WO2022054907A1 - 表面増強ラマン散乱剤 - Google Patents

表面増強ラマン散乱剤 Download PDF

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Publication number
WO2022054907A1
WO2022054907A1 PCT/JP2021/033306 JP2021033306W WO2022054907A1 WO 2022054907 A1 WO2022054907 A1 WO 2022054907A1 JP 2021033306 W JP2021033306 W JP 2021033306W WO 2022054907 A1 WO2022054907 A1 WO 2022054907A1
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Prior art keywords
enhanced raman
raman scattering
noble metal
scattering agent
equol
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PCT/JP2021/033306
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English (en)
French (fr)
Japanese (ja)
Inventor
基史 鈴木
美沙 鐘川
今日子 名村
隆夫 福岡
クマール サミール
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Daicel Corp
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Daicel Corp
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Priority to US18/026,059 priority Critical patent/US20230358683A1/en
Priority to EP21866864.8A priority patent/EP4212855A4/en
Priority to JP2022548353A priority patent/JPWO2022054907A1/ja
Priority to CN202180062509.7A priority patent/CN116057369A/zh
Publication of WO2022054907A1 publication Critical patent/WO2022054907A1/ja
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/65—Raman scattering
    • G01N21/658—Raman scattering enhancement Raman, e.g. surface plasmons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y15/00—Nanotechnology for interacting, sensing or actuating, e.g. quantum dots as markers in protein assays or molecular motors
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y20/00—Nanooptics, e.g. quantum optics or photonic crystals

Definitions

  • the present disclosure relates to a surface-enhanced Raman scattering agent, a method for performing quantification by Raman spectroscopy using the surface-enhanced Raman scattering agent, and a kit for carrying out the quantification.
  • This disclosure claims the priority of Japanese Patent Application No. 2020-153721 filed in Japan on September 14, 2020, the contents of which are incorporated herein by reference.
  • Raman spectroscopy is an analytical method that identifies a substance from the spectrum of scattered light generated when the substance is irradiated with light.
  • the problem with Raman spectroscopy is its low sensitivity.
  • Patent Document 1 describes a surface-enhanced Raman scattering substrate in which silica coated with a metal is laminated on the surface of a glass substrate, and a sample is placed on the substrate by Raman spectroscopy. It is stated that analysis can obtain the effect of enhancing Raman scattering and can be measured with high sensitivity.
  • Non-Patent Document 1 describes a surface-enhanced Raman scattering agent having a microcolumnar body constructed on a flexible sheet by a dynamic diagonal vapor deposition method.
  • Non-Patent Document 2 describes a surface-enhanced Raman scattering agent in which a noble metal nanostructure is supported on nanocellulose.
  • the surface-enhanced Raman scattering substrate described in Patent Document 1 has a problem that the usage method is limited. For example, even if the biomarker is measured directly from the skin surface of the subject, the surface-enhanced Raman scattering substrate is hard and rigid and lacks flexibility. Therefore, the surface-enhanced Raman scattering substrate is used at the inspection site. It could not be followed, and the surface-enhanced Raman scattering effect could not be obtained. In addition, it is also difficult to perform surface-enhanced Raman scattering measurement by fixing the surface-enhanced Raman scattering substrate along the uneven surface of a Raman measuring instrument with a sample collection function (for example, a curved surface such as a toilet or a potty chair). there were.
  • a sample collection function for example, a curved surface such as a toilet or a potty chair
  • Non-Patent Documents 1 and 2 has flexibility as compared with the surface-enhanced Raman scattering substrate described in Patent Document 1, but the method of use is still limited.
  • an object of the present disclosure is to provide a surface-enhanced Raman scattering agent that enables highly sensitive quantification by Raman spectroscopy and is applicable to various usage methods.
  • Another object of the present disclosure is to provide a surface-enhanced Raman scattering agent capable of directly performing surface-enhanced Raman scattering measurement by adhering it to the skin surface of a subject or fixing it to a Raman measuring instrument with a sample collection function. There is something in it.
  • Another object of the present disclosure is to provide a surface-enhanced Raman scattering measurement kit applicable to various measurement methods.
