CN112834740B - Peptide-like oligomer, preparation method thereof, pharmaceutical composition and microfluidic chip - Google Patents
Peptide-like oligomer, preparation method thereof, pharmaceutical composition and microfluidic chip Download PDFInfo
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- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 11
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- 239000011521 glass Substances 0.000 claims abstract description 17
- SDAWVOFJSUUKMR-UHFFFAOYSA-N 12-sulfanyldodecanoic acid Chemical compound OC(=O)CCCCCCCCCCCS SDAWVOFJSUUKMR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 108010043958 Peptoids Proteins 0.000 claims description 37
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- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
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- 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
- G01N33/54393—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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- 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
- G01N33/551—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being inorganic
- G01N33/552—Glass or silica
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- 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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4709—Amyloid plaque core protein
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2814—Dementia; Cognitive disorders
- G01N2800/2821—Alzheimer
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- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
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- Molecular Biology (AREA)
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- General Health & Medical Sciences (AREA)
- Cell Biology (AREA)
- Pathology (AREA)
- Food Science & Technology (AREA)
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- Biotechnology (AREA)
- Analytical Chemistry (AREA)
- Biochemistry (AREA)
- Microbiology (AREA)
- General Physics & Mathematics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention provides a peptide-like oligomer, a preparation method of the peptide-like oligomer, a pharmaceutical composition containing the peptide-like oligomer and a microfluidic chip. The nano-sheet is assembled by the peptide oligomer, and is used for modifying the glass-based microfluidic chip, and the GPTMS and the 12-mercapto-dodecanoic acid are further utilized to form covalent bonds with the nano-sheet of the peptide oligomer through reaction, so that the surface modification of the glass-based microfluidic chip is realized. The method effectively reduces the nonspecific adsorption of the chip surface, provides the coupling groups of the antibody and the small molecules, further improves the detection sensitivity and accuracy of the microfluidic chip, and provides a new choice for in vitro diagnosis. In addition, the modification method is simple, high in efficiency and low in manufacturing cost.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to a peptide-like oligomer, a preparation method of the peptide-like oligomer, a pharmaceutical composition containing the peptide-like oligomer and a microfluidic chip.
Background
The term microfluidic chip originally originated from Manz in the 90 th century of 20 and Widmer proposed micro total analysis System (μTAS). The Manz professor successfully applied MEMS technology to analytical chemistry and soon realized high-speed capillary electrophoresis on microchips, and the results were published in journal such as Science, from which rapid attention was paid to and became one of the forefront technological fields in the world today. The Lab-on-a-chip (Lab) and the microfluidic chip (Microfluidic Chip) are different names proposed in this field,as the application of this discipline expands from the original analytical chemistry to multiple research and application fields, and researchers' deep understanding of this discipline, microfluidic chips have become a generic term for this field. Microfluidic is the processing and manipulation of minute quantities (10) within channel systems of tens to hundreds of microns dimensions -9 To 10 -18 Liter) of fluid. A key feature of microfluidic chip technology is manipulation of fluids in microscale channels. It is because the micro-scale structure of the microfluidic chip significantly increases the specific surface area of the fluid, i.e. the ratio of surface area to volume, thereby resulting in a series of special effects related to the surface, such as laminar flow effects, surface tension, capillary effects, rapid thermal conduction effects, diffusion effects, etc., thus bringing about superior performance not possessed by macro-scale laboratory devices.
In the current mainstream detection scheme, the surface of the microfluidic chip is modified by coupling antibodies or molecular probes, and the molecular probes comprise targeting molecules of specific receptor proteins at tumor sites such as antibodies, polypeptides, peptoids and nucleic acid aptamers. However, the coupled functional molecules need to provide sufficient surface-active groups and blocking is also particularly important for chips in order to reduce noise from non-specific adsorption. The surface of the glass-based chip is functionalized through chemical reaction, so that the surface modification of the glass-based chip can be effectively realized, the coupling duration and the effective time of functional molecules are greatly prolonged, the activity of a natural living sample can be ensured, and the method is expected to bring new revelation to in-vitro diagnosis.
