CN109954128A - It is a kind of to may interfere with beta-amyloid aggregation and assist the functionalized nano gel removed and preparation method - Google Patents
It is a kind of to may interfere with beta-amyloid aggregation and assist the functionalized nano gel removed and preparation method Download PDFInfo
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Abstract
A kind of functional nano gel that may interfere with beta-amyloid aggregation and microglia is assisted to remove it and preparation method, the nanogel are made of protein pedestal and functionalized polymer gel shell.The nanogel can be stabilized under physiological environment, while have efficiently in conjunction with beta-amyloid protein and interfering the ability of this albumen aggregation；The lesser cluster body (and non-toxic oligomer) of neurotoxicity can be generated in conjunction with beta-amyloid protein, and this cluster body can be removed preferably by microglia, to substantially reduce intracerebral beta-amyloid protein deposition, it is finally reached the purpose for mitigating alzheimer's disease symptom；In addition, preparation method simple process, easily operated, cost is relatively low, application easy to spread.
Description
Technical field
The invention belongs to polymeric biomaterial fields, and being related to one kind may interfere with beta-amyloid aggregation and assist small glue
The preparation and application for the functionalized nano gel that cell plastid removes it.
Background technique
Alzheimer's disease (Alzheimer disease, AD) is a kind of common neurodegenerative disease in the world, it
Commonly-occurring disease is in the elderly of over-65s.There is AD patient 35,600,000 in the whole world at present, with the continuous aging of population in the world, it is contemplated that
It will be more than 100,000,000 to the middle of this century whole world AD patient.
However, the serious problem currently faced is clinically to there is no effective prevention and treatment method.Compare mainstream at present
Pathogenic hypothesis have result in deposition patch beta amyloid hypothesis and formed nerve fibre Protein tau hypothesis, this be because
It is researcher in the detection to the dead's intracerebral, first is that severe atrophy occurs for brain, second is that finding a large amount of β-in cerebral cortex
Neurofibrillary tangles caused by deposition patch caused by amyloid filamentsization and tau protein abnormal phosphorylation, and with
Also confirm that they truly have apparent damage to intracerebral nerve cell in experiment afterwards.Therefore, from 1984, neuropathologist land
Since supervention shows beta-amyloid protein and Protein tau, being even more as the AD Therapy study of target using the two is in the state increased year by year
Gesture, in particular for the research of the former amyloid protein hypothesis, some medicine enterprise giants (such as gift comes) are even in certain related drugs
Research and development on put into billions of U.S. dollars.Unfortunately, since last century till now, the experiment more than up to a hundred times is unsuccessfully to accuse
Eventually.
Existing result of study shows that AD patient has such a general character.They are geneogenous or by the ring day after tomorrow
Border influences, and leads to originally just that in the abnormal deposition of intracerebral, immediate cause is beta amyloid for more hydrophobic beta-amyloid protein
The orderly aggregation of albumen, and essential reason be then its generate with removing it is unbalance.The exactly A β of these state of aggregations, especially its widow
Aggressiveness causes the prominent function of neuron to be lost in the long-term existence of intracerebral, and continues to generate poisonous effect.
Based on the above cause of disease, the medicament research and development of most AD is generation, removing and the suppression for beta-amyloid protein
Carry out in terms of system aggregation three and perfect.For example, the inhibition of enzyme is mainly for generation；The immunotherapy master emerged in recent years
It will be for elimination；Some small molecules and peptide inhibitor, gold nano grain and polymer micelle then more bias toward inhibition
Aggregation, it is few that two or more therapeutic effect is integrated among same drug, such as inhibiting beta-amyloid protein
While aggregation formation oligomer, it is assisted to be removed from intracerebral.Therefore, developing one kind may interfere with beta-amyloid protein to toxicity
Aggregation (especially toxicity oligomer) conversion, and the nano material for assisting it to be removed by intracerebral microglia is particularly important.
Summary of the invention
Object of the present invention is to aiming at the above shortcomings existing in the prior art, provide one kind, to may interfere with beta-amyloid protein poly-
The functionalized nano gel and its preparation method and application for collecting and microglia being assisted to remove it.This nanogel can be
It is stabilized under physiological environment, while having both efficiently in conjunction with beta-amyloid protein and interfering the ability of this albumen aggregation (because of nanometer
Gel surface contain can specific capture overall length beta-amyloid protein functional polypeptide)；This nanogel and beta-amyloid protein
In conjunction with the lesser cluster body (and non-toxic oligomer) of rear generation neurotoxicity, and this cluster body can be preferably by microglia
It removes, to substantially reduce intracerebral beta-amyloid protein deposition, is finally reached the purpose for mitigating alzheimer's disease symptom；This
Outside, preparation method simple process, easily operated, cost is relatively low, application easy to spread.
