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EP1425584A2 - Analyse spectrometrique de masse amelioree, effectuee a l'aide de nanoparticules - Google Patents

Analyse spectrometrique de masse amelioree, effectuee a l'aide de nanoparticules

Info

Publication number
EP1425584A2
EP1425584A2 EP02797583A EP02797583A EP1425584A2 EP 1425584 A2 EP1425584 A2 EP 1425584A2 EP 02797583 A EP02797583 A EP 02797583A EP 02797583 A EP02797583 A EP 02797583A EP 1425584 A2 EP1425584 A2 EP 1425584A2
Authority
EP
European Patent Office
Prior art keywords
groups
nanoparticles
analyte
maldi
nanoparticle
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.)
Withdrawn
Application number
EP02797583A
Other languages
German (de)
English (en)
Inventor
Jürgen SCHMUCKER
Thomas Schiestel
Herwig Brunner
Günter Tovar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
Original Assignee
Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV filed Critical Fraunhofer Gesellschaft zur Foerderung der Angewandten Forschung eV
Publication of EP1425584A2 publication Critical patent/EP1425584A2/fr
Withdrawn legal-status Critical Current

Links

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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2458/00—Labels used in chemical analysis of biological material
    • G01N2458/15—Non-radioactive isotope labels, e.g. for detection by mass spectrometry
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/24—Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Definitions