Disclosure of Invention
At least one embodiment of the present disclosure provides a peptide-like oligomer comprising: beta-phenylethylamine subunit, 3-aminopropionic acid subunit and ethylenediamine subunit.
For example, in at least one embodiment of the present disclosure, a peptoid oligomer is provided having a structure represented by formula I:
wherein, 10 is more than or equal to n1 is more than or equal to 3, 10 is more than or equal to n2 is more than or equal to 3, n1=n2, and both n1 and n2 are natural numbers.
At least one embodiment of the present disclosure also provides a method for preparing the peptoid oligomer, wherein the method comprises a solid phase synthesis method.
For example, in a preparation method provided in at least one embodiment of the present disclosure, the preparation method includes the steps of:
(1) Attaching a first subunit of said peptoid oligomer to a solid support according to the order of attachment of the subunits of said peptoid oligomer;
(2) Reacting bromoacetic acid with an amino group of a first subunit attached to the solid support under the activation of an activator to form an amide bond;
(3) Reacting the donor of the second subunit of the peptoid oligomer with the product obtained in the step (2), and replacing bromine atoms to complete the connection of the second subunit;
(4) Repeating the connection of the bromoacetic acid and the subsequent subunits until the connection of all subunits is completed;
(5) And (3) cracking the synthesized peptide-like oligomer from the solid phase carrier to obtain the peptide-like oligomer.
At least one embodiment of the present disclosure also provides a pharmaceutical composition comprising: a peptide oligomer of any of the above; pharmaceutically acceptable auxiliary materials.
For example, in the pharmaceutical composition provided in at least one embodiment of the present disclosure, the adjuvant is any one or a combination of at least two of an excipient, a diluent, a carrier, a flavoring agent, a binder, and a filler.
The present disclosure also provides, in at least one embodiment, a use of any of the above pharmaceutical compositions in the preparation of a medicament for detecting or diagnosing a disease associated with alzheimer's disease.
The present disclosure also provides, in at least one embodiment, a use of any of the above pharmaceutical compositions in microfluidic chip modification.
For example, in an application provided by at least one embodiment of the present disclosure, the chip comprises a glass-based microfluidic chip.
The invention also provides a microfluidic chip, which comprises the oligomer nano-sheet layer and a functional layer, wherein the functional layer comprises GPTMS-guided epoxy modification and 12-mercapto-dodecanoic acid-guided closed activation layer modification.
The invention has the following beneficial effects:
the invention provides a peptide-like oligomer, a preparation method of the peptide-like oligomer, a pharmaceutical composition containing the peptide-like oligomer and a microfluidic chip. The nano-sheet is assembled by the peptide oligomer, and is used for modifying the glass-based microfluidic chip, and the GPTMS and the 12-mercapto-dodecanoic acid are further utilized to form covalent bonds with the nano-sheet of the peptide oligomer through reaction, so that the surface modification of the glass-based microfluidic chip is realized. The method effectively reduces the nonspecific adsorption of the chip surface, provides the coupling groups of the antibody and the small molecules, further improves the detection sensitivity and accuracy of the microfluidic chip, and provides a new choice for in vitro diagnosis. In addition, the modification method is simple, high in efficiency and low in manufacturing cost.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following brief description of the drawings of the embodiments will make it apparent that the drawings in the following description relate only to some embodiments of the present invention and are not limiting of the present invention.
FIG. 1 is a schematic diagram showing a method for synthesizing a peptide-like oligomer according to an embodiment of the present invention;
FIG. 2 is a schematic diagram illustrating a two-dimensional nano-sheet material according to an embodiment of the present invention;
FIG. 3 is a fluorescence microscope image of a two-dimensional nanoplatelet layer according to an embodiment of the present invention;
FIG. 4 is a flow chart of a chip surface epoxy modification according to an embodiment of the present invention;
FIG. 5 is a schematic diagram of a glass-based chip surface modification and functional layer structure according to an embodiment of the present invention;
FIG. 6 is a graph showing the result of reduction of nonspecific binding signals of a chip surface modification according to an embodiment of the present invention; the method comprises the steps of,
FIG. 7 is a graph showing the results of detection affinity for the Alzheimer's disease biomarker Abeta 42 provided in one embodiment of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present invention fall within the protection scope of the present invention.