Technical solution of the present invention:
A kind of functionalized nano gel that may interfere with beta-amyloid aggregation and microglia is assisted to remove it, by
Protein pedestal and the functionalized polymer gel shell composition that overall length beta-amyloid protein can be captured, be a kind of partial size be 14 ±
4nm and equally distributed spherical particle.Make firstly, modifying enough double bonds in protein susceptor surface by biological connection method
For the anchored site of subsequent polymerisation reaction；Then, in water phase, functional monomer and the friendship that can capture beta-amyloid protein are utilized
These small molecules are largely enriched in around protein by the hydrogen bond and van der Waals interaction of connection agent and protein susceptor surface；Most
Eventually, polymer gel shell is formed using the method in situ for causing polymerization, functional monomer is fixed on protein to high-density
Susceptor surface obtains functionalized nano gel.
The protein pedestal is measured by bovine serum albumin (Bovine serum albumin, BSA) and 30 to 60 times
The double bond modification that N- acryloxy succinimide (N-acryloxysuccinimide, NAS) is prepared in aqueous solution
Bovine serum albumin (Bovine serum albumin, BSA), i.e., acrylated bovine serum albumin(BSA).
The functional monomer is acrylamide (Acrylamide, AAm) and acrylated-Lys-Ile-figured silk fabrics
Propylhomoserin-phenylalanine-phenylalanine (Ac-Lys-Leu-Val-Phe-Phe, Ac-KLVFF), crosslinking agent N, N'- di-2-ethylhexylphosphine oxide
Acrylamide (N, N'-methylenebisacrylamide, BIS).
The home position polymerization reaction is that ammonium persulfate and tetramethylethylenediamine cause in water phase.
A kind of functionalized nano that may interfere with beta-amyloid aggregation and neural microglia is assisted to remove it is solidifying
The preparation method of glue, includes the following steps:
1) the functional monomer acryloyl of overall length beta-amyloid protein can be captured using the method synthesis of amino chemical modification
Change-Lys-Ile-valine-phenylalanine-phenylalanine (Ac-Lys-Leu-Val-Phe-Phe, Ac-KLVFF).
Pentapeptide Lys-Ile-valine-phenylalanine-phenylalanine is added into centrifuge tube, 1 to 1.5 times is worked as
The N- acryloxy succinimide and catalytic amount triethylamine of amount, sufficiently dissolve in super dry dimethyl sulfoxide, room temperature reaction 10
~15 hours, reaction terminated, acrylated Lys-Ile-valine-phenylalanine-that calibration concentration is 5mg/mL
Phenylalanine storing liquid.
2) preparation of acrylated bovine serum albumin(BSA)；
Firstly, bovine serum albumin(BSA) is added into centrifuge tube, it is dissolved in phosphate buffer, the N- acryloyl that 30 to 60 times are measured
Oxygroup succinimide is dissolved in super dry dimethyl sulfoxide, and 4 DEG C of ice-water baths are simultaneously slowly added dropwise under quickly stirring above-mentioned into centrifuge tube
N- acryloxy succinimide solution, is added dropwise, and keeps this thermotonus 2~4 hours.Immediately by this reaction solution
Collection and 0~10 DEG C of dialysed overnight in phosphate buffer, using the acrylated ox blood of BCA protein concentration detection method calibration gained
The concentration of pure albumen, and be diluted to 5mg/mL and saved in -20 DEG C of refrigerators.
