WO2012032794A1 - 核酸又は免疫クロマトグラフィー用試薬組成物、核酸又は免疫クロマトグラフィー測定方法及び核酸又は免疫クロマトグラフィー測定用キット - Google Patents
核酸又は免疫クロマトグラフィー用試薬組成物、核酸又は免疫クロマトグラフィー測定方法及び核酸又は免疫クロマトグラフィー測定用キット Download PDFInfo
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Classifications
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- 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
- G01N33/54366—Apparatus specially adapted for solid-phase testing
- G01N33/54386—Analytical elements
- G01N33/54387—Immunochromatographic test strips
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6804—Nucleic acid analysis using immunogens
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- C—CHEMISTRY; METALLURGY
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- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
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- 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
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- G01N33/54386—Analytical elements
- G01N33/54387—Immunochromatographic test strips
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54393—Improving reaction conditions or stability, e.g. by coating or irradiation of surface, by reduction of non-specific binding, by promotion of specific binding
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- 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
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- 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
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
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- G—PHYSICS
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- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
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- 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
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- Y10T436/143333—Saccharide [e.g., DNA, etc.]
Definitions
- the present invention relates to a reagent composition used for nucleic acid or immunochromatography, a nucleic acid or immunochromatography measurement method using the same, and a nucleic acid or immunochromatography measurement kit containing the same.
- the present invention reduces the binding due to non-specific reaction of components other than the analyte when performing nucleic acid or immunochromatography measurements, and improves the dispersibility of the analyte to improve the developability on the chromatographic carrier. At the same time, it is an object of the present invention to enable accurate and quick judgment even by using a low concentration analyte by promoting a specific reaction.
- the present inventor has achieved the present invention by discovering that the above problems are solved by using a combination of specific additives.
- the present invention relates to a water-soluble polymer compound having a weight average molecular weight of 8000 or more, a divalent or trivalent metal salt, a nonionic surfactant, and a nucleic acid or immunochromatography containing a water-soluble aprotic organic compound.
- Reagent composition a water-soluble polymer compound having a weight average molecular weight of 8000 or more, a divalent or trivalent metal salt, a nonionic surfactant, and a nucleic acid or immunochromatography containing a water-soluble aprotic organic compound.
- the present invention is a method for measuring a nucleic acid or immunochromatography comprising a step of developing a measurement sample using the above-described nucleic acid or reagent composition for immunochromatography.
- the present invention is a kit for measuring a nucleic acid or immunochromatography comprising the above-described chromatographic reagent composition as a developing solution for a measurement sample.
- the present invention in performing nucleic acid or immunochromatography measurement, binding due to non-specific reaction of components other than the analyte is reduced, and the dispersibility of the analyte is enhanced and the specific reaction is promoted. Thus, accurate and quick judgment can be made even when a low-concentration analyte is used.
- the nucleic acid or immunochromatography reagent composition of the present invention comprises a water-soluble polymer compound having a weight average molecular weight of 8000 or more, a divalent or trivalent metal salt, a nonionic surfactant, and a water-soluble aprotic compound. Contains organic compounds.
- the water-soluble polymer compound having a weight average molecular weight of 8000 or more is not particularly limited as long as it is a compound having a weight average molecular weight of 8000 or more and water solubility.
- the weight average molecular weight is preferably 10,000 or more. If the water-soluble polymer has a weight average molecular weight of 8000 or more, a commercially available compound having a known weight average molecular weight can be used. When using what was synthesize
- the weight average molecular weight is less than 8000, the binding force for forming a specific complex with the analyte observed in nucleic acid hybridization or antigen-antibody reaction decreases, and the detection sensitivity by chromatography decreases. More preferably, a water-soluble polymer having a weight average molecular weight of 20,000 to 1,000,000 is used. “Water-soluble” in a water-soluble polymer compound having a weight average molecular weight of 8000 or more means that the compound is dissolved in 10 g or more, preferably 50 g or more in 1 L of water at 20 ° C.
- Water-soluble polymer compounds having a weight average molecular weight of 8000 or more include, for example, polyalkylene glycols such as polyethylene glycol, polypropylene glycol, and polyethylene glycol / polypropylene glycol block copolymers; methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl 1 selected from the group consisting of celluloses such as methylcellulose and carboxymethylcellulose; vinyl polymers such as polyvinyl pyrrolidone, polyvinyl alcohol and polyvinyl methyl ether; amide polymers such as polymethacrylamide and polyacrylamide; and polyanions More than a seed.
- polyalkylene glycols such as polyethylene glycol, polypropylene glycol, and polyethylene glycol / polypropylene glycol block copolymers
- polyanions examples include polysaccharide anions, synthetic peptide anions such as polyglutamic acid and polyaspartic acid, and synthetic nucleic acid polyanions, with polysaccharide anions being preferred.
- polysaccharide anion examples include one or more selected from the group consisting of dextran sulfate, heparan sulfate, chondroitin sulfate, dermatan sulfate, keratan sulfate, hyaluronic acid, heparin and salts thereof.
- the salt examples include sodium, potassium, and magnesium salts. Among these, dextran sulfate and its salt are more preferable from the viewpoint of availability and economy.
- the amount of the water-soluble polymer compound having a weight average molecular weight of 8000 or more is preferably 0.1 to 5% by weight, more preferably 0.5 to 3% by weight, based on the reagent composition.
- a water-soluble polymer compound having a molecular weight of 8000 or more enhances the binding force for forming a specific complex with an analyte and promotes a specific reaction.
- the divalent or trivalent metal is not particularly limited as long as it is a divalent or trivalent metal.