Unless defined otherwise, technical or scientific terms used in this disclosure should be given the ordinary meaning as understood by one of ordinary skill in the art to which this invention belongs. The terms "first," "second," and the like, as used in this disclosure, do not denote any order, quantity, or importance, but rather are used to distinguish one element from another. The word "comprising" or "comprises", and the like, means that elements preceding the word are meant to encompass the elements listed after the word as well as equivalents thereof without excluding other elements.
The experimental methods used in the following examples are conventional methods unless otherwise specified. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The SPRi instrument in the following examples is Plexera Kx5V2, plexera Bioscience LLC, USA, which is mainly equipped with 660nm led light source, CCD image collector and sensor chip with microfluidic channel, which displays the change of reflected light intensity with time at each monitoring point and records as SPR curve.
"nM" herein refers to "nmol/L" and "mM" refers to "mmol/L" unless specifically stated otherwise.
The peptoid molecule has the characteristics of low immunogenicity, good tissue permeability, high stability, easy modification, low manufacturing cost and the like. However, in the application of molecular probes, the binding capacity of the peptoid small molecules and the biosensor is not strong, so that the peptoid small molecules cannot be used as probe molecules; the antibody has the characteristic of tightly combining with the biosensor, but the arrangement of the antibody molecules is disordered, and the arrangement direction of the antibody molecules on the surface of the sensor is randomly difficult to control, so that the specificity of the antibody is low, and the cost of the antibody is high. The inventor of the present disclosure found that an oligomer formed from a peptoid small molecule and an antibody can well bind the peptoid small molecule and the antibody, i.e., the peptoid oligomer has the characteristic that the antibody can be tightly bound with a biosensor, and the peptoid small molecule can be orderly formed on the surface of the sensor. In addition, the molecular probe formed by the oligomer has strong affinity with a target, and the oligomer cannot be subjected to enzymolysis, so that the activity of a natural living sample can be ensured.
Compared with polypeptide, polypeptide takes alpha amino acid as structural unit, and N-substituted glycine as structural unit. The peptoid compound has good biological activity and pharmacological properties, can effectively detect or inhibit deterioration in vivo experiments, and has good cell membrane penetrability. Currently, the mature peptoid synthesis technology is the "subunit synthesis" technology.
At least one embodiment of the present disclosure further provides a peptide-like oligomer having a molecular structural formula:
wherein, 10 is more than or equal to n1 is more than or equal to 3, 10 is more than or equal to n2 is more than or equal to 3, n1=n2, and both n1 and n2 are natural numbers.
For example, the oligomer includes: beta-phenylethylamine subunit, 3-aminopropionic acid subunit and ethylenediamine subunit.
For example, the structural formula of each subunit is as follows:
for example, in an oligomer provided in at least one embodiment of the present disclosure, the oligomer comprises subunits arranged in the following order: [ beta-phenethylamine subunit-3-aminopropionic acid subunit]n 2 -probe- [ beta-phenylethylamine subunit-ethylenediamine subunit]n 1 。
At least one embodiment of the present disclosure also provides a method of preparing an oligomer comprising synthesizing subunits by solid phase synthesis.
For example, fig. 1 is a flowchart of a method for preparing a peptoid oligomer according to one embodiment of the disclosure, the method comprising the steps of:
step S1: ligating a first subunit of the oligomer to the solid support according to the order of ligation of the subunits of the oligomer;
step S2: reacting bromoacetic acid with an amino group of a first subunit attached to a solid support under activation of an activator to form an amide bond;
step S3: reacting the donor of the second subunit of the peptoid oligomer with the product obtained in the step S2 to replace bromine atoms and complete the connection of the second subunit;
step S4: repeating the connection of bromoacetic acid and the subsequent subunits until the connection of all subunits is completed;
step S5: the synthesized oligomer is cleaved from the solid phase carrier to obtain the peptide oligomer.
