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WO2002066574A1 - Microparticules fluorescentes - Google Patents

Microparticules fluorescentes Download PDF

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Publication number
WO2002066574A1
WO2002066574A1 PCT/DE2002/000556 DE0200556W WO02066574A1 WO 2002066574 A1 WO2002066574 A1 WO 2002066574A1 DE 0200556 W DE0200556 W DE 0200556W WO 02066574 A1 WO02066574 A1 WO 02066574A1
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WO
WIPO (PCT)
Prior art keywords
fluorescent
microparticles according
fluorescent microparticles
particles
substances
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/DE2002/000556
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German (de)
English (en)
Inventor
Jörg Enderlein
Lothar Kuhnert
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Individual
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Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to DE10290599A priority Critical patent/DE10290599A5/de
Publication of WO2002066574A1 publication Critical patent/WO2002066574A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/02—Use of particular materials as binders, particle coatings or suspension media therefor
    • C09K11/025—Use of particular materials as binders, particle coatings or suspension media therefor non-luminescent particle coatings or suspension media
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
    • C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
    • C09K11/08—Luminescent, e.g. electroluminescent, chemiluminescent materials containing inorganic luminescent materials
    • 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

Definitions

  • the invention relates to fluorescent microparticles which in the core consist of polymer particles with incorporated dyes or semiconductor crystals and are coated with metallic conductive material, furthermore a method for producing these microparticles and applications of these microparticles in analytics, in particular in biology and medicine.
  • the microparticles according to the invention are notable for improved photostability and higher fluorescence intensity (fluorescence brightness).
  • Fluorescent microparticles are known from the literature and have found a wide range of applications in analysis, particularly in the detection of biologically relevant materials.
  • EP 0 596 098 describes fluorescent microparticles in which fluorescent dyes are embedded in polymers and used appropriately in biological analysis. Analogous materials are also mentioned in USP 2,994,679 and USP 3,096,333.
  • Such fluorescent microparticles are used in a wide range of applications in biology and medicine, since biologically active materials can be chemically or physically adsorptively attached to their surface. In this way, the fluorescent microparticles serve as markers or tracers for the detection of the biological material. Blood flow measurements using such microparticles are described in Circulation 83, 974 (1991). In J. Microbiol. Meth. 13, 135, (1991) the behavior of bacteria is examined. Further examples are the use in immunoassays (Anal. Biochem. 272, 165, (1999)) and nucleic acid analysis (Anal. Biochem. 198, 308, (1991), Nucleic Acid Res. 15, 2891, (1987)). A summary of applications can be found in: R.P. Haughland: Handbook of Fluorescent Probes and Research Chemicals, 7th Edition Molecular Probes, 1999.
  • the object of the invention is therefore to find fluorescent microparticles with significantly improved fluorescence brightness and photostability, which allow the use of highly sensitive detection methods with simple means, and to specify methods for their production and use.
  • the fluorescent microparticles according to the invention contain a core of a fluorescent material which consists of polymer particles which are loaded with organic dyes or of semiconductor microcrystals. These fluorescent core particles are coated with a material that is metallically conductive at the optical frequencies of the excitation and fluorescence. Depending on the diameter of the fluorescent core, the type of metallically conductive material and its layer thickness, the intensity of the emitted fluorescent light and / or the photostability of the dyes located in the core are significantly increased. This remarkable improvement in fluorescence properties occurs with both single-photon and multi-photon imaging.
  • this improvement in the fluorescence properties depends on the type of metallically conductive material, the diameter of the core and the layer thickness of the metal applied. It was found that gold, silver, copper or aluminum are particularly suitable.
  • the diameter of the fluorescent core is preferably in the range from 10 to 90 nm and the layer thickness of the metallically conductive material is preferably 1 to 10 nm. If silver is used as the metallically conductive material, the particularly preferred diameter of the core is 10 to 50 nm.
  • the core of the fluorescent microparticles consists of semiconductor material, such as CdS, CdSe, CdTe, ZnS, ZnSe, ZnTe, InP, InAs.
  • Suitable fluorescent organic dyes are dyes from the classes of coumarins, oxazines, thiazines, rhodamines, dibenzpyrans, polymethines such as cyanines, phthalocyanines or combinations thereof.
  • dyes are introduced into polymer material, for which purpose polymers or copolymers of styrene, divinylbenzene, acrylonitrile or methacrylonitrile, acrylamide or methacrylamide, acrylic or methacrylic acid esters, maleic acid derivatives, vinyl acetate, vinyl chloride, furthermore cellulose derivatives, agarose, polyurethane acid, polyhydroxybutylene , Polylactides are suitable.