- alkaline earth metals such as magnesium and calcium
- aluminum group metals such as boron and aluminum (3 Valent)
- magnesium, calcium or aluminum particularly preferably magnesium or calcium, and most preferably magnesium.
- the anion of the divalent or trivalent metal salt is not particularly limited, and examples thereof include halides such as chloride and bromide; sulfates; phosphates; carbonates; Preferably, halides such as chloride and bromide are used.
- Divalent or trivalent metal salts include magnesium salts such as magnesium chloride, magnesium sulfate, magnesium phosphate, and magnesium carbonate; calcium salts such as calcium chloride, calcium sulfate, and calcium phosphate; and aluminum chloride, aluminum sulfate, aluminum carbonate, etc. It is preferably one or more selected from the group consisting of aluminum salts.
- the amount of the divalent or trivalent metal salt is preferably 0.1 to 100 mM, more preferably 0.5 to 50 mM, and still more preferably 1 to 10 mM with respect to the reagent composition.
- a salt of a divalent or trivalent metal increases the development rate of capillary action without causing a non-specific reaction of the immune complex.
- Nonionic surfactants include, for example, polyoxyethylene alkyl ether, polyoxyethylene alkylphenol ether, alkyl glucoside, polyoxyethylene fatty acid ester, sucrose fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, fatty acid alkanolamide Is mentioned.
- the HLB of the nonionic surfactant is preferably 10-18, more preferably 13-18.
- polyoxyethylene sorbitan fatty acid ester is preferable, for example, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan tristearate and polyoxyethylene sorbitan monooleate.
- polyoxyethylene sorbitan monolaurate polyoxyethylene sorbitan monostearate
- polyoxyethylene sorbitan tristearate polyoxyethylene sorbitan monooleate
- the amount of the nonionic surfactant is preferably 0.1 to 5% by weight, more preferably 0.5 to 2.5% by weight, still more preferably 0.5 to 1% by weight, based on the reagent composition. It is.
- the water-soluble aprotic organic compound is not particularly limited as long as it is water-soluble and does not have proticity.
- Water-soluble means a property that can be mixed with water at any ratio without phase separation, and preferably 10 g or more, preferably 50 g or more of the compound is dissolved in 1 L of water at 20 ° C. It is an organic compound.
- Aprotic means a property that does not contain acidic hydrogen and does not act as a hydrogen bond donor.
- water-soluble aprotic organic compound examples include sulfoxides, N, N′-dialkylamides, ketones, nitriles, cyclic ethers and the like.
- sulfoxides examples include dimethyl sulfoxide, methyl ethyl sulfoxide, diethyl sulfoxide, butyl ethyl sulfoxide and the like.
- N, N′-dialkylamides such as dialkylacetamide such as dimethylacetamide, dialkylformamide such as dimethylformamide, N-methyl-pyrrolidone, N-ethyl-pyrrolidone, N- (2-hydroxyethyl) -2-pyrrolidone and the like And N-alkylpyrrolidone.
- ketones include acetone, acetylacetone, diethyl ketone, methyl ethyl ketone, methyl propyl ketone, isobutyl methyl ketone, ⁇ -butyrolactone, and ⁇ -valerolactone.
- Nitriles include acetonitrile, propionitrile, butyronitrile and the like.
- cyclic ethers examples include tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane and the like.
- water-soluble aprotic organic compound sulfoxides and N, N′-dialkylamides are preferable, and sulfoxides are particularly preferable.
- the amount of the water-soluble aprotic organic compound is preferably 0.2 to 5% by weight, more preferably 0.5 to 3% by weight, based on the reagent composition.
- the water-soluble aprotic organic compound improves the non-uniformity of the developing solution caused by fusion and aggregation of substances other than the analyte during development due to capillary action, and makes it difficult to cause non-specific reactions.
- the reagent composition of the present invention usually contains water as a solvent, and can be obtained by mixing the above components with water, for example, ultrapure water.
- nucleic acid or immunochromatography The reagent composition of the present invention is used for nucleic acid or immunochromatography. Nucleic acid chromatography is based on nucleic acid hybridization.
- the immunochromatography is not particularly limited as long as it is based on an antigen-antibody reaction.
- an antigen-antibody reaction there are a competitive method and a sandwich method, among which the sandwich method is widely used.
- Nucleic acid or immunochromatography uses noble metal colloidal particles such as gold, silver or platinum, metal oxide colloidal particles such as iron oxide, latex particles, etc. as labeling substances in order to label nucleic acids or antigens that are the object of analysis. It is preferable to use colloidal gold particles.
- the average particle size of these colloidal metal particles is preferably 1 to 500 nm, preferably 10 nm to 150 nm, and more preferably 40 to 100 nm, at which a particularly strong color tone can be obtained.
- the labeling substance forms a complex with a protein capable of binding to the analyte, a complementary nucleic acid or antibody having specific binding ability, and is used as a labeling reagent for labeling the analyte.
- any mode can be used as long as it can be developed at the same time as the sample containing the analysis target or later.
- the labeling reagent is dried and held in any part of the chromatographic medium, and then the developing solution and sample diluent are supplied and dropped onto the sample pad (sample addition part) on the upstream side, and developed to elute from the labeling reagent holding part. Can be deployed. Further, it can be dispersed in a developing solution or a diluting solution to form a dispersion, which can be developed and used on a chromatographic medium. From the viewpoint of storage, it is preferable that the labeling reagent is dried and held in advance in an arbitrary portion of the chromatographic medium.
