WO2023085617A1 - Structure comprenant un composé à base d'acide anthracènediboronique pour la détection du glucose, procédé de préparation pour celle-ci et utilisation de celle-ci - Google Patents

Structure comprenant un composé à base d'acide anthracènediboronique pour la détection du glucose, procédé de préparation pour celle-ci et utilisation de celle-ci Download PDF

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Publication number
WO2023085617A1
WO2023085617A1 PCT/KR2022/015534 KR2022015534W WO2023085617A1 WO 2023085617 A1 WO2023085617 A1 WO 2023085617A1 KR 2022015534 W KR2022015534 W KR 2022015534W WO 2023085617 A1 WO2023085617 A1 WO 2023085617A1
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WIPO (PCT)
Prior art keywords
glucose
acid
electrode
group
based compound
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PCT/KR2022/015534
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English (en)
Korean (ko)
Inventor
김중현
임흥섭
최홍식
박철순
송인혁
이찬희
김훈주
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재단법인 대구경북첨단의료산업진흥재단
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Priority claimed from KR1020220088272A external-priority patent/KR20230071048A/ko
Application filed by 재단법인 대구경북첨단의료산업진흥재단 filed Critical 재단법인 대구경북첨단의료산업진흥재단
Publication of WO2023085617A1 publication Critical patent/WO2023085617A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/327—Biochemical electrodes, e.g. electrical or mechanical details for in vitro measurements
    • 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
    • G01N33/66—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood sugars, e.g. galactose