3) functional monomer and crosslinking agent are enriched in using intermolecular weak interaction by acrylated protein pedestal
Around；
Acrylated bovine serum albumin(BSA) is diluted to 1mg/mL to be placed in centrifuge tube, leads to 5~10 minutes argon gas, successively
Acrylated bovine serum albumin(BSA) in molar ratio: acrylamide: acrylated-Lys-Ile-valine-phenylpropyl alcohol ammonia
Acid-phenylalanine: above-mentioned functional monomer and friendship is added in crosslinking agent N, N'- methylene-bisacrylamide=1:3000:75:300
Join agent；After mixing, tetramethylethylenediamine is added and ammonium persulfate causes home position polymerization reaction, the acrylated ox of molar ratio
Seralbumin: ammonium persulfate: tetramethylethylenediamine=1:450:900；The reaction is reacted 2~4 hours at 4 DEG C, reaction knot
Shu Hou, 0~10 DEG C of dialysed overnight in phosphate buffer；1mg/mL (BCA protein concentration detection method) is concentrated into using super filter tube
It is saved in -20 DEG C of refrigerators.
4) reaction terminates to use molecular cut off not to be wrapped on protein pedestal in 30000 bag filter removing solution
Monomer, crosslinking agent or polymer；
5) concentration of nanogel is demarcated using BCA protein concentration detection method.
The advantages of the present invention:
The advantages of functionalized nano gel provided by the invention, has: preparation method simple process, easily operated, gel table
Face is easy to edit, and cost is relatively low, application easy to spread；Can be stabilized under physiological environment, will not be because of itself coagulation caused by
Additional toxicity；It has both efficiently specific binding beta-amyloid protein and interferes the ability of this albumen pathogenic aggregation (because of nanogel
Surface contain can specific capture overall length beta-amyloid protein functional polypeptide, and nanogel structure keep isotropism).
Beneficial effect emphatically be embodied in, this nanogel with beta-amyloid protein ining conjunction with after occur at random assemble, and then production
The raw lesser cluster body (and non-toxic oligomer) of neurotoxicity, this operation can substantially reduce the content of oligomer in system；
The aggregated forms of this cluster body can be removed preferably by microglia, so that intracerebral beta-amyloid protein deposition is substantially reduced,
It is finally reached the purpose for mitigating alzheimer's disease symptom.
Detailed description of the invention
Fig. 1 is that functional nano gel interferes beta-amyloid aggregation and assists microglia to its scavenging effect machine
The synthesis of schematic diagram and nanogel processed；Wherein, (a) functional nano gel interferes beta-amyloid aggregation and assists small glue
Cell plastid is characterized to the synthesis of its scavenging effect mechanism principle figure He (b) nanogel and (c).
Fig. 2 is that functional nano gel interferes beta-amyloid aggregation；Wherein, (a) thioflavin T detection function nanometer
Gel inhibits the phenomenon that aggregation；(b) transmission electron microscope characterizes；(c) fluorescent co-location characterizes；(d) thioflavin T detection function nanometer
The case where gel depolymerization fiber；(e) transmission electron microscope characterizes.
Fig. 3 is that functional nano gel interferes beta-amyloid aggregation, mitigates the toxicity to neuron and assists small glue
Cell plastid removes it；Wherein, (a) functionalized nano gel sticks neuron for mitigating beta-amyloid protein；(b) it flows
Formula weight；(c) cells survival rate is tested；(d) functionalized nano gel is for promoting the phagocytosis of microglia to test；(e) it flows
Formula weight；(f) functionalized nano gel is used to promote the phagocytosis positioning experiment of microglia.
Specific embodiment
Below by way of non-limiting example, present invention be described in more detail.
Embodiment 1: interference beta-amyloid aggregation and the functional nano gel for assisting microglia to remove it
Preparation.
1) acrylated-Lys-Ile-figured silk fabrics ammonia of functional monomer is synthesized using the method for amino chemical modification
Acid-phenylalanine-phenylalanine (Ac-Lys-Leu-Val-Phe-Phe, Ac-KLVFF).
1.5mg pentapeptide Lys-Ile-valine-phenylalanine-is added into 1.5mL point bottom plastic centrifuge tube
Phenylalanine, 390 μ g N- acryloxy succinimides and 280 μ g high-purity triethylamines, it is sub- with the super dry dimethyl of 300 μ L
Sulfone is sufficiently dissolved in whole system and any wafer-like solid (needing 4 DEG C of low temperature ultrasonics when necessary 10 minutes) is not present, and room temperature is anti-
It answers 12 hours, reaction terminates, and obtains acrylated Lys-Ile-valine-phenylalanine-benzene that concentration is 5mg/mL
Alanine storing liquid.Freeze 4 DEG C it is spare.
2) functionalized nano gel is synthesized using aqueous solution in-situ polymerization.