- the reagent composition of the present invention comprises a blocking agent such as bovine serum albumin, protein derived from milk, skim milk, casein, gelatin, etc., as well as Blocking Peptide Fragment (TOYOBO), denatured fish DNA, yeast-derived tRNA, CE510 (JSR Corporation It is preferable to include a blocking agent such as a commercially available hydrophilic polymer. By allowing the blocking agent to coexist, the background can be lowered without lowering the sensitivity, so the S / N ratio can be improved.
- a blocking agent such as bovine serum albumin, protein derived from milk, skim milk, casein, gelatin, etc.
- TOYOBO Blocking Peptide Fragment
- denatured fish DNA yeast-derived tRNA
- CE510 JSR Corporation
- a blocking agent such as a commercially available hydrophilic polymer.
- the reagent composition of the present invention is not limited to phosphate, trishydroxymethylaminomethane hydrochloride, amino acid such as carbonate, glycine, buffer such as Good Buffer, nucleic acid, or immunochromatography as long as the effects of the present invention are exhibited. Ingredients conventional for reagent compositions can be included.
- the reagent composition of the present invention can be used as a developing solution in nucleic acid or immunochromatography.
- a developing solution water is usually used as a solvent, and a water-soluble polymer compound having a weight average molecular weight of 8000 or more, a divalent or trivalent metal salt, a nonionic surfactant, and a water-soluble aprotic compound.
- Add organic compounds The order of addition is not particularly specified, and they can be added simultaneously.
- a sample containing the analyte to be detected and a developing solution mixed in advance may be supplied and dropped on a chromatographic medium, a labeled reagent holding site, or a sample pad for development.
- the sample may be supplied and dropped on the sample pad first, and then the developing solution may be supplied and dropped on the sample pad to be developed.
- the diluted solution obtained by diluting the sample can be used by supplying and dropping it directly as a developing solution onto a chromatographic medium, a labeled reagent holding site, or a sample pad.
- the reagent composition of the present invention can be held in advance on a sample pad or a dry holding site of a labeling reagent.
- the reagent composition of the present invention used as a diluent and the reagent composition of the present invention held at the dry holding site of the sample pad or labeling reagent are used as a developing solution or a part thereof in the subsequent steps.
- the labeling reagent is held at the dry holding site, since some agglomeration may be multiplied during the development, a mode in which the labeling reagent is held in advance in the developing solution, the diluted solution or a part thereof, or the sample pad is preferable.
- the analyte of the present invention is not particularly limited as long as a substance that specifically binds to it exists or can be produced.
- “Specifically binds” means to bind based on the affinity of a biomolecule. As such a binding based on affinity, the binding between an antigen and an antibody is typical and widely used in immunoassays.
- a sugar and a lectin A bond between a hormone and a receptor, a bond between an enzyme and an inhibitor, a nucleic acid complementary to a nucleic acid, a bond with a protein capable of binding a nucleic acid and a nucleic acid, and the like.
- the analyte is antigenic itself, such as a complete antigen, or is not itself antigenic, such as a hapten (incomplete antigen), the antigenicity can be improved by making it a chemically modified product. It may be something that you have. Any detection substance that specifically binds to or can be produced by these analytes may be used. Examples of detection substances include nucleic acids complementary to the analyte nucleic acids or nucleic acid binding proteins, monoclonal antibodies, polyclonal antibodies, etc. Is mentioned.
- Examples of the analysis object of the present invention include nucleic acid (single-stranded nucleic acid or double-stranded nucleic acid) contained in cultured cell lines, peripheral blood, microorganisms such as bacteria and viruses, or amplified products thereof, carcinoembryonic antigen ( CEA), HER2 protein, prostate specific antigen (PSA), CA19-9, ⁇ -fetoprotein (AFP), immunosuppressive acidic protein (IPA), CA15-3, CA125, estrogen receptor, progesterone receptor, fecal occult blood, troponin I, Troponin T, CK-MB, CRP, human chorionic gonadotropin (HCG), luteinizing hormone (LH), follicle stimulating hormone (FSH), syphilis antibody, influenza virus, chlamydia antigen, group A ⁇ -streptococcal antigen, HBs antibody, HBs Antigen, rotavirus, adenovirus, albumin, glyc
- nucleic acids contained in cultured cell lines, peripheral blood or microorganisms such as bacteria and viruses are used, and specific examples include DNA, RNA, oligonucleotides, polynucleotides, amplified products thereof and the like.
- the nucleic acid itself may be an analysis target, or the nucleic acid may be a nucleic acid modified with a binding group or a binding protein having a binding ability with a labeling reagent.
- sample containing the substance to be detected examples include biological samples, that is, whole blood, serum, plasma, urine, saliva, sputum, nasal cavity or throat swab, cerebrospinal fluid, amniotic fluid, nipple discharge, tears, sweat, skin
- biological samples that is, whole blood, serum, plasma, urine, saliva, sputum, nasal cavity or throat swab, cerebrospinal fluid, amniotic fluid, nipple discharge, tears, sweat, skin
- leachate from milk, extracts from tissues, cells and stool, and the like milk, eggs, wheat, beans, beef, pork, chicken, and other foods containing them, and the like.
- a nucleic acid extract from cultured cell lines, peripheral blood or microorganisms such as bacteria and viruses
- a solution containing an amplified product of the extracted nucleic acid or a binding group or protein that binds to these nucleic acids. Examples include, but are not limited to, a solution containing the prepared nucleic
- FIG. An example of the detection method is shown in FIG.
- I Collect an analytical sample (eg, runny nose).
- IIi Extracting genes such as viruses from the analysis sample.
- the extracted gene or the like is amplified by a PCR method or the like using a gene amplification apparatus.