Definitions

  • the present invention relates to a structure for detecting glucose by an electrochemical method, a method for preparing the same, and a use thereof.
  • Existing personal blood glucose measurement systems mainly use glucose oxidase to measure an increased current according to electrons generated when glucose is oxidized.
  • An enzyme-based electrochemical continuous blood glucose measurement system is used for more effective blood sugar management due to individual differences and fluctuations in blood glucose levels, but it is difficult to popularize it due to high cost and short period of use (less than 2 weeks).
  • the continuous blood glucose measurement system that optically measures blood glucose using diboronic acid can be used for up to 180 days.
  • the electrochemical measurement system is not only smaller and easier to manufacture than an optical system, but also has the advantage of being able to be used for a long time. As a result of studying a technology that can measure glucose by an electrochemical method using diboronic acid, completed the present invention.
  • the present inventors confirmed that the resistance of the electrode increases as the glucose concentration increases by immobilizing one boronic acid on the surface of the electrode, and as the diboronic acid binds to glucose, the three-dimensional electrical transmission material can be more easily transferred to the electrode.
  • a technology capable of detecting glucose was derived by using the fact that the resistance of the electrode surface decreases as the glucose concentration increases as the structure is modified.
  • an object of the present invention is an electrode; and a diboronic acid anthracene-based compound bonded to the surface of the electrode through a linker, to provide a structure for detecting glucose.
  • Another object of the present invention is to provide a method for preparing the structure for detecting glucose.
  • Another object of the present invention is to provide a use of the structure for detecting glucose.
  • the present invention is an electrode; and a diboronic acid anthracene-based compound bonded to the surface of the electrode through a linker.
  • the present invention (a) reacting by adding an acid to the alcohol solution; (b) washing the electrode with the reactant of (a); (c) reacting by adding a mixture of a diboronic acid anthracene-based compound and a coupling agent to the washed electrode; and (d) washing and drying the electrode after the reaction of (c).
  • the present invention provides a kit for detecting glucose comprising the structure for detecting glucose.
  • the present invention provides a glucose detection method comprising the step of reacting the glucose detection structure with a specimen.
  • the diboronic acid anthracene-based compound is bonded to the electrode surface as a linker, and when the diboronic acid anthracene-based compound reacts with glucose present in the specimen, the resistance of the electrode surface decreases depending on the glucose concentration, and the reaction time It is fast, can improve reversibility and repeatability, can be used for a long time compared to an enzyme-type blood glucose measurement sensor, and has excellent effects that are easier to manufacture than an optical blood glucose measurement sensor.
  • 1 is a view showing a synthetic route of diboronic acid anthracene-based compounds according to an embodiment of the present invention.
  • Figure 2 shows a process of immobilizing the diboronic acid anthracene-based compound on the electrode according to an embodiment of the present invention.
  • FIG 3 is a graph obtained through Cyclic Voltametry (CV) for each glucose concentration using a structure for detecting glucose according to an embodiment of the present invention.
  • FIG. 4 is a graph showing the maximum current value for each glucose concentration measured using the structure for detecting glucose according to an embodiment of the present invention.
  • NP Nyquist Plot
  • FIG. 6 is a graph showing a resistance change ratio for each glucose concentration measured using a structure for detecting glucose according to an embodiment of the present invention.
  • FIG. 7 is a diagram showing structural changes in diboronic acid anthracene-based compounds in which diboronic acid gathers towards anthracene by glucose binding according to an embodiment of the present invention.
  • the present invention provides an electrode; and a diboronic acid anthracene-based compound bonded to the surface of the electrode through a linker.
  • the electrode may be one in which a diboronic acid anthrancene-based compound is bonded to the surface of the electrode by a linker.
  • the diboronic acid anthracene-based compound may be a compound represented by Formula 1 below, but is not limited thereto:
  • the linker may be at least one selected from the group consisting of a hydroxyl group, an ester group, an ether group, a carbonyl group, an amine group, an amide group, a cyano group, a thiol group, a thioester group, and a thioether group. , but is not limited thereto.
  • the diboronic acid anthracene-based compound is the compound represented by Formula 1
  • the diboronic acid anthracene-based compound is formed in the electrode through an amide bond between an amino group of the compound and a carboxyl group present on the surface of the electrode. Can be bonded to and immobilized on a surface
  • the structure may further include a resistance measuring unit for measuring the resistance of the electrode surface.
  • the resistance measuring unit may measure the resistance of the electrode surface of the structure, and specifically, measure the change in resistance of the electrode surface when the diboronic acid anthracene-based compound of the structure reacts with glucose present in the specimen, More specifically, it may be to measure the degree of change in the reduced electrode surface resistance while the diboronic acid anthracene-based compound of the structure binds to the diol of glucose present in the sample.
  • the structure may further include an analysis unit for quantifying the content of glucose present in the specimen from the resistance measured by the resistance measurement unit.
