KR20140106268A - Method for Detecting Biomolecules Using Magnetic Particles - Google Patents

Method for Detecting Biomolecules Using Magnetic Particles Download PDF

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KR20140106268A
KR20140106268A KR1020130020609A KR20130020609A KR20140106268A KR 20140106268 A KR20140106268 A KR 20140106268A KR 1020130020609 A KR1020130020609 A KR 1020130020609A KR 20130020609 A KR20130020609 A KR 20130020609A KR 20140106268 A KR20140106268 A KR 20140106268A
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graphene
magnetic particles
probe
magnet
biomolecules
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정봉현
권도형
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한국생명공학연구원
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    • 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
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    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/02—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance
    • G01N27/023—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance where the material is placed in the field of a coil
    • G01N27/025—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance where the material is placed in the field of a coil a current being generated within the material by induction
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54313—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being characterised by its particulate form
    • G01N33/54326—Magnetic particles
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    • C12Q2563/00—Nucleic acid detection characterized by the use of physical, structural and functional properties
    • C12Q2563/143—Magnetism, e.g. magnetic label
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    • C12Q2563/00—Nucleic acid detection characterized by the use of physical, structural and functional properties
    • C12Q2563/149—Particles, e.g. beads

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Abstract

The present invention relates to a method of electrochemically detecting biomolecules using magnetic particles on graphenes, and more particularly, to a method of electrochemically detecting biomolecules on graphene, comprising the steps of: (a) reducing graphene to an electrically neutral state; (b) binding the probe having the electrochemically active substance immobilized thereon with magnetic particles, and then binding the probe to the surface of the graphene using a magnet; (c) separating and removing the magnetic particles and the probe which do not bond to the graphene by removing the magnet; (d) inducing selective binding between the probes on the surface of the graphene and the target biomolecules to which the magnetic particles are bound, using the magnet; (e) removing the magnet to separate and remove the magnetic particles and the target biomolecule not binding to the graphene; And (f) measuring a change in current before and after the reaction.
The present invention is particularly useful because it is possible to directly control biomolecules using magnetic particles and detect minute amounts of biomolecules in a short time with high sensitivity.

Description

TECHNICAL FIELD The present invention relates to a method for detecting a biomolecule using magnetic particles,

TECHNICAL FIELD The present invention relates to a method for detecting biomolecules using magnetic particles, and more specifically, to a method for detecting biomolecules electrochemically using magnetic particles on graphene.

Recently, research on biomolecular structure has been applied to various fields such as medical diagnosis, life phenomenon identification, and drug development. However, since most of the analysis methods are limited, the necessity of developing new technology is increasing. Conventional analysis of biomolecules such as DNA uses a labeling substance so that a target molecule can be detected as a measurable signal. As a labeling substance, a radioactive substance, a fluorescent substance, an enzymatic label or a magnetic substance may be used.

Magnetic particles are attracting much attention as markers for binding assays due to their advantages such as easy control, high biocompatibility and high sensitivity. U.S. Patent No. 5,981,297 discloses a method for analyzing a target molecule using a change in magnetoresistance when a recognition substance that selectively fixes a target molecule is bonded to a magnetic material. This is a direct measurement of the magnetic flux of the magnetic field of the magnetic nanoparticles, which requires complicated and expensive equipment for measuring magnetic flux, which is difficult to miniaturize.

In addition, U.S. Patent No. 6,141,096 discloses a method of labeling a fluorescent dye on a sample DNA, reacting the probe with a probe on the chip, and detecting the fluorescent material remaining on the chip surface using a confocal microscope or a CCD camera However, such a fluorescence detection method is difficult to miniaturize, and there is a problem that a digitized output can not be seen.

Another method for detecting the binding of biomolecules such as DNA hybridization is electrochemical detection. Specifically, a method for electrochemically detecting a target nucleic acid using a DNA wrap assay is provided. In this method, a capture strand is immobilized on a substrate, and a linker, a probe chain, Electrochemically active material is connected. The electrochemically active material moves away from the substrate and then approaches the substrate when the target chain is coupled, thereby measuring a change in the redox signal by a cyclic voltammetry. However, in order to detect target biomolecules, probe biomolecules or signaling biomolecules must be designed and manufactured very precisely, and it takes a long time to detect biomolecules.

Graphene, on the other hand, is a semimetal with excellent electromagnetic and mechanical properties. The mobility of the charge carrier is faster than in silicon and can flow a lot of current, It can process positive information, improve switching speed, and is known as a material suitable for miniaturization. In addition, it has a large surface area to volume ratio, which is an advantage in sensor technology that must be highly reactive with the detection material.