  • Crosslinked polymers with anion or cation exchange groups are also suitable.
  • the metallically coated fluorescent microparticles are advantageously coated with a protective layer of oxides or sulfides.
  • polysulfides or other substances containing thiol groups are also suitable.
  • the metallized microparticles can also be coated with protein bodies such as albumin by adsorption. In this way and by coating with other substances or chemical reaction, the microparticles receive functional coupling groups such as hydroxyl, amine, A id, imide, carboxylic anhydride, sulfhydryl, sulfonate, aldehyde, azide, quinone azide.
  • Biotin, avidin, streptavidin or nucleic acid compounds can also be attached to these functional groups or by prior coating.
  • the fluorescent microparticles according to the invention are suitable for a large number of analytical applications.
  • the fluorescent microparticles according to the invention are produced in several directions.
  • hydrophobic dyes which are practically insoluble in water are combined with the polymer which is also insoluble in water.
  • Dissolve material in an organic solvent which is also miscible with water Solvents are used whose boiling point is lower than that of water.
  • methylene chloride, chloroform, dichloroethane, carbon tetrachloride, trichlorethylene, benzene, cyclohexane are suitable.
  • Polymers or copolymers of styrene, divinylbenzene, acrylonitrile or methacrylonitrile, acrylic or methacrylic acid esters, maleic acid derivatives, vinyl acetate, vinyl chloride, furthermore water-insoluble cellulose derivatives, polyurethane, polyhydroxybutyric acid, polylactides, polyvinyl alcohol, gelatin, agarose are used as the polymer material.
  • surfactants as emulsifying agents which can be carried out both to the organic and to the aqueous phase or to both phases, the two phases are mixed intensively using a high-speed stirrer, so that a finely divided emulsion is formed.
  • the droplets of the solvent which contain the polymer material and the dye, are finely divided in the continuous water phase. After the solvent has been distilled off, these droplets solidify into spheroidal microparticles. These can e.g. isolated by centrifugation, washed and further processed accordingly.
  • core particles which contain hydrophilic polymers such as agarose, polyacrylamide, water-soluble cellulose derivatives, polyvinyl alcohol, gelatin and hydrophilic dyes.
  • the polymers and the dyes are dissolved in water and this solution is emulsified again using surfactants in an organic solvent whose boiling point is above the boiling point of water.
  • an organic solvent whose boiling point is above the boiling point of water.
  • toluene, ethylbenzene, xylenes, Cu ol are suitable for this.
  • a finely divided emulsion with the organic solvent is obtained as a continuous phase.
  • the polymer material and the dyes are in the finely divided water drops. After the water has been distilled off, these droplets solidify into spheroidal microparticles. These are isolated again by centrifugation.
  • polymeric microparticles which contain anion- or cation-exchanging groups on their surface such as appropriately modified styrene-divinyl copolymers, can also be loaded with ionic dyes.
  • these fluorescent core particles are coated with a material that is metallically conductive at the optical frequencies of excitation and fluorescence.
  • Gold, silver, copper or aluminum are particularly suitable for this.
  • certain layer thicknesses in the range from 1 to 10 nm are particularly preferred in order to achieve maximum photostability and / or fluorescence intensity.
  • This improvement in fluorescence properties according to the invention depends in a complex manner on the material properties of the substances involved (polymer material and dyes), type of metallically conductive material, the geometric relationships (diameter of the core particles and layer thickness of the metallically conductive material) and the type of excitation and emission (a - or multi-photon excitation).
  • the fluorescent core particles are coated by dispersing these particles in a solvent, preferably in an aqueous medium, adding a salt or another compound of the metallically conductive material and a reducing agent.
  • Suitable metal salts are, for example, silver sulfate, silver nitrate, gold (HI) chloride, gold (I) cyanide, copper sulfate, copper nitrate.
  • a large number of reducing agents are suitable for silver or gold.
  • the following list represents a selection without claim to completeness: formaldehyde, iron (II) sulfate, tartaric acid, hydroquinone, p-aminophenol, dialkylaniline, phenidone, sulfite, oxalic acid, sugar, tartaric acid, citric acid.
  • Solutions of the metal salts and the reducing agent are expediently added alternately in small portions to the dispersed core particles and samples are taken. to track and control the coating process. The samples taken are examined for their fluorescence properties in comparison to the uncoated core particles.
  • the thickness of the coating is determined by detaching the metal layer from a defined number of microparticles and analytically determining the metal ion concentration. For example, polarography or atomic absorption spectroscopy are used for this.
  • Layer thicknesses of the metallically conductive material in the range from 1 to 10 nm and fluorescent core particles with a diameter of 10 to 90 nm have proven to be suitable. Core particles with a diameter of 10 to 50 nm are particularly suitable if silver is used as the metallic conductive material.
  • the surface of the metallized particles can be modified in order to bring about the coupling in particular of biologically or medically relevant substances.