  • Another object of the present disclosure is to provide a surface-enhanced Raman scattering measuring method using the surface-enhanced Raman scattering agent.
  • Another object of the present disclosure is to provide a method for producing the surface-enhanced Raman scattering agent.
  • the surface-enhanced Raman scattering substrate in which the surface-enhanced Raman scattering agent is fixed to the glass substrate exhibits rigidity and lacks flexibility. Since the viscous dispersion liquid in which thin pieces having a noble metal layer and / or noble metal particles are dispersed in the viscous liquid has flexibility or fluidity, it can be applied to various usage methods. The use of viscous dispersions dramatically enhances the Raman scattered light enhancement effect by significantly enhancing the local electric field that occurs when local plasmons are excited, thereby increasing the sensitivity of Raman spectroscopy. It was found that the amount of light is improved and trace quantification is possible. This disclosure has been completed based on these findings.
  • the present disclosure describes a viscous liquid having a viscosity of 50 mPa ⁇ s or more at 25 ° C. and a shear rate of 10 (1 / s).
  • the precious metal-containing thin pieces dispersed in the viscous liquid and Provided is a surface-enhanced Raman scattering agent containing.
  • the present disclosure also provides the surface-enhanced Raman scatterer in which the precious metal is gold, silver, or copper.
  • the present disclosure is also a structure in which the noble metal-containing thin pieces are forested with microcolumnar bodies on the surface of the thin pieces, and the fine columnar bodies are at least partially formed of a noble metal layer or noble metal particles.
  • the surface-enhanced Raman scattering agent is provided.
  • the present disclosure also provides the surface-enhanced Raman scattering agent, wherein the shards are slabs made of an inorganic oxide having a hydroxyl group.
  • the present disclosure also provides the surface-enhanced Raman scatterer, wherein the flakes are flakes of glass, silica, talc, mica, or titanium oxide.
  • the present disclosure also provides a surface-enhanced Raman scattering measurement kit containing the surface-enhanced Raman scattering agent.
  • the present disclosure also provides a surface-enhanced Raman scattering measurement method for performing surface-enhanced Raman scattering measurement using the surface-enhanced Raman scattering agent.
  • the present disclosure is also a method for producing the surface-enhanced Raman scattering agent, wherein a noble metal-containing thin plate is pulverized in a viscous liquid having a viscosity of 50 mPa ⁇ s or more at a shear rate of 10 (1 / s) at 25 ° C.
  • a method for producing a surface-enhanced Raman scattering agent including a step.
  • the surface-enhanced Raman scattering agent of the present disclosure has flexibility or fluidity, and also has adhesiveness. Therefore, it can be applied to various usage methods.
  • a test piece can be obtained by adhering it to a potty bowl for infants, a toilet bowl, or the like, and discharging urine so as to come into contact with the surface-enhanced Raman scattering agent.
  • the components in urine can be measured.
  • the surface-enhanced Raman scattering agent is used, the Raman scattered light expressed by the test substance can be remarkably amplified. This makes it possible to identify and / or quantify the test substance with high sensitivity.
  • the Raman peak characteristic of equol can be recognized with high sensitivity. Therefore, even in a sample in which equol and an equol-like substance coexist, equol and an equol-like substance can be distinguished, and equol in the sample can be selectively and highly sensitively quantified.
  • the surface-enhanced Raman scattering agent is used, the presence or absence of equol-producing ability can be easily and accurately determined by measuring the equol concentration contained in the urine, blood, etc. of the subject.
  • Enhanced Raman scatterers are also useful for testing for equol-producing ability.
  • the surface-enhanced Raman scattering agent of the present disclosure includes a viscous liquid and precious metal-containing flakes dispersed in the viscous liquid.
  • the viscous liquid is a viscous liquid having a viscosity of 50 mPa ⁇ s or more at 25 ° C. and a shear rate of 10 (1 / s).
  • the surface-enhanced Raman scattering agent has a structure in which precious metal-containing thin pieces are dispersed in the viscous liquid.