  • the molecules were coupled to the particles via a glutaraldehyde bridge or via a direct bond via CNBr-activated carbohydrates.
  • the particulate systems used up to now are not fully compatible with the actual MALDI analysis method and must therefore be removed before application to the sample carrier in order to avoid malfunctions in the MALDI process.
  • the particulate binding matrices are used to isolate and purify analytes, but must be released from the immobilized analytes in an additional step before the sample is applied to the MALDI sample carrier. Only then can the analytes be measured using the MALDI-TOF-MS method.
  • the analyte since the analyte in turn has specific functional groups, the too the functional groups on the nanoparticle surface are complementary and can form an affine bond with them, the analyte can be immobilized on the nanoparticle.
  • the nanoparticles contained in the suspension, on the surface of which the analyte is immobilized can then be washed according to the invention, the non-immobilized constituents of the sample being removed, and, after renewed suspension in an aqueous liquid, can be deposited on the MALDI sample carrier and is examined spectrometrically.
  • the invention there is also the possibility of depositing the nanoparticle suspension containing the bound analyte on the MALDI sample carrier immediately after binding of the analyte and examining it spectrometrically.
  • the present invention thus provides a method by means of which the analyte can be isolated from complex matrices and subsequently analyzed using MALDI-TOF-MS, without the analyte having to be separated from the nanoparticles again after immobilization on the nanoparticles ,
  • the method according to the invention thus has the decisive advantage over the methods known in the prior art that the analyte, after isolation and immobilization, can be subjected to a direct MALDI-TOF examination together with the nanoparticles used according to the invention. Since there is no need to separate analyte and particle, there are no analyte losses in this sample preparation step.
  • the nanoparticles according to the invention are very small with a diameter of ⁇ 150 nm in comparison to the commonly used particles. They therefore have a comparatively very large surface-to-volume ratio and can accordingly bind a large amount of the analyte per mass. Due to the very small diameter, very homogeneous layers and surfaces are created when the nanoparticles are embedded in the MALDI matrix, which is very important for the desorption process and the mass resolution. Several layers of the particles can even be applied to the sample carrier without disrupting the MALDI process, which leads to an additional enrichment of the analyte on the sample carrier.
  • the nanoparticles used according to the invention can be quickly separated by centrifugation and form very stable pellets. They can therefore be separated from liquid media quickly and without loss, which in turn leads to a maximum analyte yield.
  • the particle pellets can also be resuspended without any problems, which makes MALDI sample preparation easier and faster.
  • the nanoparticles used according to the invention are equipped with surfaces which are modified in different ways.
  • the nanoparticles different functional groups and thus allow the binding of different proteins.
  • a wide variety of analytes with complementary functional groups can therefore be separated from complex mixtures and investigated directly using the MALDI-TOF-MS method.
  • nanoparticles used according to the invention are therefore outstandingly suitable for a so-called peptide mapping, since they are the ones for the peptide Mapping does not interfere with the required enzymatic digestion and does not negatively influence the mass resolution.
  • peptide mapping it is also possible to covalently anchor the proteins on the surface of the nanoparticles by means of cross-linkers.
  • stringent washing steps which are particularly necessary for complex samples, can be carried out without loss of analyte.
  • nanoparticles equipped with suitable antibodies are particularly suitable for human medical and / or veterinary diagnostics, for example for the characterization of tumors, BSE tests etc. They offer a decisive time advantage over conventional methods, which is of particular interest in the case of time-critical infections ,
  • an “analyte” is understood to mean a substance in which the type and amount of its individual constituents are determined and / or which are to be separated from mixtures.
  • the analyte is a protein, but also others Compounds, for example nucleic acids or carbohydrates, etc.
  • the analyte is a protein, peptide, active substance, pollutant, toxin, pesticide, antigen or a nucleic acid.
  • a “protein” is understood to mean a molecule which comprises at least two amino acids connected to one another via an amide bond.
  • a protein can also be a Peptide, for example an oligopeptide, a polypeptide or a part, for example a protein domain.
  • Such a protein can be of natural or synthetic origin.
  • the protein can be modified from the wild-type protein by genetic engineering methods and / or contain unnatural and / or unusual amino acids.
  • the protein can be derivatized compared to the wild-type form, for example have glycosylations, it can be shortened, it can be fused to other proteins or it can be linked to molecules of another type, for example carbohydrates.
  • sample is understood to mean an aqueous or organic solution, emulsion, dispersion or suspension which contains an analyte defined above in isolated and purified form or as part of a complex mixture of different substances.