  • the surface of the metallized particles can be modified in order to bring about the coupling in particular of biologically or medically relevant substances.
  • treatment with oxidizing agents or ammonium sulfide solutions creates a thin protective layer on the metallized surfaces.
  • Aliphatic polysulfides or monomeric substances containing thiol groups are also suitable for this.
  • biomaterials In order to enable the further coupling of biomaterials, they can be coated with protein bodies such as albumin or other substances which contain functional groups.
  • protein bodies such as albumin or other substances which contain functional groups.
  • a large number of monomeric or polymeric substances such as styrene / maleic acid copolymers, polyvinyl alcohol and polyvinyl alcohol derivatives, soluble cellulose derivatives, azides, diazides, quinonediazides are suitable as coating material.
  • the fluorescent microparticles can be equipped with functional groups such as hydroxyl, amine, amide, imide, carboxylic anhydride, sulfhydryl, sulfonate, aldehyde, azide, quinone azide or biologically active substances.
  • the coating with or coupling of biotin, avidin, streptavidin or nucleic acid compounds is particularly attractive for use in bioanalytics.
  • the fluorescent microparticles according to the invention are used as fluorescent markers or tracers.
  • the use as a fluorescence marker uses the possibility that the functional groups or biologically active substances bound to the microparticles react with analyte substances and can subsequently be detected by means of a fluorescence measurement.
  • the usual procedure is as follows: a) A sample is prepared in which the analyte substances to be detected are located. b) Fluorescent microparticles equipped with functional groups or biologically active substances which are capable of recognizing the analyte substances are dispersed or applied in a suitable manner to a surface. c) The analyte substances and the fluorescent microparticles are brought together and incubated for the required reaction time. d) Microparticles that have not reacted are removed. e) The bound microparticles and thus the analyte substances are irradiated and detected using the emitted fluorescent light.
  • Proteins, peptides, DNA, RNA, oligonucleotides, polysaccharides, avidin, biotin, polymeric and non-polymeric biomolecules, antibodies, antigens, viruses or other microorganisms can be detected according to this scheme.
  • the method described can also be specifically designed as an immunoassay.
  • the detection of DNA, RNA or oligonucleotides can be used in DNA sequence analysis.
  • Cells labeled with fluorescent microparticles can be sorted out or cytometrically detected.
  • the fluorescent microparticles according to the invention can also be used as tracers for examining transport processes in fluid media inside and outside of living organisms or cells.
  • the high fluorescence intensity of the microparticles according to the invention with two-photon excitation allows excitation with inexpensive commercial diode lasers in the range 600-1100 nm and the detection of the short-wave fluorescence radiation emitted in the range 300-700 nm. Because of the high fluorescence intensity and the improved photo stability, the Microparticles according to the invention in many cases make the detection method simpler and more economical. For example, the detection of the fluorescent microparticles is also possible with a CCD camera.
  • Solution A 2% solution of silver nitrate in double distilled water
  • Solution B 2g p-aminophenol and 10g potassium carbonate are dissolved in 250 ml double distilled water
  • the amount of silver deposited on the ponds is determined.
  • the silver is oxidatively dissolved in a potassium ferricyanide solution and determined by polarography.
  • Example 1 the coating of microparticles with gold and the determination of the fluorescence properties of the particles obtained with single-photon excitation at the wavelength 635 nm and emission at 670 nm are described as in Example 1.
  • 1 g of the dye-loaded polystyrene microparticles are dispersed analogously to Example 1 in 250 ml of double-distilled water and the following solutions are prepared: Solution A: 3% solution of tetrachloroauric acid trihydrate in 11 double-distilled water
  • Solution B 2.5% solution of potassium carbonate in 11 double-distilled water
  • Solution C 3 ml 37% formaldehyde solution dissolved in 11 double-distilled water
  • Example 3 describes the determination of the fluorescence properties for two-photon excitation.
  • the starting material used was polystyrene microparticles with a diameter of 50 nm, which were loaded with the dye rhodamine 6G.
  • the coating of these microparticles with silver or gold was carried out analogously to Example 1 and Example 2.
  • a pulsed diode laser pulse repetition rate 80 MHz, pulse width 50 ps was excited at the wavelength of 790 nm and the fluorescence emission at wavelengths in the range of 450 - 600 nm measured.
  • the fluorescence intensity increased by a factor of 1000 compared to the non-metallized particles when measuring the fluorescent light at the wavelength of 460 nm.
  • the photostability for these microparticles increased among the same measurement conditions by a factor of 2.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Materials Engineering (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Cell Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Nanotechnology (AREA)
  • Inorganic Chemistry (AREA)
  • Investigating, Analyzing Materials By Fluorescence Or Luminescence (AREA)
  • Luminescent Compositions (AREA)

