CN104004125A - Dual-fluorescence functional polymer nanometer microsphere with pH response and application thereof in tumor tissue detection - Google Patents
Dual-fluorescence functional polymer nanometer microsphere with pH response and application thereof in tumor tissue detection Download PDFInfo
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Abstract
The invention discloses a dual-fluorescence functional polymer nanometer microsphere with pH response and application thereof in tumor tissue detection and belongs to the technical field of high polymer materials. The method comprises the following steps: firstly synthesizing an emulsion microsphere of a composite fluorescence molecule A, introducing a polymer with a pH response function into a shell layer of the microsphere by adopting a seed emulsion polymerization method, and thus preparing the emulsion microsphere with a core-shell structure; further compounding a fluorescence molecule B into the shell layer of the microsphere, and thus obtaining the dual-fluorescence-emission functional polymer nanometer microsphere with pH response. The microsphere presents different fluorescence intensity and fluorescence color under different pH value conditions from acidity to alkalinity. The microsphere is applied to tissue detection based on the pH response function of the nanometer microsphere fluorescent property, the microsphere presents violet fluorescence in the normal tissue (pH about 7.4), the microsphere presents pink fluorescence in the tumor tissue (pH of less than 6.5), and the microsphere can be used for preparing a fluorescent material and has wide application prospects in the fields of tumor cell and tissue detection, drug sustained release and the like.
Description
Technical field
The invention belongs to technical field of polymer materials, be specifically related to a kind of two fluorescent functional polymer nano-microspheres of pH response and the fluorescent material for the preparation of application in tumor tissues detection thereof.
Background technology
Intelligent material be environment is had can perception, can respond and have the type material of function ability of discovery.Mainly contain temperature sensitive, pH sensitivity, electricity sensitivity, light, magnetic and biological susceptibility hydrogel material.Although the history of intelligent material research, exploitation is not long, because its unique performance is not only being widely applied aspect industrial and agricultural production and daily life, and developing high-tech is played an important role.In recent years, the research work of intelligent material is unprecedentedly active, and novel high polymer and the hydrogel thereof wherein with intelligent behavior are with the fastest developing speed.This family macromolecule energy perception goes out ambient environmental conditions, as variations such as temperature, acidity, pressure, sound wave, electric field, magnetic field, light waves, produces performance change simultaneously.Therefore, have a good application prospect in fields such as chemical sensor, convertor, switchette, artificial-muscle, medicament slow release, immobilized enzyme.
Decades in the past, the development of cell labeling technique receives much concern, and at present, multiple injectable materials, for the research of cell marking, comprising: organic molecule, fluorescin and inorganic-quantum-dot.But they self exist certain limitation, the molar absorption coefficient of organic molecule is lower, the less stable of fluorescin, and inorganic-quantum-dot has very high bio-toxicity owing to containing a large amount of heavy metal elements in its structure, these factors are all limiting the application of these materials in cell marking.There is response function, fluorescence stable, and the lower fluorescent polymer materials of bio-toxicity is subject to investigator's attention gradually, and plays an important role in cell marking.
In the detection of conventional fluorescent mark, main employing is the image forming material with single fluorescence color, and under coenocorrelation, background fluorescent signal has interference to a great extent to it, causes detecting effect and easily occurs error.In order to address this problem, the image forming material of constructing two fluorescent emission is necessary.Particularly, for tumor tissues and healthy tissues, pH value is to distinguish the important physical signs of the two.In tumor tissues, pH is acid state (pH<6.5), and the pH of healthy tissues is neutral state (pH～7.4).Therefore, prepare the fluorescent nanometer microsphere of the two emission functions of a kind of pH of having responsiveness, normal cell and tumour cell are distinguished to imaging, and then realize that cancer is diagnosed and treated is the target of medical circle and a Worth Expecting of region of chemistry.
Summary of the invention
One of object of the present invention is to provide a kind of two fluorescent emission Nano microspheres of pH response.