  • a sample can be a biological fluid, such as blood, lymph, tissue fluid, etc., ie a fluid that was taken from a living or dead organism, organ or tissue, but a sample can also be a culture medium, for example a fermentation medium, in the organism , for example microorganisms, or human, animal or plant cells have been cultivated, but a sample in the sense of the invention can also be an aqueous solution, emulsion, dispersion or suspension of an isolated and purified analyte.
  • a sample can already have been subjected to purification steps but can also be pre-cleaned lie.
  • the “provision of a sample” can therefore mean the extraction of a sample defined above as well as the partial or complete purification of the sample or of the analyte after sample collection.
  • nanoparticle is understood to mean a particulate binding matrix which comprises a core with a surface which has functional groups which are able to bind complementary functional groups of the analyte covalently or non-covalently, where the analyte is immobilized on the nanoparticles.
  • Nanoparticles have a size of ⁇ 500 nm, preferably ⁇ 150 nm. Nanoparticles are characterized in that the core, in contrast to the surface, is chemically inert.
  • the “provision of nanoparticles” can do both Production of the nanoparticles, that is to say the production of the cores using emulsion polymerisation, sol-gel processes, etc., and the modification of the core surface by applying functional groups, and also the use of finished nanoparticles which have already been produced.
  • the “provision of a suspension of the nanoparticles in an aqueous liquid” can involve both suspending nanoparticles in liquids, in particular aqueous media, optionally using additional constituents, for example pH agents, suspending aids, etc., and also using ready-made nanoparticles - Kel suspensions mean.
  • a first functional group is understood to mean a functional group of the analyte to be immobilized, which is capable of interacting with a second functional group, that is to say a chemical group applied to the surface of the core, in such a way that a affine binding of a covalent or non-covalent type can take place between the two binding partners in such a way that the analyte is immobilized on the nanoparticle.
  • the first functional group ie the functional group of the analyte
  • the first functional group is selected from the group consisting of carboxy groups, amino groups, thiol groups, biotin groups, Strep Tag I groups, Strep -Tag II groups, His-Tag groups, Flag-Tag groups, antibodies against Protein A, antibodies against Protein G, biotinylated antibodies and biotinylated receptors.
  • the receptors can be, for example, MHC proteins, cytokines, T cell receptors such as the CD-8 protein and others. Even more complex layers can be built up.
  • an antibody can have a streptavidin group and a biotinylated antibody group and a protein group, where the protein can be a receptor, for example.
  • the second functional group that is the functional group on the surface of the nanoparticle, is selected according to the invention from the group consisting of amino groups, carboxy groups, maleiminimido groups, avidin groups, streptavidin Groups, neutravidin groups, metal chelate complexes, protein A units, protein G units, antibodies, receptor units or parts thereof.
  • antibodies or receptors can also be immobilized directly on the nanoparticle as a second functional group.
  • a nanoparticle used according to the invention thus has a second functional group on its surface, which is linked covalently or non-covalently to a first functional group of an analyte to be immobilized, the first functional group being a different group than the second functional group.
  • the two groups that bond with one another must be complementary to one another, that is, be able to form a covalent or non-covalent bond with one another.
  • the second functional group is an amino group.
  • the second functional group is a carboxy group.
  • a thiol group is selected as the first functional group according to the invention, the second functional group is a maleimido group according to the invention.
  • biotin groups and / or Strep-Tag I groups and / or Strep-Tag II groups are used according to the invention as the first functional groups, the second functional group is an avidin group and / or a steptavidin group and / or a neutravidin group.
  • the second functional group according to the invention is a maleinimido group. If an antibody against protein A is used according to the invention, protein A is used as a second functional group according to the invention. If, according to the invention, an antibody against protein G is used as the first functional group, the second functional group is protein G.
  • the aforementioned first and / or second functional groups can be connected to the analyte to be immobilized, in particular the protein to be immobilized, or to the core using a spacer, or introduced to the core or in the analyte by means of a spacer.
  • the spacer thus serves on the one hand as a spacer of the functional group from the nucleus or analyte, and on the other hand as a carrier for the functional group.
  • such a spacer can be alkylene groups or ethylene oxide oligomers with 2 to 50 C atoms, which is substituted in a preferred embodiment and has heteroatoms.
  • the spacer can be flexible and / or linear.
  • the first functional groups are a natural component of the analyte, in particular a protein.
  • unnatural amino acids for example, can be inserted into the protein molecule by genetic engineering methods or during chemical protein synthesis, for example together with spacers or linkers.
  • Such unnatural amino acids are compounds which have an amino acid function and a radical R and are not defined by a naturally occurring genetic code, these amino acids particularly preferably having a thiol group.
  • it can also be provided to modify a naturally occurring amino acid, for example lysine, for example by derivatizing its side chain, in particular their primary amino group, with the carboxylic acid function of levulinic acid.