Abstract

La présente invention concerne des microparticules fluorescentes qui sont constituées au centre de particules polymères auxquelles sont incorporées de substances colorantes, ou de cristaux semi-conducteurs, et qui sont recouvertes d'une substance métallique conductrice. Cette invention concerne également un procédé permettant la production de ces microparticules et des applications de ces microparticules en analytique notamment en biologie et en médecine. Les microparticules de l'invention se caractérisent par une photostabilité améliorée et une intensité de fluorescence (luminosité de fluorescence) supérieure.
PCT/DE2002/000556 2001-02-16 2002-02-12 Microparticules fluorescentes Ceased WO2002066574A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE10290599A DE10290599A5 (de) 2001-02-16 2002-02-12 Fluoreszierende Mikroteilchen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10108808.6 2001-02-16
DE10108808A DE10108808A1 (de) 2001-02-16 2001-02-16 Fluoreszierende Mikroteilchen

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WO2002066574A1 true WO2002066574A1 (fr) 2002-08-29

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035795A3 (fr) * 2001-10-25 2003-06-05 Univ Manchester Materiau organique photostabilise
WO2006084339A1 (fr) * 2005-02-14 2006-08-17 Australian Nuclear Science & Technology Organisation Nanoparticules en couches
WO2008127139A1 (fr) * 2007-04-11 2008-10-23 Institut Molekulyarnoi Biologii Im. V.A. Engeldardta Rossiiskoi Akademii Nauk Colorants d'indocyanine fluorescents et leurs dérivés destinés à l'analyse de macromolécules biologiques
EP1590659A4 (fr) * 2003-02-07 2010-04-21 Univ Texas Microspheres a coques multiples a couches de chromatographie et de detection integrees utilisees dans des capteurs en mosaiques
CN102516696A (zh) * 2011-12-19 2012-06-27 东南大学 一种生物荧光纳米温度计的制备方法
CN102598625A (zh) * 2009-11-09 2012-07-18 三星电子株式会社 利用通用即插即用在输入系统改变输入类型的方法和装置
CN105985598A (zh) * 2016-06-17 2016-10-05 燕山大学 一种染料-石墨烯-聚乙烯醇三元荧光复合物及制备方法
CN108586758A (zh) * 2018-05-10 2018-09-28 宁波新斯维箱包有限公司 微胶囊及其制备方法
DE102017114537A1 (de) 2017-06-29 2019-01-03 Endress+Hauser Conducta Gmbh+Co. Kg Sensormembran, Sensorkappe und optischer Sensor