For example, the oligomer comprises a side chain formed by the left side peptide-like compound and the right side peptide-like compound, and further comprises various probes embedded in the peptide-like compound for detection, wherein the left side chain comprises amino groups, the right side chain comprises carboxyl groups, the side chain helps the oligomer to form a two-dimensional lamellar structure, so that the middle probes are exposed on the surface of a sensor for detecting various targets, and the side chain can further enable the oligomer to be arranged more orderly.
For example, in the oligomer, n1=n2=3, n1=n2=4, n1=n2=6, n1=n2=8, or n1=n2=10.
It should be noted that when n1 and n2 are smaller than 3, there is a problem that the chain length is too short to be assembled; when n1 and n2 are greater than 10, the chains formed are too long, and the density of the intermediate inserted peptoid compound of the oligomer is too low, a decrease in affinity occurs, and thus specific binding to the target molecule cannot be achieved.
Example one
The molecular structure is as follows:
the preparation method of the oligomer with n1=n2=4, n1=n2=6 or n1=n2=8 specifically comprises the following steps:
(1) Rink amide AM resin (initial resin for polypeptide synthesis, substitution level 0.3 mmol/g) was swelled and deprotected with piperidine, and beta-phenethylamine was equimolar mixed with 1-hydroxybenzotriazole and coupled under activation of N-methylmorpholine.
(2) 10mL of bromoacetic acid with the concentration of 2mol/L and 10mL of N, N' -Diisopropylcarbodiimide (DIC) with the concentration of 3.2mol/L are added into Rink amide AM resin, and the mixture is reacted for 30min at 38 ℃ to acylat the amino groups at the tail ends of the resin;
(3) Adding 2mol/L primary amine, reacting for 90min at 37 ℃, and replacing bromine atoms through nucleophilic substitution reaction to complete synthesis of one subunit;
(4) Repeating the steps (2) and (3) until synthesis of the rest units is completed;
(5) After the synthesis was completed, the side chain protecting groups were removed and the oligomer was cleaved from the resin with 95% trifluoroacetic acid, 2.5% ultrapure water and 2.5% triisopropylsilane, respectively, by mass percent, for further use.
In the process of forming the oligomer with the structure, subunit feeding sequences are as follows:
beta-phenethylamine, 3-aminopropionic acid, beta-phenethylamine, 3-aminopropionic acid; beta-phenethylamine, 3-aminopropionic acid, beta-phenethylamine, 3-aminopropionic acid; beta-phenethylamine, 3-aminopropionic acid, beta-phenethylamine, 3-aminopropionic acid; beta-phenethylamine, 3-aminopropionic acid, beta-phenethylamine, 3-aminopropionic acid; acetic acid amine, butanediamine, alpha-methylbenzylamine, butanediamine, isobutylamine, piperonyl amine, butanediamine; beta-phenethylamine, ethylenediamine, biphenylethylamine, ethylenediamine; beta-phenethylamine, ethylenediamine, biphenylethylamine, ethylenediamine; beta-phenethylamine, ethylenediamine, biphenylethylamine, ethylenediamine; beta-phenethylamine, ethylenediamine, biphenylethylamine, ethylenediamine.
For example, the oligomer may be dissolved to a material in an amount ratio of dimethyl sulfoxide: water=2:1 dimethyl sulfoxide (DMSO) and water (H 2 O) to a concentration of 2mM.
The preparation method of the two-dimensional nano sheet material provided by the embodiment of the invention comprises the following steps:
(1) The peptoid oligomer is distributed at a gas-liquid interface through amphipathy;
(2) Applying lateral pressure to the molecular chains of the peptoid oligomer to form a compact monomolecular layer;
(3) By further increasing the lateral pressure applied to the critical point, the monolayer collapses into the aqueous solution to form a bilayer.