- IIv A gene or the like is added to the immunoassay kit.
- V A developing solution is added to develop genes and the like.
- Vi For example, positive or negative is determined after 15 minutes.
- the determination method is shown in FIG. A positive or negative determination is made based on the presence or absence of a red line. If a red line appears in the Test line (T position), the target virus or the like is positive (FIG. 2A), and if it does not appear, the target virus or the like is negative (FIG. 2B).
- the internal control line (position I) detects the patient's own normal human cells that are included when a specimen such as a virus is collected from the patient's nose or the like. Therefore, the internal control line appears when the sample collection is inappropriate (for example, when nasal swabs are insufficient) or when there is a problem with amplification (PCR) of genes, etc. Without inspection, the inspection will be redone.
- the Flow control line (C position) does not appear, it means that the measurement has failed, and re-inspection occurs.
- FIG. 3 shows the measurement principle.
- An amplification gene eg, biotin-modified and amplified single-stranded DNA
- a labeling substance eg, gold colloid
- the amplified gene-gold colloid complex moves on the DNA fixed to the T line and the I line by capillary action.
- a complementary DNA that binds only to DNA derived from the target virus is fixed on the T line, and a complementary DNA that binds only to DNA derived from normal human cells is fixed in advance on the I line. Form a line.
- a biotin-labeled protein that binds to a labeling substance for example, streptavidin-conjugated gold colloid
- a labeling substance for example, streptavidin-conjugated gold colloid
- the present invention further relates to a method for measuring nucleic acid or immunochromatography, and this method includes a step of developing a sample to be measured using the reagent composition.
- This step includes a mode in which the reagent composition is used as a diluent for the measurement sample, or is held in advance on a sample pad, and this is used as at least a part of a developing solution during subsequent development.
- the present invention is a kit for measuring a nucleic acid or immunochromatography, and this kit contains the reagent composition described above as a developing solution for a measurement sample.
- This kit includes the above-described reagent composition as a diluent for a measurement specimen, or an embodiment in which the reagent composition is held in advance on a sample pad and used as a developing solution after dilution. That is, the developing solution can be used for pre-mixing with a sample containing the analyte to be detected, and this mixed solution is supplied and dropped on a chromatographic medium, a labeling reagent holding site, or a sample pad for development. You can also. Alternatively, the sample may be supplied and dropped on the sample pad first, and then the developing solution may be supplied and dropped on the sample pad to be developed.
- the diluted solution obtained by diluting the sample can be used by supplying and dropping the developing solution directly onto the chromatographic medium, the labeling reagent holding site, or the sample pad as the developing solution.
- the developing solution can be held in advance in a dry holding portion of the sample pad or the labeling reagent in nucleic acid or immunochromatography.
- the developing solution used as a diluent, the developing solution held in the dry holding portion of the sample pad or the labeling reagent is used as all or a part of the developing solution in the subsequent developing step.
- the labeling reagent is held at the dry holding site, it is not preferable because some agglomeration may be multiplied during the development, and the reagent composition is used as a developing solution (including use as a diluent) or a part thereof, or An embodiment in which the sample pad is previously held is preferable.
- nucleic acid chromatography [1. Preparation of dilution solution for capture probe) 87.7 g of sodium chloride and 44.1 g of sodium citrate dihydrate were weighed, dissolved in 800 mL of purified water, and adjusted to pH 7.0. The solution was made up to 1000 mL and sterilized by autoclave to prepare a capture probe dilution.
- reaction sites on chromatographic media The influenza A virus capture probe was diluted with a probe diluent to a concentration of 2.0 ⁇ M. This solution was applied to a 25 ⁇ 2.5 cm nitrocellulose membrane (Millipore) using a coating machine (BioDot), dried at 50 ° C. for 5 minutes, and further dried at 80 ° C. for 1 hour. Reaction sites on the chromatographic medium.
- Example 1 to 8 and Comparative Examples 1 to 4 CE510 (JSR) was added to ultrapure water in the amounts shown in Table 1 to 10% Tween 20, 0.1 M magnesium sulfate, dimethyl sulfoxide, 20% dextran sulfate sodium (weight average molecular weight: 500,000), and 2%. (Corporation) was added and mixed. Further, 10% sodium azide as a preservative was added to 0.05% and mixed to obtain a reagent composition.
- Example 9 to 14 and Comparative Examples 5 to 9 In ultrapure water, a water-soluble polymer having a weight average molecular weight of 8000 or more is 2%, a divalent or trivalent metal salt is 5 mM, a nonionic surfactant is 1%, as shown in Table 2. A water-soluble aprotic organic compound was added to 0.95%, and CE510 (JSR Corporation) was added to 2% and mixed. Furthermore, 10% sodium azide as a preservative was added to and mixed at 0.05% to obtain reagent compositions of Examples 9-14.
- the color development intensity was visually evaluated after 10 minutes of sample development according to the following criteria. +++: Very strongly confirmed red color of the labeling substance. ++: Strongly confirmed red color of the labeling substance. +: The red of the labeling substance is confirmed. ⁇ : The color is weak and the red color of the labeling substance is difficult to confirm. -: The labeling substance is not red. Unevenness of development was evaluated by visually observing the tip flow shape of the red gold colloid during development.
- reaction sites on chromatographic media An influenza A virus capture antibody (mouse-derived anti-influenza A monoclonal antibody (first antibody)) was diluted with an antibody diluent to a concentration of 1.0 mg / ml. This solution was applied to a 25 ⁇ 2.5 cm nitrocellulose membrane (Millipore) using a coating machine (BioDot), dried at 50 ° C. for 5 minutes, and further dried at room temperature for 1 hour. Thus, reaction sites on the chromatographic medium were prepared.