  • the surface-enhanced Raman scattering agent contains at least a noble metal-containing fragment and the viscous liquid, and may further contain one or more other components.
  • Other components include, for example, thickeners, surfactants, dispersion stabilizers (eg, citric acid), pH regulators (eg, toluene, xylene, hydrochloric acid), preservatives (eg, neutral formarin, azide). Sodium, timol, isothiazolone compounds), deodorants, fragrances and the like.
  • the noble metal-containing fragment can be brought into contact with the test substance at a high concentration, and the surface-enhanced Raman scattering effect can be improved by holding the contact-like body.
  • it is preferably a gel-like dispersion.
  • the viscosity of the surface-enhanced Raman scattering agent at 25 ° C. and a shear rate of 10 (1 / s) is, for example, 50 to 100,000 mPa ⁇ s, preferably 100 to 50,000 mPa ⁇ s, and particularly preferably 200 to 30,000 mPa ⁇ s.
  • the viscosity can be measured using a viscosity / viscoelasticity measuring device (rheometer, trade name “RheoStress600”, manufactured by HAAKE).
  • the intensity of the Raman scattered light is amplified by the interaction between the Raman scattered light and the electromagnetic wave on the surface of the noble metal structure. Therefore, even if the concentration of the test substance contained in the sample is very small, it can be quantified with high accuracy.
  • the limit of the 4,4'-bipyridine concentration that can be measured by Raman spectroscopy is about 10 mmol / L at most.
  • the surface-enhanced Raman scattering agent of the present disclosure even if the content of 4,4'-bipyridine in the sample is very small, it can be quantified with high accuracy.
  • 1 mmol / L 4,4'-bipyridine can be measured.
  • equol can also be measured with high sensitivity. It is known that when an adult subject has an equol-producing ability, the equol concentration in urine is usually 1 to 75 ⁇ mol / L. Therefore, if the equol contained in the urine of the subject is quantified using the surface-enhanced Raman scattering agent, it can be easily determined whether or not the subject has an equol-producing ability.
  • the noble metal-containing thin piece is a structure having a structure in which a noble metal component is attached to the surface of the thin piece.
  • the average thickness of the thin pieces is, for example, 10 to 50 ⁇ m.
  • the average thickness of the thin pieces is obtained by dividing the weight of the thin pieces by the density to obtain the volume, and then dividing this by the area of the thin pieces.
  • the average value of the equivalent circle diameter (according to the image analysis method) of the thin piece is, for example, 10 to 500 ⁇ m, preferably 20 to 50 ⁇ m.
  • the surface of the thin piece may be flat, but may be mechanically or chemically surface-treated.
  • the thin pieces are preferably thin pieces made of an inorganic oxide having a hydroxyl group, and examples thereof include thin pieces such as silica, talc, mica, titanium oxide, and glass.
  • thin pieces such as silica, talc, mica, titanium oxide, and glass.
  • mica thin pieces are preferable. This is because mica is easy to crush into thin pieces and has a function as an internal standard for surface-enhanced Raman scattering.
  • the precious metal at least one selected from gold, silver, and copper is preferable.
  • the noble metal-containing thin piece is preferably a structure having a noble metal layer on the surface of the thin piece, or having noble metal particles on the surface of the thin piece, or having a noble metal layer on the surface of the thin piece and having noble metal particles. Is.
  • the precious metal-containing thin pieces are particularly excellent in the effect of enhancing Raman scattered light, and are structures in which fine columnar bodies are forested on the surface of the thin small pieces, and at least a part of the fine columnar bodies is a precious metal. It is preferably a structure formed of a layer or noble metal particles, more preferably a structure having a structure in which microcolumnar bodies having a noble metal layer stand on the surface of the thin pieces, and particularly preferably the thin pieces. It is a structure having a noble metal layer on the surface of the above-mentioned structure and having a structure in which microcolumnar bodies having the noble metal layer stand on the surface of the noble metal layer.
  • the microcolumnar body may be a microcolumnar body composed of noble metal particles, that is, a rod-shaped noble metal particle, and the noble metal layer is laminated on the microcolumnar layer composed of a substance other than the noble metal. You may.
