Na) phosphate pH7. /500 mM NaCl/25 mM EDTA.
  • 5xMEI buffer 250 mM (Na) phosphate pH6.8/500 mM NaCl/25 mM EDTA.
  • TNB buffer 50 mM Tris-HCl pH 7.4/150 mM NaCl/0.5% (w/v) blocking reagent (Boehringer) .
  • TNT buffer 50 mM Tris-HCl pH 7.4/150 mM NaCl/0.05% (v/v)
  • DAB/Ni solution 0.05% (w/v) diaminobenzedine (DAB, Sigma)/
  • 2xSSPE 0.3 M NaCl/20 mM Na phosphate pH 7.2/4 mM EDTA.
  • lxSSTE buffer 0.15 M NaCl/50 mM Tris-HCl pH 7.5/5 mM EDTA.
  • lxSSC buffer 0.15 M NaCl/15 mM sodium citrate/pH 7.5.

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Abstract

L'invention concerne un particule métallique constituée d'un noyau métallique et d'une coquille silanée. Le noyau comprend un métal choisi dans le groupe composé par l'or, l'argent, le platine, le palladium, le rhodium, le ruthénium, l'osmium, l'iridium, et des mélanges de ceux-ci, la coquille comprenant un reste de mercaptosilane, lié audit noyau métallique. Cette coquille silanée peut en outre être entourée par une autre coquille, constituée de silicate, de titanate, de zirconate, d'aluminate, de borate, ou de préférence de restes silanés, les restes de cette seconde coquille pouvant former un réseau. La particule métallique de la présente invention peut être une particule colloïdale, sa taille pouvant être inférieure ou égale à 5 nm, par exemple entre 0,8 et 1,5 nm. Cette particule peut en outre être porteuse d'une molécule étrangère liée par covalence. L'invention concerne également un procédé de fabrication de cette particule, un matériau ou un dispositif comprenant cette particule, incorporée à une matrice ou reposant sur un support, ainsi que diverses utilisations de cette particule.
PCT/NL1997/000381 1997-07-04 1997-07-04 Particule metallique, sa preparation et son utilisation, et materiau ou dispositif comprenant cette particule metallique WO1999001766A1 (fr)

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AU33608/97A AU3360897A (en) 1997-07-04 1997-07-04 A metal particle, its preparation and use, and a material or device comprising the metal particle

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WO2000010010A3 (fr) * 1998-08-11 2000-05-18 Union Biometrica Technology Ho Essais de liaison mettant en oeuvre la resonance optique de particules colloidales
US6413786B1 (en) 1997-01-23 2002-07-02 Union Biometrica Technology Holdings, Inc. Binding assays using optical resonance of colloidal particles
US6706408B2 (en) 2002-05-16 2004-03-16 Surmodics, Inc. Silane coating composition
EP1308228A4 (fr) * 2000-08-11 2004-12-01 Ishihara Sangyo Kaisha Solution metallique colloidale, procede de production de cette solution et materiau de revetement contenant cette solution
FR2863053A1 (fr) * 2003-11-28 2005-06-03 Univ Claude Bernard Lyon Nouvelles sondes hybrides a luminescence exaltee
WO2005008222A3 (fr) * 2003-05-30 2005-07-14 Nanosphere Inc Procede de detection d'analytes fonde sur l'illumination evanescente et sur la detection par diffusion de complexes de sondes de nanoparticules
EP1670054A1 (fr) * 2004-12-09 2006-06-14 Interuniversitair Microelektronica Centrum ( Imec) Méthode de dépôt d'une couche monomoléculaire auto-assemblée
US7106938B2 (en) 2004-03-16 2006-09-12 Regents Of The University Of Minnesota Self assembled three-dimensional photonic crystal
WO2005122235A3 (fr) * 2004-06-08 2007-06-21 Nanosys Inc Procedes et dispositifs permettant de former des monocouches de nanostructures et dispositifs comprenant de telles monocouches
EP1361619A3 (fr) * 2002-05-09 2007-08-15 Konica Corporation Transistor à couche mince organique, substrat de transistor à couche mince organique, et sa méthode de fabrication
FR2901715A1 (fr) * 2006-06-01 2007-12-07 Centre Nat Rech Scient Nouveaux nanomateriaux hybrides, leur preparation et leur utilisation en tant que filtres pour capteurs de gaz
EP1899730A2 (fr) * 2005-07-07 2008-03-19 University of Newcastle upon Tyne Immobilisation de molecules biologiques
EP1886802A3 (fr) * 2001-08-03 2008-07-30 NanoGram Corporation Structure incorporant des mélanges de particules inorganiques-polymères
WO2009027432A1 (fr) 2007-08-28 2009-03-05 Basf Se Tio2 photoactif dans des matériaux de revêtement
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US20110250122A1 (en) * 2008-11-07 2011-10-13 The Regents Of The University Of California Core-Shell Nanocatalyst For High Temperature Reactions
DE102008060708A1 (de) 2008-12-05 2010-06-17 Dianogen Gmbh Beschichtung von Kunststoffsubstraten für den medizinischen Einsatz zur Verbesserung der bildgebenden Eigenschaften
US20130099162A1 (en) * 2010-04-30 2013-04-25 Ocean's King Lighting Science & Technology Co.,Ltd Borate based red light emitting material and preparation method thereof
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