(Marissa Wu et al., Langmuir, 27, 2011, 2731-2738) discloses a method of spectroscopically detecting biomolecules using fluorescently labeled DNA on graphene oxide, ), There is a problem that detection takes a long time because biomolecules approach the substrate through diffusion through the solution.

The present inventors have made intensive efforts to solve the above problems. As a result, the present inventors have found that when biomolecules are detected using grains on graphene, biomolecules can be directly controlled and biomolecules can be detected with high sensitivity in a short time And completed the present invention.

It is an object of the present invention to provide a method for detecting biomolecules in a simple and rapid manner using magnetic particles on graphene.

In order to accomplish the above object, the present invention provides a method for producing graphene comprising: (a) reducing graphene to an electrically neutral state; (b) binding the probe having the electrochemically active substance immobilized thereon with magnetic particles, and then binding the probe to the surface of the graphene using a magnet; (c) separating and removing the magnetic particles and the probe which do not bond to the graphene by removing the magnet; (d) inducing selective binding between the probes on the surface of the graphene and the target biomolecules to which the magnetic particles are bound, using the magnet; (e) removing the magnet to separate and remove the magnetic particles and the target biomolecule not binding to the graphene; And (f) measuring a change in current before and after the reaction. The present invention also provides a method for detecting a biomolecule using magnetic particles.

The biomolecule detection method according to the present invention can directly control biomolecules using magnetic particles and can detect a small amount of biomolecules present in a very low concentration with a high sensitivity within a short time. Using the biosensor, RT- PCR, biochip, and the like.

FIG. 1 (a) shows a conventional method of detecting biomolecules by diffusion, and FIG. 1 (b) shows the present invention in which biomolecules are detected using magnetic particles.
2 schematically shows a stepwise method of detecting biomolecules using the magnetic particles of the present invention.
3 shows a differential pulse voltammetry (DPV) method of a biomolecule detection method according to the conventional method (a) and the present invention (b).
4 shows the differential pulse current curve according to the concentration level of the target biomolecule.
FIG. 5 shows a differential pulse current curve according to measurement time for a sample containing RNA complementary to the probe DNA and a sample containing non-complementary RNA.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.

In the present invention, biomolecules in a solution can be directly controlled using magnetic particles, so that biomolecules can be detected with high sensitivity within a short time.

Thus, in one aspect, the present invention provides a method of reducing graphene, comprising: (a) reducing graphene to an electrically neutral state; (b) binding the probe having the electrochemically active substance immobilized thereon with magnetic particles, and then binding the probe to the surface of the graphene using a magnet; (c) separating and removing the magnetic particles and the probe which do not bond to the graphene by removing the magnet; (d) inducing selective binding between the probes on the surface of the graphene and the target biomolecules to which the magnetic particles are bound, using the magnet; (e) removing the magnet to separate and remove the magnetic particles and the target biomolecule not binding to the graphene; And (f) measuring a change in current before and after the reaction.

In the present invention, graphene refers to a two-dimensional thin film of a honeycomb structure made of one layer of carbon atoms. The carbon atoms form a hexagonal honeycomb structure spreading in two dimensions when chemically bonded by an sp 2 hybrid orbit. The aggregate of carbon atoms having this planar structure is graphene. Graphene is flexible, has very high electrical conductivity and has a large surface area.

In the present invention, the term 'target biomolecule' refers to a biomolecule to be detected and may be DNA, RNA, peptide, lipid, carbohydrate, protein, enzyme or cell.

In the present invention, 'probe' is a substance capable of specifically binding to a target biomolecule, and DNA, RNA, peptide, lipid, carbohydrate, protein, enzyme or cell can be used. If the target biomolecule is DNA or RNA, the probe may be DNA or RNA having a sequence complementary to the target biomolecule or a fragment thereof.

In the present invention, the probe is immobilized with a substance having an electrochemical activity, and the substance having electrochemical activity may be selected from the group consisting of metallocene including ruthenium, ruthenium, methylene blue ), A viologen, an alkylammonium or adamantyl group. The electrochemically active substance causes an electrochemical reaction to obtain a unique differential pulse current curve, thereby enabling detection of the presence or concentration of the target biomolecule.