Synthesis functionalized nano gel is the process of two steps.
Firstly, 100mg bovine serum albumin(BSA) is added into 50mL round bottom plastic centrifuge tube, it is dissolved in 15mL phosphate buffer
In (pH=7.4,10mM), 15mg N- acryloxy succinimide is dissolved in super dry dimethyl sulfoxide to clarification, 4 DEG C of ice
Simultaneously above-mentioned N- acryloxy succinimide solution quickly is slowly added dropwise under stirring in water-bath, after being added dropwise, keeps this temperature
Reaction 4 hours.Immediately this reaction solution collected and 4 DEG C of dialysed overnight (molecular cut offs: 30000) in phosphate buffer
To remove the N- acryloxy succinimide of unreacted or partial hydrolysis, gained is demarcated using BCA protein concentration detection method
The concentration of acrylated bovine serum albumin(BSA), and be diluted to 5mg/mL and saved backup in -20 DEG C of refrigerators.
Then, above-mentioned acrylated bovine serum albumin(BSA) 1mg/mL is diluted to be placed in 2mL round bottom plastic centrifuge tube,
Lead to 5~10 minutes argon gas, sequentially adds bovine serum albumin(BSA) 1mg, acrylamide 3mg: acrylated-Lys-Ile-
Valine-phenylalanine-phenylalanine 0.8mg:N, N'- methylene-bisacrylamide 0.7mg.After mixing, tetramethyl is added
Base ethylenediamine 5 μ L and ammonium persulfate 1.7mg cause home position polymerization reaction.The reaction reacts 3 hours at 4 DEG C, after reaction,
4 DEG C of dialysed overnight (molecular cut offs: 30000) to remove unreacted monomer, crosslinking agent, initiator in phosphate buffer
Deng.Finally 1mg/mL (BCA protein concentration detection method) is concentrated into using super filter tube to save backup in -20 DEG C of refrigerators.
Embodiment 2: the application of the nanogel of beta-amyloid aggregation is interfered.
1) application of the overview function nanogel in terms of inhibiting beta-amyloid protein monomer aggregation.
Beta-amyloid protein monomer is dissolved in phosphate buffer (pH=7.4,10mM, 10mM NaCl), and will be dense
Fixed to 40 μM of degree, this solution is to prevent aggregation ready-to-use.Functional nano gel is then diluted to 200 μ g/mL, etc.
Volume is sufficiently mixed with beta-amyloid protein monomer solution, and sealed membrane is closed, and is incubated under the conditions of 37 DEG C, in different time section
Point sampling tracks identification functional material to the shadow of beta-amyloid protein monomer aggregation dynamics using Thioflavine-T assay method
It rings, and the sample after 7 days is passed through into its morphological change of transmission electron microscope observation.The phosphate buffer of equivalent is not born
Carry the naked nanogel of Lys-Ile-valine-phenylalanine-phenylalanine function pentapeptide and pure function pentapeptide with
Beta-amyloid protein monomer solution is sufficiently mixed as a control group.In addition, for the composition for determining sample products, respectively by β-starch
Sample protein monomer and functional nano gel mark different fluorescent molecules, aobvious using laser co-focusing such as fluorescein and rhodamine
Micro mirror carries out common location research to product.
2) application of the overview function nanogel in terms of depolymerization beta-amyloid protein fiber.
Beta-amyloid protein monomer is dissolved in phosphate buffer (pH=7.4,10mM, 10mM NaCl), and will be dense
Degree is fixed to 40 μM, and 37 DEG C of conditions are incubated for 96 hours in advance to ensure to obtain fiber.Functional nano gel is then diluted to 200
μ g/mL is sufficiently mixed with beta-amyloid protein fiber solution in equal volume, and sealed membrane is closed, and is incubated under the conditions of 37 DEG C, not
It is sampled with timing node, identification functional material is tracked to beta-amyloid protein monomer aggregation dynamic using Thioflavine-T assay method
Influence, and the sample after 7 days is passed through into its morphological change of transmission electron microscope observation.The phosphate-buffered of equivalent
Liquid, unsupported Lys-Ile-valine-phenylalanine-phenylalanine function pentapeptide naked nanogel and pure function
Pentapeptide and beta-amyloid protein monomer solution are sufficiently mixed as a control group.