  • the noble metal-containing thin piece is preferably a structure in which a layer made of a substance other than the noble metal and a noble metal layer are laminated on the surface of the thin piece.
  • the substance other than the noble metal is preferably a transparent substance in that plasma resonance is generated by the light emitted from the light source.
  • the transparent substance include SiO 2 , Ta 2 O 5 , TiO 2 , LiF and the like.
  • the portion where the precious metal layer is provided may be at least a part of the microcolumnar body, and may be any of the tip portion, the end portion, and the central portion of the microcolumnar body. Further, it may be provided in only one part of the above-mentioned parts, or may be provided in two or more parts.
  • microcolumnar body stands upright perpendicular to the surface of the thin piece, but it may be slightly inclined. Further, it is preferable that the distance between the adjacent microcolumnar bodies is small so that the scattering of the light emitted from the light source does not become a problem. Adjacent microcolumn states may be in contact with each other.
  • the microcolumnar body has an anisotropic shape because it is particularly excellent in the effect of enhancing Raman scattered light.
  • the ratio (aspect ratio) of the length in the longitudinal direction to the length in the lateral direction when the microcolumnar body is cut in a plane substantially parallel to the thin piece is 2 or more.
  • a remarkable enhancing effect of Raman scattered light can be obtained by causing a difference in the transmission characteristics of the incident light with respect to the optical axis direction.
  • the microcolumnar body having an anisotropic shape on the surface of the thin piece is formed while being oriented in one direction.
  • the structure (1) having a structure in which irregularly shaped microcolumnar bodies having a laminated structure of a transparent layer and a noble metal layer stand on the surface of a thin piece is, for example, from a thin plate (preferably an inorganic oxide having a hydroxyl group). It can be manufactured through a step of manufacturing a fine columnar transparent layer, a step of manufacturing a precious metal layer, and a step of crushing the thin plate). Then, the order of carrying out the manufacturing process of the transparent layer of the microcolumnar and the manufacturing process of the noble metal layer can be appropriately selected according to the structure of the desired microcolumnar body.
  • the manufacturing process of the fine columnar transparent layer and the manufacturing process of the noble metal layer may be alternately repeated.
  • This step is a step of forming a fine columnar transparent layer.
  • the thin plate is tilted by about 45 ° to 88 ° with respect to the incident direction of the vapor deposition flow of the transparent microcolumnar material, and the thickness is 5 to 100 nm.
  • the in-plane orientation of the thin plate is reversed by 180 °.
  • a thin plate having an anisotropic transparent layer extending long in the direction perpendicular to the surface is obtained.
  • the thin plate is a thin plate that becomes a thin piece when it is crushed, and is a thin plate-like material formed of the same material as the thin piece.
  • This step is a step of laminating precious metal layers.
  • the transparent layer standing upright on the surface of a thin plate on which the fine columnar transparent layer obtained through the above steps is formed.
  • the noble metal can be vapor-deposited on the tip of the microcolumnar layer. This makes it possible to form a microcolumnar body formed by laminating a transparent layer and a precious metal layer.
  • the precious metal vapor deposition may be carried out while the thin plate is inverted in-plane, as in the case of producing the transparent microcolumnar layer, but the diagonal vapor deposition may be performed only from one direction without inverting the in-plane.
  • the thickness of the precious metal layer can be appropriately selected depending on the light source used, but is, for example, 50 nm or less.
  • a structure (2) having a structure in which anisotropic microcolumnar bodies having a transparent layer / noble metal layer laminated structure stand on the surface of the thin plate can be obtained.
  • the viscous liquid used in the pulverization step it is preferable to use a viscous liquid which may contain a surface-enhanced Raman scattering agent, and in particular, the viscosity at 25 ° C. and a shear rate of 10 (1 / s) is 50 to 50. It is preferable to use a viscous liquid of 100,000 mPa ⁇ s (particularly preferably a gel-like dispersion). As a result, the impact of pulverization can be softened, and the retention of the structure of the microcolumnar body can be improved.