- the labeling reagent solution was prepared by the above procedure.
- Example 15 and Comparative Examples 10 to 13 As shown in Table 5, 1% 10% Tween20, 5 mM 0.1M magnesium sulfate, 0.95% dimethyl sulfoxide, 20% sodium dextran sulfate (weight average molecular weight: 500,000) were added to ultrapure water. 2% and CE510 (JSR Corporation) were added to 2% and mixed. Furthermore, 10% sodium azide as a preservative was added to 0.05% and mixed to obtain the reagent compositions of Example 15 and Comparative Examples 10-13.
- the presence or absence of influenza A virus in the sample was measured by the following method.
- One tube of the suction trap was inserted into the suction pump, and the other tube was inserted into the back of the nasal cavity of a person who was not infected with influenza A, and the suction pump was set to a negative pressure to collect nasal discharge.
- the collected nasal discharge was diluted 20 times with the above-prepared developing solution, and this was used as a negative specimen sample.
- what added commercially inactivated influenza A virus so that protein concentration might be 25 ng / mL and 50 ng / mL to the negative sample sample was made into the positive sample sample.
- Test Example 1 150 ⁇ L of both the negative specimen sample and the positive specimen sample was placed on the sample pad of the immunochromatographic test piece and developed, and visually judged after 15 minutes. The standards for color development intensity and development unevenness were the same as those for nucleic acid chromatography. The test results are shown in Table 6.
- the binding due to the non-specific reaction of components other than the analyte is reduced, the dispersibility of the analyte is increased, and the specific reaction is promoted. Even when using a low-concentration analyte, an accurate and quick judgment can be made.
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Abstract
Description
しかし、いずれの添加物の組み合わせも、未だ、非特異的な反応の抑制や感度、クロマト担体上の展開性の向上は十分には達成されていない。
重量平均分子量8000以上の水溶性高分子化合物は、重量平均分子量が8000以上であり、かつ、水溶性を有する化合物であれば特に限定されない。重量平均分子量は、10000以上であるのが好ましい。前記水溶性高分子は重量平均分子量8000以上であれば重量平均分子量既知の市販の化合物を用いることができる。合成したものを用いる場合は、高分子の分子量測定に汎用されるゲル浸透クロマトグラフィー(以下GPC)により測定された重量平均分子量が8000以上のものを使用する。重量平均分子量が8000未満の場合、核酸のハイブリダイゼーションや抗原抗体反応に見られる分析対象物との特異的複合体を形成させる結合力が低下し、クロマトグラフィーによる検出感度が低下してしまう。より好ましくは重量平均分子量2万~100万の水溶性高分子が用いられる。重量平均分子量8000以上の水溶性高分子化合物における「水溶性」とは、20℃の水1Lに対して、化合物が10g以上、好ましくは50g以上溶解することをいう。
2価又は3価の金属は、2価又は3価の金属であれば特に限定されないが、例えば、マグネシウム、カルシウム等のアルカリ土類金属(2価)、ホウ素、アルミニウム等のアルミニウム族金属(3価)が挙げられ、好ましくはマグネシウム、カルシウム又はアルミニウムであり、特に好ましくはマグネシウム又はカルシウムであり、最も好ましくはマグネシウムである。アルカリ金属(1価)を用いた場合、展開速度が低下し、かつ、非特異反応も増大してしまう。
2価又は3価の金属の塩は、免疫複合体の非特異反応を起こさず毛細管現象の展開速度を高める。