Experimental result is as shown in Fig. 2, the results showed that functional nano gel is shown compared with other three groups of controls more
The ability of apparent interference beta-amyloid aggregation, this ability are higher by 1.8 than pure functional pentapeptide in terms of inhibiting aggregation
Times, it is 2.02 times higher than pure functional pentapeptide in terms of depolymerization has formed fiber.It is noted that it is solidifying that functionalized nano is added
After glue, high degree affects its form for assembling product.It is formed by spheric cluster body and is mingled with considerable amount of function
Change nanogel, this may be to show one of the reason of a series of subsequent neurotoxicities mitigate and be conducive to removing phenomenon.
Embodiment 3: mitigate to neuronal cell injury and the application for assisting microglia to remove beta-amyloid protein.
1) overview function nanogel is in mitigation to the application in terms of neuronal cell injury.
Fluorescein-labeled 100 μM of beta-amyloid protein monomers and functional nano gel are incubated at 4 DEG C 24 hours with
Cluster body is obtained, is then added and extremely includes mouse pheochromocytoma cells (imictron cell) (murine
Pheochromocytoma, PC-12) DMEM culture medium (contain 5% fetal calf serum) in, trained in carbon dioxide cell incubator
It supports 3 hours, then remove culture medium and is rinsed three times with sterile phosphate buffer, paraformaldehyde room temperature fixes 5~15 minutes,
Sterile phosphate buffer rinses three times, and DAPI nuclear targeting 1~3 minute, sterile phosphate buffer rinsed three times.Swashing
The interaction of cell and beta-amyloid protein is observed under light Laser Scanning Confocal Microscope.The phosphate buffer of equivalent, it is unsupported rely
The naked nanogel of propylhomoserin-Ile-Val-phenylalanine-phenylalanine function pentapeptide and pure function pentapeptide and β-shallow lake
After powder sample protein monomer solution is sufficiently mixed incubation, under the same conditions as a control group with the culture of mouse pheochromocytoma cells.
Finally using flow cytometry come the power of quantitative analysis cell and beta-amyloid protein interaction.
Under the conditions of same ratio, beta-amyloid protein after above-mentioned material is added is observed with CCK-8 Apoptosis method of testing
The influence for surviving situation to mouse pheochromocytoma cells.
2) application of the overview function nanogel in terms of assisting microglia to remove intracerebral beta-amyloid protein.It will
In step 1) mixed solution of gained different materials and beta-amyloid protein monomer respectively with mouse microglia tumor (murine
Microglial, BV-2) it co-cultures and (contains 3% fetal calf serum in this culture medium), colloid is observed under laser confocal microscope
The ability of cell clearance beta-amyloid protein.In addition, functional nano gel is marked rhodamine, under similarity condition, again
Determine that it assists removing of the microglia to beta-amyloid protein.
Experimental result is added as shown in figure 3, the results showed that during co-culturing with mouse pheochromocytoma cells
After functionalized nano gel, the interaction of cell and beta-amyloid protein is significantly reduced, compared with other three control groups
There is apparent significant difference, at the same time, the activity of cell is also obviously improved, and functions nanogel can lead to
It crosses to form cluster body and be effectively protected neuronal cell and sticks attack from beta-amyloid protein.Importantly, above-mentioned cluster
Body also shows the property completely different with toxicity oligomer in terms of beta-amyloid protein intracerebral removing, and this cluster body can be with
It is removed more significantly by intracerebral microglia.
Claims (7)
1. a kind of functionalized nano gel that may interfere with beta-amyloid aggregation and microglia is assisted to remove it, described
Nanogel is made of protein pedestal with the functionalized polymer gel shell that can capture overall length beta-amyloid protein, is a kind of
Partial size is 14 ± 4nm and equally distributed spherical particle；Firstly, modifying foot in protein susceptor surface by biological connection method
The double bond of amount；Then, in water phase, the functional monomer and crosslinking agent and protein pedestal that can capture beta-amyloid protein are utilized
These small molecules are largely enriched in around protein by the hydrogen bond and van der Waals interaction on surface；Finally, gathered using in situ cause
The method of conjunction forms polymer gel shell, and functional monomer is fixed on protein susceptor surface to high-density and obtains functionalization
Nanogel.
2. the functionalization that may interfere with beta-amyloid aggregation according to claim 1 and microglia is assisted to remove it
Nanogel, which is characterized in that the protein pedestal is bovine serum albumin (the Bovine serum modified by double bond
Albumin, BSA) it constitutes.