  • the crushing time varies depending on the crushing method, but for example, when a stainless steel ball (SUS ball) having a diameter of 1.0 mm is crushed by rotating it at a revolution of 2000 rpm and a rotation of 800 rpm, it is about 1 to 10 minutes. In terms of being able to improve the surface-enhanced Raman scattering effect, it is preferably 4 to 9 minutes, and particularly preferably more than 4 minutes and less than 6 minutes.
  • SUS ball stainless steel ball
  • the viscous liquid is a liquid having a viscosity of 50 mPa ⁇ s or more at 25 ° C. and a shear rate of 10 (1 / s).
  • As the viscous liquid it is preferable to use a liquid having a low Raman activity in terms of improving the quantification accuracy of the test substance.
  • the viscous liquid can bring the noble metal-containing fragment into contact with the test substance at a high concentration, and by holding the contact state, the surface-enhanced Raman scattering effect can be improved.
  • it is preferably a gel-like dispersion.
  • the viscous liquid contains a water-soluble solvent and an oil-based solvent.
  • the viscous liquid contains a solvent such as water, alcohol, and an oil agent. These can be used alone or in combination of two or more.
  • alcohols such as methanol, ethanol, propanol and butanol
  • polyhydric alcohols such as ethylene glycol, propylene glycol, butylene glycol and glycerin.
  • oil agent examples include hydrocarbon oils such as mineral oil and liquid paraffin; sunflower oil, macadamia nut oil, avocado oil, almond oil, wheat germ oil, rice germ oil, olive oil, soybean oil, corn oil, sunflower oil and beef fat. , Johova oil, evening primrose oil, palm oil, mountain tea flower oil, rose hip oil, squalane, turtle oil, mink oil, egg yolk oil, lanolin, whale wax, candelilla wax, montan wax, rice wax, lanolin wax, cellac and other animal and vegetable oils.
  • hydrocarbon oils such as mineral oil and liquid paraffin
  • sunflower oil macadamia nut oil
  • avocado oil almond oil, wheat germ oil, rice germ oil, olive oil, soybean oil, corn oil, sunflower oil and beef fat.
  • Johova oil evening primrose oil, palm oil, mountain tea flower oil, rose hip oil, squalane, turtle oil, mink oil, egg yolk oil, lanolin, whale wax, candelilla wax, montan wax, rice wax, lanolin wax, cellac
  • Hydrocarbon oils such as hexane, cyclohexane, isododecane, benzene, toluene, poly ⁇ olefin, liquid paraffin; ethers such as tetrahydrofuran; halogenated hydrocarbons such as carbon tetrachloride, chlorobenzene; kerosine, gasoline, light oil, heavy oil, etc.
  • Petroleum components such as dimethylpolysiloxane and methylphenylpolysiloxane; Ester oils such as octyldodecyl oleate, cetyl ethylhexanate, glyceryltriisooctane, neopentylglycoldiisooctanete; hexadecyl alcohol, oleyl alcohol Higher alcohols such as; higher fatty acids such as lauric acid, isostearic acid, oleic acid; aromatic carboxylic acids, pyridine and the like.
  • Silicone oils such as dimethylpolysiloxane and methylphenylpolysiloxane
  • Ester oils such as octyldodecyl oleate, cetyl ethylhexanate, glyceryltriisooctane, neopentylglycoldiisooctanet
  • Solvents with high raman activity include, for example, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), dimethylacetamide (DMAA), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), cyclohexanone, lactam. , Lactone, N, N, N, N-tetramethylurea and the like.
  • the amount used in the case of using two or more in combination, the total amount thereof
  • the amount used is, for example, 30% by weight or less of the total amount of the viscous liquid contained in the surface-enhanced Raman scattering agent. It is more preferably 20% by weight or less, particularly preferably 10% by weight or less, most preferably 5% by weight or less, and particularly preferably 1% by weight or less.
  • a thickener When the viscosity of the solvent is low, a thickener can be added to thicken the solvent.
  • the thickener can be appropriately selected depending on the type of solvent.
  • examples of the thickener include cellulose-based polymer compounds such as hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, and carboxymethyl cellulose; plant-based natural polymer compounds such as carrageenan and guar gum; and xanthan gum and the like.