For example, fig. 2 is a schematic diagram of a two-dimensional oligomer forming process according to an embodiment of the present disclosure, and as shown in fig. 2, the two-dimensional oligomer forming process includes: placing an oligomer provided by an embodiment of the present disclosure in a langmuir tank, the oligomer comprising a hydrophilic end and a hydrophobic end, the oligomer being arranged disordered at an interface of a gas and a liquid in the absence of an external force; then applying an external force to the unordered oligomers, wherein the oligomers are orderly arranged at a gas-liquid interface; further, an external force is applied to the ordered arrangement of oligomers, which are extruded under the gas-liquid interface, under which hydrophilic ends are exposed to the outside and hydrophobic ends are formed to the inside, thereby forming a two-dimensional structure.
The formation process of the oligomer nano-sheet layer is as follows: the oligomer obtained in example one above, at a concentration of 2mM, was dissolved in a solution containing 10mM 4-hydroxyethyl piperazine ethanesulfonic acid, 100mM sodium chloride, ph=8.0, diluted to a sheet forming buffer to a final concentration of 1-100 μm, for example, 20 μm, and then manually shaken: the peptoid solution is stably stored for 22 hours at room temperature, then is manually and gently shaken for 30 seconds, is further stabilized for 1 minute, and the shaking-stabilizing process is repeated for 5 times; or a machine shaking method: the peptoid solution was slowly spun (0.6 rpm) in the tube from horizontal to vertical, once every 450 seconds; the resulting peptoid nanoplatelet solution was added to nile red to a final concentration of 1 μm, and the solution was placed on 1% agar and observed using a fluorescence microscope (ver. A1, carl Zeiss Far East, germany) as shown in fig. 3, and a distinct nanoplatelet structure was observed.
The microfluidic chip is used for biomedical detection and diagnosis, except that the nonspecific binding is one of the most main factors causing false positive or false negative, so that the shielding of nonspecific adsorption has great scientific and commercial significance. Although the blocking reagent such as BSA, ethanolamine and the like in the traditional sense can reduce partial non-specific binding, the effect is not ideal, and particularly for targets with extremely low content, the requirements on sensitivity and specificity are more strict, so that the detection sensitivity and specificity are improved by a chip surface modification technology, and the method has extremely important scientific significance.
The embodiment of the disclosure provides a method for finishing the surface modification of a glass chip by combining the peptide-like nano-sheet layer through covalent connection, wherein 3-glycidol ether oxygen propyl methyl diethoxy silane (GPTMS) and 12-mercapto dodecanoic acid form a complete functional molecular layer through three-step reaction.
Wherein, GPTMS formula is:
the structural formula of the 12-mercapto dodecanoic acid is as follows:
as shown in fig. 4, the main steps of epoxy modification of the surface of the glass chip of the present invention are as follows:
(1) In an aqueous solution system, the methyl of GPTMS and water molecules are subjected to hydrolysis reaction to generate Si-OH;
(2) The GPTMS molecule containing Si-OH and Si-OH on the surface of the glass chip undergo condensation reaction to form Si-O-Si bond.
The glass chip modified by the epoxy is modified by a dense monomolecular layer by using 12-mercapto dodecanoic acid, the surface of the chip is effectively sealed, and-COOH required by the coupling of the peptide-like nanosheet is provided, and the specific steps are as follows:
(1) Placing the epoxy modified chip in pure water for full cleaning;
(2) Placing the chip in 1M 12-mercaptododecanoic acid water solution for full reaction for 24 hours to form a dense monomolecular layer;
(3) The chip was depth-washed with 10 XPBS, 1 XPBS, and ultra-pure water, respectively, for use.
The functional layer modification is carried out by utilizing the nano-sheet layer assembled by the peptide-like oligomer with the probe to form a complete chip structure, as shown in fig. 5, the specific steps are as follows:
(1) Sequentially performing deep cleaning on the epoxy modified and sealed chip by using 10 XPBS, 1 XPBS and ultrapure water;
(2) EDC/NHS is added in the ratio of 1:1 to carry out carboxyl activation;
(3) And (5) spotting the peptoid nanosheets, and washing the chip after incubation overnight.