非イオン性界面活性剤は、例えば、ポリオキシエチレンアルキルエーテル、ポリオキシエチレンアルキルフェノールエーテル、アルキルグルコシド、ポリオキシエチレン脂肪酸エステル、ショ糖脂肪酸エステル、ソルビタン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、脂肪酸アルカノールアミドが挙げられる。非イオン性界面活性剤のHLBは、10~18が好ましく、13~18がより好ましい。非イオン性界面活性剤としては、ポリオキシエチレンソルビタン脂肪酸エステルが好ましく、例えば、モノラウリン酸ポリオキシエチレンソルビタン、モノステアリン酸ポリオキシエチレンソルビタン、トリステアリン酸ポリオキシエチレンソルビタン及びモノオレイン酸ポリオキシエチレンソルビタンからなる群から選択される1種以上が特に好ましい。
水溶性非プロトン性有機化合物は、水溶性であり、プロトン性を有しない有機化合物であれば特に限定されない。「水溶性」とは、相分離することなく、水と任意の比率で混合されうる性質を意味し、好ましくは、20℃の水1Lに対して、化合物が10g以上、好ましくは50g以上溶解する有機化合物である。「非プロトン性」とは、酸性水素を含まず、水素結合供与体として作用しない性質を意味する。
本発明の試薬組成物は、核酸又は免疫クロマトグラフィーに用いられるものである。
核酸クロマトグラフィーは、核酸のハイブリダイゼーションに基づくものである。
本発明の試薬組成物は、本発明の効果を奏する限り、リン酸塩、トリスヒドロキシメチルアミノメタン塩酸塩、炭酸塩、グリシンなどのアミノ酸、グッドバッファーなどの緩衝剤、核酸又は免疫クロマトグラフィー用の試薬組成物として慣用の成分を含むことができる。
上記被検出物質を含む試料としては、例えば、生体試料、即ち、全血、血清、血漿、尿、唾液、喀痰、鼻腔又は咽頭拭い液、髄液、羊水、乳頭分泌液、涙、汗、皮膚からの浸出液、組織や細胞及び便からの抽出液等の他、牛乳、卵、小麦、豆、牛肉、豚肉、鶏肉などやそれらを含む食品等の抽出液等が挙げられる。また、培養細胞株、末梢血あるいは細菌、ウィルス等の微生物等に含まれる核酸の抽出液、抽出された核酸の増幅物を含む液、あるいはそれら核酸と結合能を有する結合基や結合蛋白質で修飾された核酸を含む液が挙げられるがこれらに限定されない。
検出方法の例を図1に示す。(i)分析試料(例えば、鼻水)を採取する。(ii)分析試料からウィルス等の遺伝子等を抽出する。(iii)必要に応じて、抽出した遺伝子等をPCR法等により遺伝子増幅装置を用いて増幅する。(iv)遺伝子等を免疫測定用キットに添加する。(v)展開液を添加して遺伝子等を展開する。(vi)例えば15分後に、陽性又は陰性を判定する。
判定方法を図2に示す。陽性又は陰性の判定は、赤いラインの有無で決定する。Testライン(T位置)に赤いラインが現れれば、対象ウィルス等陽性(図2(a))、出現しなければ、対象ウィルス等陰性(図2(b))となる。この時internalコントロールライン(I位置)は、患者の鼻等からウィルス等の検体を採取する際に一緒に含まれる患者自身の正常ヒト細胞を検出する。そのため検体採取の際の分析試料の採取が不適切な場合(例えば、鼻腔ぬぐいが不十分な場合)や、あるいは遺伝子等の増幅(PCR)に不具合が生じた場合には、internalコントロールラインが出現せず、検査のやり直しとなる。またFlowコントロールライン(C位置)が出現しない場合は、測定に不具合が生じたこととなり、再検査となる。
図3に測定原理を示す。免疫測定用キットに添加された増幅遺伝子(例えばビオチン修飾され増幅された一本鎖DNA)等は、標識物質(例えば、金コロイド)に、例えばビオチン-ストレプトアビジンを介して結合する。その後、展開液を添加すると、増幅遺伝子-金コロイド複合体は毛細管現象によりTライン及びIラインに固定されたDNA上を移動する。Tラインには対象ウィルス等由来のDNAにのみ結合する相補DNAが、Iラインには正常ヒト細胞由来のDNAにのみ結合する相補DNAがあらかじめ固定されているため、陽性の場合は金コロイドによる赤いラインを形成する。
本発明は核酸又は免疫クロマトグラフィー測定キットであり、このキットは、前記の試薬組成物を測定検体の展開液として含む。このキットは、前記の試薬組成物を測定検体の希釈剤として含むか、あるいは、サンプルパッド等に予め保持し、希釈後に、これが展開液として使用される態様も含む。すなわち、展開液は、検出する分析対象物を含む試料と予め混合するために使用でき、この混合液をクロマトグラフ媒体、標識試薬保持部位、あるいは、サンプルパッド上に供給・滴下して展開させることもできる。また、先に試料をサンプルパッド上に供給・滴下して後、展開液をサンプルパッド上に供給・滴下して展開させてもよい。展開液を試料希釈液として使用する場合には、試料を希釈した希釈液は、そのまま展開液としてクロマトグラフ媒体、標識試薬保持部位、あるいはサンプルパッド上に供給・滴下することにより使用できる。その他に、展開液は、核酸又は免疫クロマトグラフィーにおいて、サンプルパッドや標識試薬の乾燥保持部位に予め保持させることもできる。希釈剤として使用された展開液やサンプルパッドあるいは標識試薬の乾燥保持部位に保持された展開液は、その後の展開工程における展開液の全部又はその一部として使用される。標識試薬の乾燥保持部位に保持させる場合、展開の際に多少の凝集が乗じることがあるため好ましくなく、前記の試薬組成物を展開液(希釈液としての使用を含む)又はその一部、あるいはサンプルパッドに予め保持させる態様が好ましい。
〔1.捕獲プローブ用希釈液の作成〕
塩化ナトリウムを87.7g、及びクエン酸ナトリウム2水和物を44.1g秤量し、精製水800mLに溶解し、pH7.0に調整した。この溶液を1000mLにメスアップして、オートクレーブ滅菌を行って捕獲プローブ用希釈液を作成した。
インフルエンザAウィルス捕獲プローブをプローブ用希釈液で2.0μMの濃度になるように希釈した。この液を、塗布機(BioDot社製)を用いて、25×2.5cmのニトロセルロース膜(ミリポア社製)に塗布し、50℃で5分間乾燥させた後、さらに80℃で1時間乾燥させてクロマトグラフ媒体上の反応部位を作製した。