  • a diboronic acid anthracene-based compound is bonded to the surface of an electrode by a linker, and when the diboronic acid anthracene-based compound reacts with glucose present in a specimen, an electron mediator ( electron mediator) is more easily accessible to the electrode surface, and the resistance of the electrode surface decreases in a glucose concentration-dependent manner, thereby confirming that glucose in the sample can be detected and specifically quantified.
  • the present invention comprises the steps of (a) immersing an electrode in an acid solution to immobilize an acid on the electrode; (b) reacting by adding a mixture of a diboronic acid anthracene-based compound and a coupling agent to the acid-immobilized electrode; and (c) washing and drying the electrode after the reaction of (b).
  • the electrode, the diboronic acid anthracene-based compound, and the structure for detecting glucose are as described above.
  • the acid may be at least one selected from the group consisting of mercaptobenzoic acid, mercaptohexanol, mercaptodecanoic acid, mercaptodecanol, thioglycolic acid, and mercaptopropionic acid, but is not limited thereto. .
  • the solvent in the acid solution may be an organic solvent such as alcohol, dimethyl sulfoxide (DMSO), or dimethyl formamide (DMF), and when the acid is water-soluble, water It can also be used as a solvent.
  • organic solvent such as alcohol, dimethyl sulfoxide (DMSO), or dimethyl formamide (DMF)
  • DMSO dimethyl sulfoxide
  • DMF dimethyl formamide
  • the reaction time in step (a) may be 10 minutes to 24 hours, specifically, 10 minutes or more, 20 minutes or more, 30 minutes or more, 1 hour or more, 2 hours or more, 4 hours or more It can be more than 6 hours, more than 8 hours, more than 10 hours, more than 12 hours, more than 14 hours, more than 16 hours, more than 18 hours, more than 20 hours, or more than 22 hours, less than 24 hours, less than 22 hours, less than 20 hours.
  • the coupling agent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide) (1- (3-dimethylaminopropyl) -3-ethylcarbodimide, EDC) and N-hydroxysulfosuk Shinimide (N-hydroxysulfosuccinide, NHS) may be included.
  • the reaction time in step (b) may be 1 to 24 hours, specifically 1 hour or more, 2 hours or more, 4 hours or more, 6 hours or more, 8 hours or more, 10 hours or more , 12 hours or more, 14 hours or more, 16 hours or more, 18 hours or more, 20 hours or more, or 22 hours or less, 24 hours or less, 22 hours or less, 20 hours or less, 18 hours or less, 16 hours or less, 14 hours or less , 12 hours or less, 10 hours or less, 8 hours or less, 6 hours or less, 5 hours or less, 4 hours or less, 3 hours or less, or 2 hours or less, but is not limited thereto.
  • the drying step may be drying with gas, and the gas may be drying with one or more selected from the group consisting of an inert gas.
  • the present invention provides a kit for detecting glucose comprising the structure for detecting glucose.
  • the description of the structure for detecting glucose may also be applied to a kit for detecting glucose.
  • the present invention provides a method for detecting glucose comprising reacting the structure for detecting glucose with a specimen.
  • the description of the structure for detecting glucose can also be applied to a method for detecting glucose.
  • the detection method may be to detect glucose to a degree of change in electrode surface resistance reduced while the diboronic acid anthracene-based compound binds to a diol of glucose, but is not limited thereto, and the detection method and Resistance change measurement may use a method commonly used in the art.
  • Acetylated diboronic anthracene containing two primary amines was synthesized according to the synthetic route shown in FIG. 1 .
  • the detailed synthesis procedure is as follows.
  • reaction mixture was extracted with methylene chloride (600 mL). The organic layer of the mixture was separated and dried over anhydrous magnesium sulfate. The dried compound was stirred in 500 mL of hexane for 0.5 h until a precipitate formed. After filtering off the precipitate, an oily compound 1 (21.5 g, 89.9%) was obtained and purified by silica gel chromatography using dichloromethane/hexane (1:8, v/v) as an eluent.
  • 9,10-Dimethylanthracene (20.0 g, 0.1 mol) was dissolved in methylene chloride (600 mL). Acetyl chloride (0.4g, 0.12mol) and aluminum chloride (18.8g, 0.149mol) were added to the mixture and stirred at 0-5°C. After stirring for an additional 5 hours and refluxing for 1 hour, the reaction mixture was allowed to warm to room temperature. 1 kg of ice and 50 mL of hydrochloric acid were added to the reaction mixture. The mixture was extracted with methylene chloride and water.
  • the electrode After reacting with 1 mM mercaptobenzoic acid (MBA) in ethanol for 10 minutes, the electrode (220BT, Metrohm) was washed with ethanol. Then, in 0.1x PBS, 2 mM diboronic acid anthranthene compound (Compound 7 above), 100 mM 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide) (1-(3-dimethylaminopropyl)- 3-ethylcarbodimide, EDC) and 150 mM N-hydroxysulfosuccinimide (N-hydroxysulfosuccinide, NHS) were dispensed in 20 ul to the working electrode and reacted for 1 hour. Thereafter, the electrode was washed with distilled water and dried with nitrogen gas to prepare a structure in which the diboronic acid anthracene-based compound was fixed on the surface of the electrode.
  • MBA mercaptobenzoic acid
  • Electrochemical Impedence Spectroscopy was performed for each glucose concentration of 0, 40, 100, 200, 300, 400, 500, and 600 mg/dL using the glucose detection structure prepared in the above example, and the results are It is shown as a Nyquist Plot (NP) of the electrode.
  • the size of the semicircle decreased as the glucose concentration increased.
  • the size of the semicircle that is, the resistance, decreased as the glucose concentration increased.
  • the structure according to the present invention has a fast reaction time when reacting with glucose present in a specimen, can improve reversibility and repeatability, can be used for a long time compared to an enzyme-type blood glucose measurement sensor, and is easier to manufacture than an optical blood glucose measurement sensor. .