  • antibody used in the present specification also includes antibody fragments that have been generated either by modification of whole antibodies or by de novo synthesis using recombinant DNA techniques.
  • antibody includes both intact molecules and fragments thereof, such as Fab, F (ab ') 2 and Fv, which can bind the epitope determinant.
  • proteins modified for example with unnatural amino acids, natural but unnaturally derivatized amino acids or specific strep tags, or antibody-bound proteins with complementarily reactive nanoparticle surfaces for binding in this way bring that a suitable specific, in particular non-covalent linkage of the proteins and thus an immobilization of the proteins to the 0- surfaces takes place.
  • nanoparticles which comprise a core are used in the method according to the invention.
  • sen which can be prepared from alkoxysilanes, preferably using a sol-gel process.
  • a “core” is understood to mean a chemically inert substance which serves as a framework for the immobilized analyte.
  • the core of the nanoparticles according to the invention therefore preferably consists of alkoxysilane condensates which are additionally crosslinked
  • the cores of the nanoparticles used according to the invention have a high specific weight according to the invention.
  • the specific weight of the cores is increased by the fact that during their production a cocondensation with heavy compounds , in particular tungstates etc.
  • the core of the nanoparticles according to the invention has a diameter ⁇ 500 nm, in particular 30 nm to 400 nm, preferably 50 nm to 150 nm.
  • ion exchange functions are anchored separately or additionally on the surface of the nanoparticles.
  • the salt content of the matrix is often a critical parameter, since ion accumulation suppresses ionization or causes broadening of the peaks, or peaks also occur. This problem can be avoided with nanoparticles that have a high ion exchange capacity and thereby fix disruptive salts in the matrix.
  • Nanoparticles with an ion exchange function are particularly suitable for optimizing the MALDI analysis of nucleic acids, since these can be converted into a defined mass state.
  • a preferred embodiment of the invention relates to nanoparticles whose surface is functionalized by the application of amino groups.
  • such nanoparticles are particularly suitable for the covalent immobilization of at least one protein with activated carboxy groups and / or at least one nucleic acid and for their separation from a complex mixture and direct investigations using MALDI-TOF-MS.
  • nanoparticles whose surface has carboxy groups.
  • Such nanoparticles are particularly suitable for the covalent immobilization of at least one protein with freely accessible amino groups and for its separation from a complex mixture and for direct analysis using MALDI-TOF-MS.
  • nanoparticles are provided, the surface of which has avidin groups, streptavidin groups and / or neutravidin groups.
  • Such nanoparticles are particularly suitable for immobilizing proteins with biotin groups and / or strep-tag groups and for separating them from a complex mixture and for direct analysis using MALDI-TOF-MS.
  • peptides and / or proteins can be specifically bound to the nanoparticles, which allow an internal calibration of the molecular weight (peak position) and / or the concentration (peak height).
  • Figure 2 shows further mass spectra.
  • This reaction on the one hand increases the density of the functional carboxy groups and, on the other hand, Ni 2+ ions can be bound to this surface by complexation. This surface is then capable of binding His-tag modified proteins.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Analytical Chemistry (AREA)
  • Biotechnology (AREA)
  • Nanotechnology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Other Investigation Or Analysis Of Materials By Electrical Means (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne un procédé amélioré d'analyse spectrométrique de masse, s'utilisant notamment pour la spectrométrie de masse du temps de vol de désorption/ionisation par impact laser assistée par matrice (MALDI-TOF-MS), à l'aide de nanoparticules. Un analyte est ajouté à une suspension de nanoparticules et la suspension contenant l'analyte lié est ensuite précipitée directement sur un porte-échantillons MALDI et est examinée par spectrométrie de masse. L'invention concerne en outre les nanoparticules appropriées pour ce procédé.
EP02797583A 2001-08-31 2002-08-16 Analyse spectrometrique de masse amelioree, effectuee a l'aide de nanoparticules Withdrawn EP1425584A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10144250 2001-08-31
DE10144250A DE10144250A1 (de) 2001-08-31 2001-08-31 Verbesserte massenspektrometrische Analyse unter Verwendung von Nanopartikeln
PCT/EP2002/009196 WO2003021267A2 (fr) 2001-08-31 2002-08-16 Analyse spectrometrique de masse amelioree, effectuee a l'aide de nanoparticules

Publications (1)

Publication Number Publication Date
EP1425584A2 true EP1425584A2 (fr) 2004-06-09

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EP02797583A Withdrawn EP1425584A2 (fr) 2001-08-31 2002-08-16 Analyse spectrometrique de masse amelioree, effectuee a l'aide de nanoparticules

Country Status (6)

Country Link
US (1) US7202472B2 (fr)
EP (1) EP1425584A2 (fr)
JP (1) JP2005502050A (fr)
CA (1) CA2457945A1 (fr)
DE (1) DE10144250A1 (fr)
WO (1) WO2003021267A2 (fr)

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Also Published As

Publication number Publication date
WO2003021267A2 (fr) 2003-03-13
WO2003021267A3 (fr) 2003-12-18
CA2457945A1 (fr) 2003-03-13
US7202472B2 (en) 2007-04-10
JP2005502050A (ja) 2005-01-20
DE10144250A1 (de) 2003-04-03
US20050037516A1 (en) 2005-02-17

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