The emulsion microballoon of the first synthetic a kind of composite fluorescence molecule A of the present invention, then, taking the emulsion microballoon that obtains as seed, adopts the method for seeded emulsion polymerization, the polymkeric substance with pH response function is incorporated into the shell of microballoon, prepares the emulsion microballoon of nucleocapsid structure.Further fluorescence molecule B is compound in the shell of microballoon, obtains the functional polymer Nano microsphere of two fluorescent emission with pH response.Be compounded in the regulation and control that the fluorescence molecule B of shell and the effect of polymkeric substance are subject to environment pH, photoluminescent property changes; And the photoluminescent property that is assembled in the fluorescence molecule A in core is not subject to the impact of pH, keep photoluminescent property constant.Cause polyalcohol nucleocapsid Nano microsphere to present different fluorescence intensities and fluorescence color from acidity to alkaline different pH condition.Under neutral and alkaline condition, the stratum nucleare fluorescence molecule A (ruddiness) of Nano microsphere and shell fluorescence molecule B (blue light) are simultaneously luminous, and entirety presents the composite fluorescence (purple) of the two; Along with pH reduces, under acidic conditions, the fluorescence of shell fluorescence molecule B weakens gradually, and the fluorescence molecule A of Nano microsphere stratum nucleare luminous (ruddiness) is constant; PH response function based on Nano microsphere photoluminescent property, be applied in tissue detection, healthy tissues (pH～7.4) presents purple fluorescence, tumor tissues (pH<6.5) presents pink fluorescence, it can be for the preparation of fluorescent material, thereby has broad application prospects in the field such as tumour cell and tissue detection, medicament slow release.
Two fluorescent emission polymer nano-microspheres with pH response of the present invention, it is prepared by following steps:
(1) the N-isopropylacrylamide NIPAM monomer that takes 2-10mmol is dissolved in the deionized water of 100-200mL, then adds the polymerization single polymerization monomer 1,1 × 10 of 10-50mmol
-6-5 × 10
-6the fluorescence molecule A of mol, under room temperature and nitrogen protection, mechanical stirring 30-60min; Then be warming up to gradually 60-70 DEG C, add 5-15mL to contain the aqueous solution of 0.3-0.6mmol initiator, initiated polymerization, obtains the polymer seeds microballoon containing fluorescence molecule A after reaction 12-24h; Finally remove the impurity such as unconverted monomer, initiator in liquid phase by high speed centrifugation, the more centrifugal polymer seeds microballoon containing fluorescence molecule A obtaining is dissolved in 50-100mL deionized water stand-by;
(2) polymer microballoon of step (1) is proceeded to seeded emulsion polymerization: in the polymer seeds microspheres solution of step (1), add the polymerization single polymerization monomer 1 of 10-60mmol and the pH responsiveness polymerization single polymerization monomer 2 of 1-5mmol, under room temperature and nitrogen protection, mechanical stirring 30-60min, then be warming up to gradually 70-85 DEG C, add 15mL to contain the aqueous solution of 0.5 – 1.5mmol initiator, initiated polymerization, reaction obtains the polymer nano-microspheres of nucleocapsid structure after 12-24h; Finally remove the impurity such as unconverted monomer, initiator in liquid phase by high speed centrifugation, the more centrifugal nucleocapsid structure polymer nano-microspheres obtaining is dissolved in 50-100mL deionized water stand-by;
(3) measure the core-shell nano microballoon emulsion that 10-30mL step (2) obtains, the fluorescence molecule B that takes 2-10 μ mol joins in this core-shell nano microballoon emulsion, at 30-40 DEG C, under the condition of nitrogen protection, under magnetic agitation, reacts 3-8h; Finally remove the not compound fluorescence molecule B of liquid phase by high speed centrifugation, obtain fluorescence molecule A and the compound two fluorescent core shell polymeric Nano microspheres of B.
The object of the invention is two be to provide a kind of tumor tissues detect in application fluorescent material, it is to prepare taking foregoing pair of fluorescent core shell polymeric Nano microsphere as major ingredient.
Inoculated tumour cell in the subcutis of nude mice (tongue squamous cell carcinoma, cervical cancer cell), after 7 days, cell forms after tumor tissues through diffusion propagation, two fluorescent core shell polymeric Nano microspheres that step (3) is obtained are mixed with the aqueous solution that concentration is 1-5mg/mL, measure 10-40 μ L and be injected into respectively tumor tissues and the normal subcutis of nude mice, after 24h, carry out respectively slicing treatment, then carry out imaging by laser confocal microscope.