The ferrocene is a representative material of metallocene which is an aromatic transition metal complex, and is a compound in which cyclopentadiene, which is a pentagonal ring-shaped ligand, is coordinated to both iron ions. The ferrocene causes an electrochemical reaction to obtain a unique differential pulse current curve, thereby enabling detection of the presence or concentration of the target biomolecule.

The magnetic particles used in the present invention are materials having a size ranging from several nanometers to several tens of nanometers. Any magnetic particles can be used as long as they can be applied to magnetism migration according to the prior art. Preferably, Fe 2 O 3 Or magnetic nanoparticles containing Fe 3 O 4 .

The surface of the magnetic particles can be charged with a positive charge or a negative charge to improve the binding between the biomolecule and the probe. For example, in the present invention, when magnetic particles having positive electric charge are used, they can be bonded by electrostatic bonding to biomolecules and probes that are negatively charged. In addition, since the magnetic particles are attracted to the magnet and move according to a direction of applying a magnetic field from the outside, when the magnetic particles are bonded to the probe and the target biomolecule, they can be attracted to a desired position and reacted. Can be shortened.

In the present invention, a magnet can be used as long as it can attract magnetic particles through a magnetic field.

In the steps (c) and (e) of the present invention, a buffer is used to remove substances not bound to graphene. The buffer may be water or PBS (phosphate buffered saline) But is not limited thereto.

In the present invention, a method of measuring a change in current for detecting biomolecules can be performed by a differential pulse current method using a potentiometer or a circulating voltage-current method. If the target biomolecule is present in the sample, the current may change as the target biomolecule and the substance having electrochemical activity bind to the immobilized probe.

Hereinafter, a biomolecule detection method according to the present invention will be described in detail with reference to the drawings.

In the step (a) of the present invention, graphene is raised on an ITO (Indium Tin Oxide) electrode and a voltage (-1.2 V) is applied to reduce the graphene to an electrically neutral state. However, And it is possible to reduce graphene using a conventional known method.

In order to bind the probe to the surface of the graphene, as shown in FIG. 2, ferrocene-immobilized DNA was used as a probe, and magnetic particles were bonded thereto by electrostatic bonding (step (b)). As the magnetic particles are bonded to the probe, the probe can be attracted to the graphene surface using a magnet. At this time, single stranded DNA (ssDNA) and graphene are π-π conjugated due to the nature of the molecular structure to form a complex.

When the magnet is removed, the magnetic particles and graphene-free DNA are separated from the graphene, and the separated materials can be removed using water or PBS buffer (step (c)).

When the complementary RNA or the target biomolecule is reacted with the ssDNA (probe DNA) bound to the graphene (step (d)), hybridization occurs between the target RNA and the probe ssDNA, stranded DNA, dsDNA). At this time, when the magnetic particles are bound to the target biomolecule and attracted to the complex using the magnet, the detection time can be shortened.

Since the formed dsDNA is a rigid structure, when the dsDNA is generated, the probe DNA is dissociated from the complex (see FIG. 2). However, when nonspecific RNA that is not complementary to the probe DNA is reacted, the DNA bound to the graphene remains without being separated from the complex (FIG. 5). That is, as shown in FIG. 5, a differential pulse current curve was measured using a sample containing RNA complementary to the DNA of the probe and a sample containing non-complementary RNA, and the results were compared. As a result, Can effectively detect complementary RNA.

The magnetic particles, biomolecules and dissociated dsDNA that are not bound to graphene can be separated from the graphene by removing the magnet and then removed using a buffer (step (e)).

In the present invention, the current was measured using graphene as a working electrode, Ag / AgCl as a reference electrode, and Pt as a counter electrode (step (f)). A differential pulse current curve can be obtained by applying a suitable range of voltages through which the electrochemically active material according to the present invention can react to the working electrode through a constant voltage.

Conventionally, in order to attract probes and biomolecules on a substrate, it takes a long time to detect them depending on diffusion. In the present invention, it is possible to artificially attract probes and biomolecules to which magnetic particles are bonded by applying a magnetic field 1). Therefore, it is advantageous in detection of a very low concentration, and the detection time can be shortened.

[Example]

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for illustrating the present invention and that the scope of the present invention is not construed as being limited by these embodiments.

Example  1: Target biomolecule detection

Graphene was deposited on the ITO (Indium Tin Oxide) electrode and then reduced at -1.2 V to form an electrically neutral graphene.