The chip structure is shown in fig. 5, and is sequentially provided with an oligomer nanosheet layer, a GPTMS and 12-mercaptododecanoic acid modified functional molecule layer, a structural layer, a PVX layer, a Gate (integrated circuit layout) layer and a glass substrate layer from top to bottom. Wherein the structural layer, the PVX layer, the Gate layer and the glass substrate layer are the basic structure of the biochip.
The oligomer provided by the embodiment of the disclosure has simple synthesis process and strong binding capacity with Abeta 42, and has extremely high affinity modification on the surface of the glass-based chip, so that the capture of Abeta 42 can be effectively realized, and the blood diagnosis of Alzheimer disease can be further realized.
For example, FIG. 6 is a graph showing the results of the non-specific binding signals of the chips of the present invention and the comparative example over time, wherein bio-chip is the chip containing the peptoid oligomer and the modified functional molecule layer provided in the above-described examples, and control is the chip containing the peptoid oligomer without GPTMS and 12-mercaptododecanoic acid modification. The modified chip can be seen to greatly reduce the nonspecific binding signal and improve the specificity and the signal-to-noise ratio. The test steps for reducing the nonspecific binding signal after the chip is modified by using the enzyme-labeled instrument are as follows:
(1) Sequentially performing deep cleaning on the modified chip by using 10 XPBS, 1 XPBS and ultrapure water;
(2) EDC/NHS is added in the ratio of 1:1 to carry out carboxyl activation;
(3) Performing peptide-like nanosheet spotting, sufficiently incubating overnight, cleaning the chip, and using the chip directly coated with the probe and the chip blocked by 2.5% BSA and 5% ethanolamine as a control;
(4) The PBS solution of FITC-HSA is prepared, the test chip and the control chip of the step (3) are introduced at the flow rate of 2 mu L/s, and fluorescent signals are collected every minute.
For example, the procedure for testing the binding capacity between oligomer and aβ42 using surface plasmon resonance imaging techniques is as follows:
(1) Dissolving the oligomer-assembled nanoplatelets to ddH 2 The concentration of the oligomer in O is 1-1000 mu M;
(2) The oligomer solution is spotted on the surface of a chip which is modified by epoxy and is sealed, each sample is repeated for 3 spots, after the sample is placed for 12 hours at the temperature of 4 ℃, the chip is cleaned by 10 XPBS, 1 XPBS and ultrapure water in sequence, then the chip is sealed by 1M aminoethanol hydrochloride for 30 minutes, then the chip is cleaned by ultrapure water for 5 times, and finally the chip is dried by nitrogen;
(3) Mounting a chip on an SPRi instrument, measuring an SPRi angle and adjusting the SPRi angle to an optimal optical position, selecting related detection points including sample points and blank points in a detection area, and setting an experimental flow rate to be 3 mu L/s;
(4) PBS was selected as buffer solution and passed through the flow cell until the baseline was stable, and then sequentially passed through concentrations of 5.68nM, 11.4nM, 22.8nM, 45.6nM and 91.2nM, the binding time was 300 seconds, the dissociation time was 300 seconds, and phosphoric acid was passed through each concentration to regenerate.
For example, fig. 7 is a graph of the results of surface plasmon resonance detection of oligomers bound to aβ42 at concentrations of 5.68nM, 11.4nM, 22.8nM, 45.6nM and 91.2nM, respectively, in example one of the present disclosure, where a.u. represents the binding signal of the mobile phase after passing through the array minus the baseline signal of the initial PBS buffer, the curve is the test results for PlexArray HT, the fitted line is a biaevaluation 4.1 fit, 91.2nM detection line, 45.6nM detection line, 22.8nM detection line, 11.4nM detection line and 5.68nM detection line, in order from top to bottom. The a.u. is a unit for reflecting the strength of the binding signal in surface plasmon resonance imaging, and is a dimensionless unit. Fitted, the equilibrium dissociation constant KD is 1.57×10 -10 Molar/liter, which indicates that the peptide-like nanosheet with probe has a fairly high affinity level for aβ42.
For example, the oligomer is a two-dimensional nanoplatelet material, which allows the oligomer to be coupled to the sensor and the peptoid oligomer with affinity to be displayed on the surface of the sensor.