In aforesaid method, polymerization single polymerization monomer 1 is vinylbenzene (St), fluorostyrene (F-St), methyl methacrylate (MMA) or glycidyl methacrylate (GMA);
In aforesaid method, pH responsiveness polymerization single polymerization monomer 2 is that vinylformic acid (AA), methacrylic acid (MAA), methyl acrylate (MA), methacrylic acid are received (NaMA) or dimethylaminoethyl methacrylate (DMAEMA);
In aforesaid method, initiator is Potassium Persulphate (K
2s
2o
8), ammonium persulphate ((NH
4)
2s
2o
8), Sodium peroxoborate (NaBO
34H
2o), Sodium Persulfate (Na
2s
2o
8) or azo-bis-isobutyl cyanide (AIBN);
In aforesaid method, fluorescence molecule A can be rare earth compounding RaXnYm, and its Rare Earth Ion Ra can be: europium (Eu), terbium (Tb), thulium (Tm) lanthanum (La), erbium (Er), ytterbium (Yb); The first X ligand can be: thenoyltrifluoroacetone (TTA), methyl ethyl diketone (acac), diphenylpropane-1,3-dione(DPPO) (DBM), Whitfield's ointment (sal), the integer of n=1～3, the number of expression part; Ligands Y can be 1,10-phenanthroline (Phen), the integer of m=0～1, the number of expression part; Fluorescence molecule A can also be semiconductor nano (CdTe, CdSe, CdS, PbS, PbSe, PbTe, Ag
2s), rhodamine B (RhB), metal nanometre cluster (Au, Ag nano-cluster) etc.;
In aforesaid method, fluorescence molecule B is bromination (N, N, N-triethyl-3-(4-(1, 2-phenylbenzene-2-(4-(2-triethylamine) oxyethyl group) vinyl) vinyl) phenyl) propyl group amine (TAPE), bromination 2, 2 ', 2 ' '-(4, 4 ', 4 ' '-(2-(4-(3-s triethylamine) propyl group) phenyl) 1, 1, 2-triphenyl vinyl three oxygen) three (N, N, N-triethyl ethamine) (TTAPE) or hexaphenyl thiophene cough up (HPS), Silole (silacyclopentadiene) and derivative 1 thereof, 1-bis-[p-(diethyl amino methyl) benzene]-2, 3, 4, 5-tetra-benzo Silole (A
2hPS), 3-(4-(1,2-phenylbenzene-2-(4-sulfo group oxyethyl group) phenyl) vinyl) propyl group-1-sodium sulfonate (TPE).
Tool of the present invention has the following advantages: 1, the Nano microsphere of this pair of fluorescent emission function has sensitive pH response function.Its fluorescence intensity and fluorescence color are with environment pH intelligent control.2, the size of this responsiveness fluorescent nanometer microsphere is little of nano level, is applicable to being applied to multiple detection; 3, the grain size of this responsiveness fluorescent nanometer microsphere can be controlled in 100-500 nanometer; 4, the pH responding range of prepared pH response fluorescent nanometer microsphere is that 4.0-7.6 presents different fluorescence colors; 5, this pH response fluorescent nanometer microsphere has good response function within the scope of wider pH, is the optics that a kind of novel pH detects; 6. this pH response fluorescent nanometer microsphere can be distinguished and be detected normal and cancer cell tissue by photoluminescent property, obtains biological detecting function and application.
Brief description of the drawings
Fig. 1: the stereoscan photograph of the EuPS/PNIPAM-PAA/TAPE nuclear shell structure nano microballoon of preparing for embodiment 1; Nano microsphere particle diameter is evenly approximately 252nm.
Fig. 2: the EuPS/PNIPAM-PAA/TAPE core-shell nano microballoon of preparing for embodiment 1 is at the fluorescence spectrum figure of pH:4-7.6 range; Microballoon has good fluorescent emission performance at wavelength 468nm and 613nm place, along with pH value reduces, at the fluorescence kept stable at 613nm place, reduces gradually in the fluorescence intensity at 468nm place.
Fig. 3: the EuPS/PNIPAM-PAA/TAPE core-shell nano microballoon of preparing for embodiment 1 reduces gradually with pH:7.6-4, presents respectively the different fluorescence colors such as purple, cyan, pink colour, redness.Show that this fluorescent nanometer microsphere has sensitive pH responsiveness.
Fig. 4: the EuPS/PNIPAM-PAA/TAPE core-shell nano microballoon of preparing for embodiment 1 is at the confocal microscope photo of healthy tissues and tumor tissues (tongue squama cancerous tissue).Present purple fluorescence in healthy tissues, and present pink colour fluorescence at tumor tissues.