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Abstract

La présente invention concerne une structure pour la détection du glucose par un procédé électrochimique, un procédé de préparation de celle-ci et une utilisation de celle-ci. Dans la structure selon la présente invention, un composé à base d'acide anthracènediboronique est lié à une surface d'électrode par l'intermédiaire d'un lieur, et ainsi lorsque le composé à base d'acide anthracènediboronique réagit avec du glucose présent dans un échantillon, la résistance au niveau de la surface d'électrode est réduite d'une manière dépendant de la concentration en glucose, ce qui présente d'excellents effets en ce que le temps de réaction est rapide, la réversibilité et la répétabilité peuvent être améliorées, elle peut être utilisée pendant une longue durée comparativement à un capteur de mesure de glucose à base d'enzyme, et la fabrication est aisée comparativement à un capteur de mesure de glucose de type optique.
PCT/KR2022/015534 2021-11-15 2022-10-13 Structure comprenant un composé à base d'acide anthracènediboronique pour la détection du glucose, procédé de préparation pour celle-ci et utilisation de celle-ci WO2023085617A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2021-0156646 2021-11-15
KR20210156646 2021-11-15
KR1020220088272A KR20230071048A (ko) 2021-11-15 2022-07-18 디보론산 안트라센계 화합물을 포함하는 포도당 검출용 구조체, 이의 제조방법 및 용도
KR10-2022-0088272 2022-07-18

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050130248A1 (en) * 2002-02-04 2005-06-16 Yissum Research And Development Company Of The Hebrew University Of Jerusalem Biosensor carrying redox enzymes
US20120244037A1 (en) * 2010-07-22 2012-09-27 National Institute For Materials Science Sensing device and biosensor
KR20130009488A (ko) * 2011-07-15 2013-01-23 엘지전자 주식회사 당화당백질 측정용 전극 및 이것의 제조방법
KR20150126476A (ko) * 2014-05-02 2015-11-12 광운대학교 산학협력단 전기화학적 활성을 나타내는 나노입자를 이용한 당화혈색소 측정용 바이오센서

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050130248A1 (en) * 2002-02-04 2005-06-16 Yissum Research And Development Company Of The Hebrew University Of Jerusalem Biosensor carrying redox enzymes
US20120244037A1 (en) * 2010-07-22 2012-09-27 National Institute For Materials Science Sensing device and biosensor
KR20130009488A (ko) * 2011-07-15 2013-01-23 엘지전자 주식회사 당화당백질 측정용 전극 및 이것의 제조방법
KR20150126476A (ko) * 2014-05-02 2015-11-12 광운대학교 산학협력단 전기화학적 활성을 나타내는 나노입자를 이용한 당화혈색소 측정용 바이오센서

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PARK ET AL.: "a disposable electrochemical glucose sensor with non-enzymatic molecular recognition layer", BIOCHIPS FOR NEW PANDEMIC CHALLENGES, 17 November 2021 (2021-11-17) *
PARK MIN; HEO YUN JUNG: "Biosensing Technologies for Chronic Diseases", BIOCHIP JOURNAL, KOREAN BIOCHIP SOC, SEOUL , SOUTH KOREA, vol. 15, no. 1, 22 February 2021 (2021-02-22), Seoul , South Korea , pages 1 - 13, XP037397336, ISSN: 1976-0280, DOI: 10.1007/s13206-021-00014-3 *

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