  • Micromolecular-based natural polymer compounds include Animal-based natural polymer compounds such as casein and gelatin; Steel-based polymer compounds such as carboxymethyl starch; Vinyl-based polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium polyacrylate, and carboxyvinyl polymer Compounds; Polyether-based polymer compounds such as polyethylene glycol, polypropylene glycol and polyglycerin; Polyoxyalkylene-modified saccharides such as polyoxyethylene methyl glucoside and polyoxypropylene methyl glucoside can be mentioned.
  • examples of the thickener include sugar fatty acid ester, 12-hydroxystearic acid, 1,3; 2,4-dibenzylidene-D-sorbitol, N-lauroyl-L-glutamic acid-.
  • examples thereof include ⁇ , ⁇ -bis-n-butylamide, benzene fatty acid amide, cyclohexane fatty acid amide and the like.
  • the sugar fatty acid ester includes, for example, a dextrin fatty acid ester such as dextrin palmitate and dextrin myristin; an inulin fatty acid ester such as inulin stearate.
  • the surface-enhanced Raman scattering measuring method of the present disclosure is a measuring method by surface-enhanced Raman scattering spectroscopy using the surface-enhanced Raman scattering agent. More specifically, a substance contained in the test body is analyzed by analyzing the scattered light generated by irradiating the test body with excitation light using a test body in which the surface-enhanced Raman scattering agent is brought into contact with the sample. Is a method of identifying and quantifying.
  • the method for bringing the surface-enhanced Raman scattering agent into contact with the sample is not particularly limited as long as the sample can be brought into contact with the surface of the noble metal-containing thin pieces in the surface-enhanced Raman scattering agent.
  • a method of fixing the surface-enhanced Raman scattering agent on the surface of a base material and dropping a liquid sample (if the sample is not liquid, prepared in a liquid state), or the surface-enhanced Raman on a sample stage or the like examples thereof include a method of mixing a scattering agent and a liquid sample.
  • the equol measuring method is a method for measuring (identifying and / or quantifying) equol contained in a sample by using the surface-enhanced Raman scattering measuring method. More specifically, a test piece in which the surface-enhanced Raman scattering agent is brought into contact with a sample is used as a test piece, and the scattered light generated when the test piece is irradiated with excitation light is analyzed to quantify the equol contained in the test piece. How to do it.
  • equol in a sample in which equol and an equol-like substance are mixed is analyzed by analyzing a peak that appears characteristically in equol, that is, a peak that appears in equol but does not appear in an equol-like substance. It can be selectively quantified.
  • the peaks that characteristically appear in the equol may vary slightly depending on the experimental conditions such as the measuring equipment used, but for example, 1530 to 1630 cm -1 , 1230 to 1330 cm -1 , 1140 to 1240 cm -1 , and 535.
  • At least one wavenumber region selected from the group of ⁇ 635 cm -1 preferably at least 1 selected from the group of 1570 to 1590 cm -1 , 1270 to 1290 cm -1 , 1180 to 1200 cm -1 and 570 to 590 cm -1 .
  • the surface-enhanced Raman scattering agent is used to amplify the Raman scattering of equol contained in the sample, so that selective and high-sensitivity measurement of equol is possible.
  • the equol-producing ability test method is a method for testing whether or not a subject has an ability to produce equol, and the equol-producing ability test method uses equol in a sample collected from a subject as the equol. Includes measuring by measuring method.
  • the subject When the subject has equol-producing ability, the subject has equol-producing bacteria in the intestine, and when the subject ingests daidzein, which is a kind of isoflavone, the equol-producing bacteria metabolize daidzein to produce equol. Then, the produced equol is absorbed from the intestinal tract and taken into the blood, and a part of the equol is excreted in the urine. Therefore, if urine, blood, or intestinal contents and the supernatant obtained by centrifuging these are used as a sample and the equol contained in the sample is quantified, whether or not the subject has equol-producing ability. (Or whether or not the subject has an equol-producing bacterium) can be easily determined.