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102008033940B3 (de) * 2008-07-18 2010-01-21 Innovent E.V. Verfahren zum Bestimmen einer Schichtqualität
CN110672574B (zh) * 2019-11-06 2021-10-15 湖北师范大学 一种用于检测Cu2+的比率荧光传感器及其制备方法和应用

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US5326692A (en) * 1992-05-13 1994-07-05 Molecular Probes, Inc. Fluorescent microparticles with controllable enhanced stokes shift
DE19933104A1 (de) * 1999-07-15 2001-01-18 Ingo Klimant Phosphoreszierende Mikro- und Nanopartikel als Referenzstandard und Phosphoreszenzmarker

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US5326692A (en) * 1992-05-13 1994-07-05 Molecular Probes, Inc. Fluorescent microparticles with controllable enhanced stokes shift
US5326692B1 (en) * 1992-05-13 1996-04-30 Molecular Probes Inc Fluorescent microparticles with controllable enhanced stokes shift
DE19933104A1 (de) * 1999-07-15 2001-01-18 Ingo Klimant Phosphoreszierende Mikro- und Nanopartikel als Referenzstandard und Phosphoreszenzmarker

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DABBOUSI B O: "(CDSE)ZNS CORE-SHELL QUANTUM DOTS: SYNTHESIS AND CHARACTERIZATIONS OF A SIZE SERIES OF HIGHLY LUMINESCENT NANOCRYSTALLITES", JOURNAL OF PHYSICAL CHEMISTRY. B, MATERIALS, SURFACES, INTERFACES AND BIOPHYSICAL, WASHINGTON, DC, US, vol. 101, no. 46, 13 November 1997 (1997-11-13), pages 9463 - 9475, XP002095418, ISSN: 1089-5647 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003035795A3 (fr) * 2001-10-25 2003-06-05 Univ Manchester Materiau organique photostabilise
EP1590659A4 (fr) * 2003-02-07 2010-04-21 Univ Texas Microspheres a coques multiples a couches de chromatographie et de detection integrees utilisees dans des capteurs en mosaiques
WO2006084339A1 (fr) * 2005-02-14 2006-08-17 Australian Nuclear Science & Technology Organisation Nanoparticules en couches
US8871272B2 (en) 2005-02-14 2014-10-28 Australian Nuclear Science & Technology Organisation Layered nanoparticles
US9295654B2 (en) 2005-02-14 2016-03-29 Australian Nuclear Science & Technology Organisation Layered nanoparticles
WO2008127139A1 (fr) * 2007-04-11 2008-10-23 Institut Molekulyarnoi Biologii Im. V.A. Engeldardta Rossiiskoi Akademii Nauk Colorants d'indocyanine fluorescents et leurs dérivés destinés à l'analyse de macromolécules biologiques
CN102598625A (zh) * 2009-11-09 2012-07-18 三星电子株式会社 利用通用即插即用在输入系统改变输入类型的方法和装置
CN102598625B (zh) * 2009-11-09 2015-07-01 三星电子株式会社 利用通用即插即用在输入系统改变输入类型的方法和装置
CN102516696A (zh) * 2011-12-19 2012-06-27 东南大学 一种生物荧光纳米温度计的制备方法
CN105985598A (zh) * 2016-06-17 2016-10-05 燕山大学 一种染料-石墨烯-聚乙烯醇三元荧光复合物及制备方法
DE102017114537A1 (de) 2017-06-29 2019-01-03 Endress+Hauser Conducta Gmbh+Co. Kg Sensormembran, Sensorkappe und optischer Sensor
CN108586758A (zh) * 2018-05-10 2018-09-28 宁波新斯维箱包有限公司 微胶囊及其制备方法

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