金コロイド懸濁液(田中貴金属工業社製:平均粒子径40nm)20mLに40mMのリン酸緩衝液(pH8.5)1mLを加えて撹拌した。次に、リン酸緩衝液(pH8.5)で0.01mg/mLの濃度になるように希釈したストレプトアビジンを4mL加え、室温で15分間静置した。次いで、CE510(JSR Corporation)を1mL加え、室温で15分間静置した。8000×gで15分間遠心分離を行った。遠心分離後、上清を除去し、1重量%の牛血清アルブミン(BSA)を含む緩衝液(pH7.4)4mLを加えて標識試薬溶液を作成した。
上記3で作製した標識試薬溶液400μLをグラスファイバー製パッド(16mm×100mm)に均一になるように添加した後、真空乾燥機にて乾燥させ、標識試薬保持部材とした。次いで、バッキングシートから成る基材に、上記調製したクロマトグラフ媒体、標識試薬保持部材、試料を添加する部分に用いるサンプルパッド(ミリポア社製:300mm×30mm)、及び展開した試料、余剰の標識試薬を吸収するための吸収パッドを貼り合わせた。最後に裁断機で幅が5mmとなるように裁断し、クロマトグラフ媒体とした。
(実施例1~8及び比較例1~4)
表1に記載の量で、超純水に、10%Tween20、0.1M硫酸マグネシウム、ジメチルスルホキシド、20%デキストラン硫酸ナトリウム(重量平均分子量:50万)、及び2%となるようにCE510(JSR Corporation)を加えて混和した。さらに防腐剤として10%アジ化ナトリウムを0.05%となるように加えて混和して試薬組成物を得た。
超純水に、表2に示すような種類で、重量平均分子量8000以上の水溶性高分子を2%、2価又は3価の金属の塩を5mM、非イオン性界面活性剤を1%、水溶性非プロトン性有機化合物を0.95%、及びCE510(JSR Corporation)を2%となるように加えて混和した。さらに防腐剤として10%アジ化ナトリウムを0.05%となるように加え混和して実施例9~14の試薬組成物を得た。
上記作製したクロマトグラフ媒体を用いて、以下の方法で試料中のインフルエンザAウィルスの存在の有無を測定した。すなわちインフルエンザウイルス感染患者の鼻水から抽出したインフルエンザAウィルスの遺伝子を増幅する際にビオチンで修飾され一本鎖DNAとして増幅し、2.0×106 copies/μL(copy=複製物1分子)の陽性検体を得た。この15μLを試料添加孔に添加した。その後、ただちに展開液100μLを試料添加孔に添加した。15分後にラインの形成の有無を目視で確認した。尚、インフルエンザAウィルスに感染していない正常人から採取した陰性検体も、鼻水から抽出し同様に作成及び測定した。
分析対象物(DNA量)とラインの色の濃さ(すなわち発色強度)との間に、y=βMの関係が成り立つとして考えた(表4)。その理由は、金コロイドおよびニトロセルロース膜に固定された相補DNAは十分量用意されているため、添加したDNAの量に応じてニトロセルロース膜のTラインあるいはIライン上に形成される複合体の量が増加し、強い発色強度が得られることになるからである。分析試料にDNAが入っていない場合は金コロイドのみが展開液とともに展開されるが、この金コロイドは膜に固定されたDNAと反応することはなく、Tラインが形成されることはない。
+++:非常に強く標識物質の赤色が確認されるもの。
++ :強く標識物質の赤色が確認されるもの。
+ :標識物質の赤色が確認されるもの。
± :発色が弱く標識物質の赤色が確認し難いもの。
- :標識物質の赤色が確認されないもの。
展開ムラは、展開中の赤色金コロイドの先端流形を目視する方法で評価した。
実施例9~14及び比較例5~9の試薬組成物を展開液として用いて、陽性検体の4倍希釈液、6倍希釈液及び8倍希釈液並びに陰性検体のそれぞれの発色及び展開ムラを試験した。その結果を表4に示す。
〔1.捕獲抗体用希釈液の作成〕
イソプロピルアルコールを50mMリン酸緩衝液(pH7.4)で5%となるように混和希釈し捕獲抗体用希釈液を作成した。
インフルエンザAウィルス捕獲抗体(マウス由来抗インフルエンザAモノクローナル抗体(第一抗体))を抗体用希釈液で1.0mg/mlの濃度になるように希釈した。この液を、塗布機(BioDot社製)を用いて、25×2.5cmのニトロセルロース膜(ミリポア社製)に塗布し、50℃で5分間乾燥させた後、さらに室温で1時間乾燥させてクロマトグラフ媒体上の反応部位を作製した。
金コロイド懸濁液(田中貴金属工業社製:平均粒子径40nm)0.5mlに、リン酸緩衝液(pH7.4)で0.05mg/mlの濃度になるように希釈したマウス由来抗インフルエンザAモノクローナル抗体(第二抗体)を0.1ml加え、室温で10分間静置した。次いで、1重量%の牛血清アルブミン(BSA)を含むリン酸緩衝液(pH7.4)を0.1ml加え、更に室温で10分間静置した。その後、十分撹拌した後、8000×gで15分間遠心分離を行い、上清を除去した後、0.5重量%のBSAを含むリン酸緩衝液(pH7.4)を2ml加えた。以上の手順で標識試薬溶液を作製した。
上記作製した標識試薬溶液を15mm×300mmのグラスファイバーパッド(ミリポア社製)に均一になるように添加した後、真空乾燥機にて乾燥させ、標識試薬保持部材を作製した。次に、バッキングシートから成る基材に、上記作製したクロマトグラフィー媒体、標識試薬保持部材、試料を添加する部分に用いるサンプルパッド(ミリポア社製:300mm×30mm)、及び展開した試料、余剰の標識試薬を吸収するための吸収パッドを貼り合わせた。最後に裁断機で幅が5mmとなるように裁断し、クロマトグラフ媒体とした。
(実施例15及び比較例10~13)
表5に記載するように、超純水に、10%Tween20を1%、0.1M硫酸マグネシウムを5mM、ジメチルスルホキシドを0.95%、20%デキストラン硫酸ナトリウム(重量平均分子量:50万)を2%、及びCE510(JSR Corporation)を2%となるように加えて混和した。さらに、防腐剤として10%アジ化ナトリウムを0.05%となるように加えて混和して、実施例15及び比較例10~13の試薬組成物を得た。