  • Examples of the equol-producing bacterium include microorganisms belonging to the genus Lactococcus, the genus Slackcia, the genus Adlercreutzia, the genus Asaccharobacter, and the genus Eggerthella. More specifically, for example, Lactococcus garviae, Adlercreutzia equolifaciens, Asaccharobacter Celatus, and Eggerthella sp. YY7918 can be mentioned.
  • the surface-enhanced Raman scattering measurement kit of the present disclosure is a kit for performing measurement by surface-enhanced Raman scattering spectroscopy, and includes at least the above-mentioned surface-enhanced Raman scattering agent.
  • the kit may include other configurations other than the surface-enhanced Raman scattering agent, and preferably includes a device capable of identifying Raman peaks.
  • a Raman spectroscopic measuring device including, for example, a light source, a filter for removing Rayleigh scattered light, a spectroscope for decomposing Raman scattered light into a spectrum, a detector, and the like.
  • the light source for example, a light source that emits laser light (preferably near infrared laser light) is preferable.
  • Examples of the method of using the measurement kit include the following methods. 1. 1. A test piece is formed by contacting the surface-enhanced Raman scattering agent with the sample. 2. 2. The test piece is irradiated with the irradiation light from the light source to develop Raman scattered light and Rayleigh scattered light. 3. 3. The Rayleigh scattered light is removed by passing the scattered light through a filter. 4. The scattered light after the Rayleigh scattered light is removed is introduced into the spectroscope, and the introduced scattered light is decomposed into a spectrum in the spectroscope. 5. Detect the spectrum with a detector.
  • the light source for example, a light source that emits laser light (preferably near infrared laser light) is preferable.
  • the Raman scattering of the test substance can be amplified by the surface-enhanced Raman scattering agent. Therefore, it is possible to quantify a trace amount of the test substance.
  • the measurement kit may be, for example, an equol measurement kit.
  • the measurement kit may be a kit for testing equol-producing ability.
  • each configuration of the present disclosure and combinations thereof are examples, and the configurations can be added, omitted, replaced, and changed as appropriate within the range not deviating from the gist of the present disclosure. Further, the present disclosure is not limited to the embodiments, but is limited only by the description of the scope of claims.
  • Preparation Example 1 (Preparation of a structure having a structure in which microcolumnar bodies having a transparent layer / precious metal layer laminated structure stand together)
  • the surface-enhanced Raman scattering substrate of the structure having a structure in which irregularly shaped microcolumnar bodies having a transparent layer / noble metal layer laminated structure were planted was produced by the dynamic diagonal vapor deposition method described in Japanese Patent No. 4783907. In detail, it was created by the following method.
  • a mica substrate cut into a size of 50 ⁇ 50 mm 2 was cleaved to a thickness of 15 to 30 ⁇ m capable of retaining its shape, and washed with ultraviolet rays to obtain a mica thin plate. Then, the mica thin plate was attached to a dynamic diagonal vapor deposition apparatus and exhausted until it became 3 ⁇ 10 -4 Pa or less, and an Ag mirror surface layer, a SiO 2 microcolumnar layer, and an Ag layer were formed in this order. First, silver was vapor-deposited to a film thickness of 200 nm at a vapor deposition angle of 0 ° and an average vapor deposition rate of about 0.20 nm / s to prepare an Ag mirror surface layer.
  • silica (SiO 2 ) particles having a purity of 99.99% were vapor-deposited on the Ag mirror surface layer at a vapor deposition angle of 0 ° and an average vapor deposition rate of 0.2 to 0.3 nm / s to a film thickness of 105 nm.
  • a SiO 2 microcolumnar layer was constructed using a continuous two-way diagonal vapor deposition method, which is a type of dynamic diagonal vapor deposition method.
  • Example 1 (Preparation of precious metal-containing thin pieces dispersed in a viscous liquid) Ultrapure water and hydroxyethyl cellulose (HEC) powder (SE400, Daicel FineChem Ltd.) were placed in a container with a 30 mm lid and stirred with a stirrer for 2 minutes. The rotation speed during stirring was 2000 rpm for revolution and 800 rpm for rotation. The HEC concentration was 10% by weight. This gave a viscous liquid. The viscosity of the viscous liquid was measured using a leometer (trade name "Physica MCR301", manufactured by Antonio Par) under the conditions of a temperature of 25 ° C. and a shear rate of 10 (1 / s). It was s.