As shown in FIG. 2, Fc-DNA complexes in which magnetic particles were bound were prepared by reacting ferrocene (Fc) -fixed probe DNA with magnetic particles (Fe 2 O 3 ). The Fc-DNA complex was attracted to the graphene surface using a magnet to bind the DNA to the graphene. The unbound residue was separated from the graphene by removing the magnet, and then washed with a buffer. Magnetic particles (Fe 2 O 3 ) were bound to the RNA to be detected and then hybridized with DNA bound on graphene using a magnet. Thereafter, the magnet was peeled off and the unbonded residue was removed and washed with a buffer.

The Fc-DNA complex remaining on the graphene was measured for current using a differential pulse current method. It was confirmed that the biomaterial can be detected through the characteristic change due to the specific and complementary binding between the target RNA and the probe DNA (FIG. 5). Further, as shown in FIG. 3, it is confirmed that a very small amount of biomaterial can be detected because the sensitivity is higher than that of the conventional method, and in particular, the present invention can detect with high sensitivity even at the atomomolar concentration level (FIG.

While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. something to do. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (8)

A method for detecting a biomolecule using magnetic particles, comprising the steps of:
(a) reducing the graphene to an electrically neutral state;
(b) binding the probe having the electrochemically active substance immobilized thereon with magnetic particles, and then binding the probe to the surface of the graphene using a magnet;
(c) separating and removing the magnetic particles and the probe which do not bond to the graphene by removing the magnet;
(d) inducing selective binding between the probes on the surface of the graphene and the target biomolecules to which the magnetic particles are bound, using the magnet;
(e) removing the magnet to separate and remove the magnetic particles and the target biomolecule not binding to the graphene; And
(f) measuring the current change before and after the reaction.
The method according to claim 1, wherein the probe is selected from the group consisting of DNA, RNA, peptides, lipids, carbohydrates, proteins, enzymes and cells.
The method of claim 1, wherein the electrochemically active material is selected from the group consisting of ferrocene, ruthenium, methylene blue, viologen, alkylammonium, and adamantyl groups. A method for detecting a biomolecule using the magnetic particle.
The method for detecting a biomolecule according to claim 1, wherein the magnetic particles are Fe 2 O 3 or Fe 3 O 4 .
The method according to claim 1, wherein the target biomolecule is selected from the group consisting of DNA, RNA, peptides, lipids, carbohydrates, proteins, enzymes and cells.
The method according to claim 1, wherein the separation and removal are performed using a buffer.
The method according to claim 6, wherein the buffer is water or PBS (phosphate buffered saline).
The method according to claim 1, wherein the measurement of the current change is performed by a differential pulse voltammetry (DPV) method using a potentiometer or a circulating voltage-current method.
KR1020130020609A 2013-02-26 2013-02-26 Method for Detecting Biomolecules Using Magnetic Particles KR20140106268A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20170047622A (en) 2015-10-23 2017-05-08 주식회사 아모라이프사이언스 Method of fixing a protein on the particles
CN108226485A (en) * 2018-02-12 2018-06-29 中国人民解放军陆军军医大学 Complex immunity magnetic bead that hepatic stellate cells isolates and purifies and preparation method thereof
KR20210132375A (en) 2020-04-27 2021-11-04 하이브리드테크놀로지 주식회사 Method for isolating nucleic acid using integrated magnetite nanoparticles on graphene oxide
WO2022139478A1 (en) * 2020-12-23 2022-06-30 한국전자기술연구원 Method for manufacturing working electrode for biosensor comprising magnetic particles, electrode manufactured thereby, and method for measuring concentration of biomarker in sample using manufactured electrode

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20170047622A (en) 2015-10-23 2017-05-08 주식회사 아모라이프사이언스 Method of fixing a protein on the particles
US11169147B2 (en) 2015-10-23 2021-11-09 Amolifescience Co., Ltd. Method for immobilizing protein on particle
CN108226485A (en) * 2018-02-12 2018-06-29 中国人民解放军陆军军医大学 Complex immunity magnetic bead that hepatic stellate cells isolates and purifies and preparation method thereof
CN108226485B (en) * 2018-02-12 2020-06-30 中国人民解放军陆军军医大学 Composite immunomagnetic bead for separating and purifying hepatic stellate cells and preparation method thereof
KR20210132375A (en) 2020-04-27 2021-11-04 하이브리드테크놀로지 주식회사 Method for isolating nucleic acid using integrated magnetite nanoparticles on graphene oxide
WO2022139478A1 (en) * 2020-12-23 2022-06-30 한국전자기술연구원 Method for manufacturing working electrode for biosensor comprising magnetic particles, electrode manufactured thereby, and method for measuring concentration of biomarker in sample using manufactured electrode

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