上記で作製したクロマトグラフ媒体を用いて、以下の方法で試料中のインフルエンザAウィルスの存在の有無を測定した。吸引トラップの片方の管を吸引ポンプに、もう片方の管をインフルエンザAに感染していない人の鼻腔の奥部まで挿入し、吸引ポンプを陰圧にして鼻汁を採取した。採取した鼻汁を上記作成した展開液で20倍に希釈し、これを陰性検体試料とした。また、陰性検体試料に、蛋白濃度が25ng/mL、50ng/mLとなるように市販の不活化インフルエンザAウィルスを加えたものを陽性検体試料とした。
陰性検体試料、陽性検体試料とも150μLをイムノクロマトグラフィー用試験片のサンプルパッド上に載せて展開させ、15分後に目視判定をした。発色強度及び展開ムラの基準は核酸クロマトグラフィーと同様の基準とした。
試験結果を表6に示す。
2:増幅した遺伝子
3:展開液
4:陰性の発色ストリップ
5:陽性の発色ストリップ
6:増幅したDNA
7:展開液
8:金コロイド
9:膜固定プローブ
10:ニトロセルロース膜
Claims (13)
- 重量平均分子量8000以上の水溶性高分子化合物、2価又は3価の金属の塩、非イオン性界面活性剤、及び、水溶性非プロトン性有機化合物を含有する核酸又は免疫クロマトグラフィー用試薬組成物。
- 重量平均分子量8000以上の水溶性高分子化合物が、ポリアルキレングリコール類、セルロース類、ビニル系高分子類、アミド系高分子類及びポリアニオンからなる群から選択される1種以上である、請求項1に記載の試薬組成物。
- ポリアニオンが多糖アニオンである、請求項2に記載の試薬組成物。
- 多糖アニオンが、デキストラン硫酸、ヘパラン硫酸、コンドロイチン硫酸、デルマタン硫酸、ケラタン硫酸、ヒアルロン酸、ヘパリン及びその塩からなる群から選択される1種以上である、請求項3に記載の試薬組成物。
- 水溶性非プロトン性有機化合物が、スルホキシド類及びN,N’-ジアルキルアミド類からなる群から選択される1種以上である、請求項1~4のいずれか1項に記載の試薬組成物。
- 2価又は3価の金属の塩が、マグネシウム塩、カルシウム塩及びアルミニウム塩からなる群から選択される1種以上である、請求項1~5のいずれか1項に記載の試薬組成物。
- 非イオン性界面活性剤が、モノラウリン酸ポリオキシエチレンソルビタン、モノステアリン酸ポリオキシエチレンソルビタン、トリステアリン酸ポリオキシエチレンソルビタン及びモノオレイン酸ポリオキシエチレンソルビタンからなる群から選択される1種以上である、請求項1~6のいずれか1項に記載の試薬組成物。
- 核酸クロマトグラフィー用である、請求項1~7のいずれか1項に記載の試薬組成物。
- 免疫クロマトグラフィー用である、請求項1~7のいずれか1項に記載の試薬組成物。
- 核酸又は免疫クロマトグラフィーが金コロイド粒子を標識物質として使用する、請求項1~9のいずれか1項に記載の試薬組成物。
- 核酸又は免疫クロマトグラフィーにおける展開液として使用する、請求項1~10のいずれか1項に記載の試薬組成物。
- 請求項1~11のいずれか1項に記載の試薬組成物を用いて測定検体を展開する工程を含む、核酸又は免疫クロマトグラフィー測定方法。
- 請求項1~11のいずれか1項に記載の試薬組成物を測定検体の展開液として含む、核酸又は免疫クロマトグラフィー測定用キット。
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JP6651794B2 (ja) * | 2015-11-05 | 2020-02-19 | 富士レビオ株式会社 | 心筋トロポニンi測定試薬及び方法 |
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JP6371808B2 (ja) * | 2016-08-09 | 2018-08-08 | 積水メディカル株式会社 | イムノクロマトグラフィー検出キット |
JP6426872B1 (ja) * | 2018-08-02 | 2018-11-21 | 積水メディカル株式会社 | イムノクロマト用試験片及びイムノクロマト検出キット |
CN111770955B (zh) * | 2018-11-01 | 2022-12-23 | 韩国浦项科技大学校企公司 | 包含非共价连接的有机纳米结构分子的硝酸纤维素膜 |
JPWO2021045061A1 (ja) * | 2019-09-02 | 2021-03-11 | ||
KR20240019075A (ko) * | 2021-06-07 | 2024-02-14 | 덴카 주식회사 | 분변 검체의 검사 방법 및 그것을 위한 이뮤노크로마토그래피 시험편 |
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CN113874522A (zh) * | 2019-05-29 | 2021-12-31 | 藤仓化成株式会社 | 固相附着用组合物、利用该组合物的固相载体以及该固相载体的生产方法和使用方法 |
Also Published As
Publication number | Publication date |
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JP4638555B1 (ja) | 2011-02-23 |
EP2615457A1 (en) | 2013-07-17 |
CA2810789A1 (en) | 2012-03-15 |
AU2011300193A1 (en) | 2013-04-18 |
CN103097895B (zh) | 2015-07-01 |
JP2012058058A (ja) | 2012-03-22 |
KR20130138775A (ko) | 2013-12-19 |
EP2615457B1 (en) | 2016-01-13 |
US20130171740A1 (en) | 2013-07-04 |
CA2810789C (en) | 2017-05-23 |
AU2011300193B2 (en) | 2015-05-14 |
EP2615457A4 (en) | 2014-03-05 |
CN103097895A (zh) | 2013-05-08 |
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