3. the functionalization that may interfere with beta-amyloid aggregation according to claim 1 and microglia is assisted to remove it
Nanogel, which is characterized in that the functional monomer is acrylamide (Acrylamide, AAm) and acrylated-bad ammonia
Acid-Ile-Val-phenylalanine-phenylalanine (Ac-Lys-Leu-Val-Phe-Phe, Ac-KLVFF), crosslinking agent
For N, N'- methylene-bisacrylamide (N, N'-methylenebisacrylamide, BIS).
4. the functionalization that may interfere with beta-amyloid aggregation according to claim 1 and microglia is assisted to remove it
Nanogel, which is characterized in that the home position polymerization reaction is that ammonium persulfate and tetramethylethylenediamine cause in water phase.
5. a kind of function of may interfere with beta-amyloid aggregation as described in claim 1 and microglia is assisted to remove it
Change the preparation method of nanogel, it is characterised in that include the following steps:
1) functional monomer that can capture overall length beta-amyloid protein using the method synthesis of amino chemical modification is acrylated-bad
Propylhomoserin-Ile-Val-phenylalanine-phenylalanine (Ac-Lys-Leu-Val-Phe-Phe, Ac-KLVFF)；
2) preparation of acrylated bovine serum albumin(BSA)；
3) functional monomer and crosslinking agent are enriched in around acrylated protein pedestal using intermolecular weak interaction；
4) reaction terminates that molecular cut off is used to remove the list not being wrapped in solution on protein pedestal for 30000 bag filter
Body, crosslinking agent or polymer；
5) concentration of nanogel is demarcated using BCA protein concentration detection method.
6. preparation method according to claim 5, which is characterized in that acrylated bovine serum albumin(BSA) described in step 2)
Preparation method be: bovine serum albumin(BSA) is added into centrifuge tube, is dissolved in phosphate buffer, by 30 to 60 times measure N- acryloyl
Oxygroup succinimide is dissolved in super dry dimethyl sulfoxide, and 4 DEG C of ice-water baths are simultaneously slowly added dropwise under quickly stirring above-mentioned into centrifuge tube
N- acryloxy succinimide solution, is added dropwise, and keeps this thermotonus 4 hours；Immediately this reaction solution is received
Collect and 4 DEG C of dialysed overnights in phosphate buffer, using the acrylated bovine serum albumin of BCA protein concentration detection method calibration gained
White concentration, and be diluted to 5mg/mL and saved in -20 DEG C of refrigerators.
7. preparation method according to claim 5, which is characterized in that step 3) is described to be enriched in albumen for functional monomer
Method around matter pedestal is: acrylated bovine serum albumin(BSA) being diluted to 1mg/mL and is placed in centrifuge tube, leads to 5~10 points
Clock argon gas, successively acrylated bovine serum albumin(BSA) in molar ratio: acrylamide: acrylated-Lys-Ile-figured silk fabrics
Propylhomoserin-phenylalanine-phenylalanine: above-mentioned function is added in crosslinking agent N, N'- methylene-bisacrylamide=1:3000:75:300
Property monomer and crosslinking agent；After mixing, tetramethylethylenediamine is added and ammonium persulfate causes home position polymerization reaction, molar ratio
Acrylated bovine serum albumin(BSA): ammonium persulfate: tetramethylethylenediamine=1:450:900；The reaction is reacted 4 hours at 4 DEG C,
After reaction, 0~10 DEG C of dialysed overnight in phosphate buffer；1mg/mL (BCA protein concentration inspection is concentrated into using super filter tube
Survey method) it is saved in -20 DEG C of refrigerators.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113057963A (en) * | 2021-03-31 | 2021-07-02 | 华中科技大学 | Specific capture carrier for eliminating beta-amyloid and application thereof |
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| CN107530445A (en) * | 2014-11-26 | 2018-01-02 | 加利福尼亚大学董事会 | Stealthy Nano capsule for protein delivery |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113057963A (en) * | 2021-03-31 | 2021-07-02 | 华中科技大学 | Specific capture carrier for eliminating beta-amyloid and application thereof |
| CN113057963B (en) * | 2021-03-31 | 2022-05-20 | 华中科技大学 | Specific capture carrier for eliminating beta-amyloid and application thereof |
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