  • a leometer trade name "Physica MCR301", manufactured by Antonio Par
  • Example 2 Measurement of surface-enhanced Raman scattering
  • the following surface-enhanced Raman scattering was measured for the gel-like dispersion liquid 1 obtained with a stirring time of 5 minutes.
  • a 5 ⁇ 5 mm 2 hole was provided in a 1.5 mm thick silicon gum to prepare a cell containing the gel-like dispersion liquid 1, and 30 ⁇ L of a 1 mM 4,4'-bipyridine aqueous solution was placed on the upper surface of the gel-like dispersion liquid 1. After dripping, a cover glass was hung. After 60 minutes had passed, the cell was placed at the measurement site of the Raman spectroscope RAM200 manufactured by Lambda Vision Co., Ltd., and the cell was irradiated with a 785 nm (100 mW) laser for 1 second to obtain a Raman scattering spectrum by averaging twice (2 times). FIG. 1). A typical surface-enhanced Raman scattering spectrum of 4,4'-bipyridine is shown in FIG.
  • Example 3 Surface-enhanced Raman scattering was measured in the same manner as in Example 2 except that the dispersion obtained by changing the stirring time in the range of 1 minute to 10 minutes was used, and a Raman scattering spectrum was obtained. Then, the peak height around 1600 cm -1 was plotted for each stirring time of the dispersion liquid (Fig. 2).
  • Comparative Example 1 The gold colloid was salted and aggregated, and then immediately dispersed in a 10% by weight viscous liquid of HEC. The dispersion method was carried out by stirring in the same procedure as in Example 1. As a result, the gel-like dispersion liquid 3 was obtained.
  • the Raman scattering spectrum of 4,4'-bipyridine was obtained in the same manner as in Example 2 except that the gel-like dispersion 3 was used instead of the gel-like dispersion 1 (FIG. 3).
  • the viscous liquid is a surface-enhanced Raman scattering agent having a viscosity of 50 mPa ⁇ s or more at 25 ° C. and a shear rate of 10 (1 / s).
  • a surface-enhanced Raman scattering agent having a structure in which precious metal-containing thin pieces are dispersed in a gel-like dispersion.
  • the noble metal-containing thin pieces are a structure in which microcolumnar bodies stand on the surface of the thin pieces, and at least a part of the fine columnar bodies is formed of a noble metal layer or noble metal particles.
  • the surface-enhanced Raman scattering agent according to any one of [3].
  • the noble metal-containing thin piece is a structure having a noble metal layer on the surface of the thin piece and having a structure in which microcolumnar bodies having the noble metal layer stand on the surface of the noble metal layer [1].
  • the surface-enhanced Raman scattering agent according to any one of [5]. [7] Any of [1] to [6], wherein the precious metal-containing thin piece is a structure having a structure in which microcolumnar bodies having an anisotropic shape on the surface of the thin piece are oriented in one direction and are forested. One of the surface-enhanced Raman scatterers.
  • the noble metal-containing thin pieces are structures having a structure in which a transparent layer composed of a substance other than the noble metal and a microcolumnar body having a noble metal layer stand on the surface of the thin pieces.
  • the noble metal-containing thin piece has a microcolumnar body having a layer composed of at least one selected from SiO 2 , Ta 2 O 5 , TiO 2 and LiF and a noble metal layer on the surface of the thin piece.
  • a surface-enhanced Raman scattering measurement kit comprising the surface-enhanced Raman scattering agent according to any one of [1] to [13].
  • the surface-enhanced Raman scattering agent of the present disclosure By using the surface-enhanced Raman scattering agent of the present disclosure, the Raman peak characteristic of equol can be recognized with high sensitivity. Therefore, the surface-enhanced Raman scattering agent is suitable as a surface-enhanced Raman scattering agent for quantifying equol.

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