Two-dimensional peptoid nanomaterials play an increasingly important role in biology and electronics, such as sensing, growth and filtration of templates, and testing of proteins for their molecular recognition and catalytic ability as mimics of proteins. The Langmuir trough experimental device reveals that the formation of the peptoid nanosheet layer is an unusual thermodynamic equilibrium process of self-assembly of peptoid molecules and conversion of external mechanical energy into chemical energy of the peptoid molecules.
For example, the pharmaceutical composition further comprises: the peptoid oligomer of any one of the foregoing claims; pharmaceutically acceptable auxiliary materials.
For example, the adjuvant includes any one or a combination of at least two of an excipient, a diluent, a carrier, a flavoring agent, a binder, and a filler.
For example, the excipient may be, for example, an emulsion or oily suspension, or a polyalkylene glycol such as polypropylene glycol.
The embodiment of the invention provides a peptide-like oligomer, a preparation method of the peptide-like oligomer, a pharmaceutical composition containing the peptide-like oligomer and a microfluidic chip. Has at least one of the following beneficial effects:
(1) In the peptoid nanosheet layer provided in at least one embodiment of the present disclosure, the peptoid nanosheet layer with the probe has a strong binding capacity with the target molecule, and the equilibrium dissociation constant KD in the binding kinetic constant of the nanosheet layer and the target molecule obtained by the surface plasmon resonance technology is 10 -10 On the order of moles/liter;
(2) In the chip modification technology provided by at least one embodiment of the present disclosure, chip epoxidation and carboxylation can be effectively performed;
(3) In the chip modification technology provided by at least one embodiment of the present disclosure, a chip based on the modification technology can effectively reduce non-specific binding to substances other than a target;
(4) The synthesis method of the peptoid oligomer provided by at least one embodiment of the present disclosure is simple, the preparation efficiency is high, and the manufacturing cost is low;
(5) The assembling method of the peptoid nano-sheet layer provided by at least one embodiment of the present disclosure is simple, the preparation efficiency is high, and the manufacturing cost is low.
The following points need to be described:
(1) The drawings of the embodiments of the present invention relate only to the structures related to the embodiments of the present invention, and other structures may refer to the general designs.
(2) In the drawings for describing embodiments of the present invention, the thickness of layers or regions is exaggerated or reduced for clarity, i.e., the drawings are not drawn to actual scale.
(3) The embodiments of the invention and the features of the embodiments can be combined with each other to give new embodiments without conflict.
The above description is only specific embodiments of the present invention, but the scope of the present invention should not be limited thereto, and the scope of the present invention should be determined by the claims.
Claims (3)
1. A microfluidic chip is characterized in that the microfluidic chip comprises a nano sheet layer and a functional layer,
the nano-sheet layer contains a peptoid oligomer shown in a formula I,
the functional layer comprises GPTMS-guided epoxy modification and 12-mercapto dodecanoic acid-guided closed activation layer modification;
i type
Wherein, n1 is more than or equal to 10 and more than or equal to 3, n2 is more than or equal to 10 and more than or equal to 3, n1=n2, and n1 and n2 are both natural numbers;
the main steps of epoxy modification are as follows:
(1) In an aqueous solution system, the methyl of GPTMS and water molecules are subjected to hydrolysis reaction to generate Si-OH;
(2) The GPTMS molecule containing Si-OH and Si-OH on the surface of the glass chip undergo condensation reaction to form Si-O-Si bond;
the modification of the blocking activation layer comprises the following steps:
(1) Placing the epoxy modified chip in pure water for full cleaning;
(2) The chip was placed in a 1m aqueous solution of 12-mercaptododecanoic acid to react well to form a dense monolayer.
2. The microfluidic chip according to claim 1, wherein the microfluidic chip comprises a nano-sheet layer, a functional layer, a structural layer, a PVX layer, a Gate layer and a glass substrate layer from top to bottom.
3. The microfluidic chip according to claim 1, wherein in formula i, n1=n2=3, n1=n2=4, n1=n2=6, n1=n2=8, or n1=n2=10.
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