Embodiment
Embodiment 1:
(1) the NIPAM monomer that takes .4.42mmol is dissolved in 185mL deionized water, joins in the three-necked bottle of 500mL, adds 1.4 × 10
-6the rare earth compounding Eu (TTA) of mol
3phen, the vinylbenzene (St) of 5mL, under room temperature and nitrogen protection; mechanical stirring (400rpm) 30min; then be warming up to gradually 70 DEG C, add the aqueous solution that 15mL contains initiator potassium persulfate (KPS) 0.3mmol in system, initiated polymerization.Reaction is carried out 12h and is finished.Obtain the polymer seeds microballoon containing rare earth compounding.Remove the impurity such as unconverted monomer, initiator in liquid phase by high speed centrifugation (18500r/min), then be dissolved in 100mL deionized water stand-by.
(2) seed microspheres solution step (1) being obtained is slowly poured in the three-necked bottle of 500mL; as seed; synthesize EuPS/PNIPAM-PAA core-shell particles by seeded emulsion polymerization; in system, add 40mmol NIPAM, the AA of 3mmol, under room temperature and nitrogen protection; mechanical stirring (300rpm) 30min; then be warming up to gradually 70 DEG C, add the aqueous solution that 15mL contains initiator potassium persulfate (KPS) 0.3mmol in system, initiated polymerization.Reaction is carried out 12h and is finished, and obtains the nucleocapsid structure polymer nano-microspheres containing rare earth compounding.Remove the impurity such as liquid phase unconverted monomer, initiator by high speed centrifugation (18800r/min), be dissolved in 100mL deionized water stand-by.
(3) measuring the EuPS/PNIPAM-PAA Nano microsphere that 10mL step (2) obtains pours in the three-necked bottle of 100mL; take micro-TAPE molecule 5.2 μ mol and put into core-shell nano microballoon emulsion; at 35 DEG C, under the condition of nitrogen protection, magnetic agitation reaction 3h.By high speed centrifugation processing, remove the TAPE molecule of liquid phase on not compound, obtain fluorescence molecule TAPE and Eu (TTA)
3two fluorescence nucleocapsid Nano microspheres that Phen is compound.The fluorescent nanometer microsphere obtaining is dissolved in 25mL water.
(4) in the subcutis of nude mice, inoculate tongue squamous cell carcinoma, after 7 days, cell forms after tumor tissues through diffusion propagation, two fluorescent core shell polymeric Nano microspheres that step (3) is obtained are mixed with the solution that concentration is 2mg/mL, measure 20 μ L and inject respectively tumor tissues and the normal subcutis of the nude mice of tumour, after 24h, carry out respectively slicing treatment, then carry out imaging by laser confocal microscope.
Embodiment 2:
(1) the NIPAM monomer that takes 5mmol is dissolved in 100mL deionized water, joins in the three-necked bottle of 500mL, adds 1.5 × 10
-6the CdTe of mol, the fluorostyrene (F-St) of 5mL, under room temperature, under nitrogen protection, mechanical stirring (400rpm) 30min, is then warming up to 70 DEG C gradually, adds 10mL to contain initiator Sodium Persulfate (Na
2s
2o
8) aqueous solution of 0.3mmol in system, initiated polymerization, reaction is carried out 12h and is finished.The polymer seeds microballoon containing CdTe obtaining is removed the impurity such as unconverted monomer, initiator in liquid phase by high speed centrifugation (18500r/min), then is dissolved in 100mL deionized water stand-by.
(2) seed microballoon emulsion step (1) being obtained is slowly poured in the three-necked bottle of 500mL; as seed; synthesize CdTe-PFS/PNIPAM-PMAA core-shell particles by seeded emulsion polymerization; in system, add 45mmol NIPAM; the MAA of 3.5mmol, under room temperature and nitrogen protection, mechanical stirring (300rpm) 30min; then be warming up to gradually 70 DEG C, add 15mL to contain initiator Sodium Persulfate (Na
2s
2o
8) aqueous solution of 0.6mmol in system, initiated polymerization.Reaction is carried out 12h and is finished, and obtains the nucleocapsid structure polymer nano-microspheres containing CdTe.Remove the impurity such as liquid phase unconverted monomer, initiator by high speed centrifugation (18800r/min), be dissolved in 100mL deionized water stand-by.
(3) measuring the CdTe-PFS/PNIPAM-PMAA Nano microsphere that 10mL step (2) obtains pours in the three-necked bottle of 100mL; take micro-d-TPE molecule 5.2 μ mol and put into core-shell nano microballoon emulsion; at 35 DEG C, under the condition of nitrogen protection, magnetic agitation reaction 5h.By high speed centrifugation processing, remove HPS molecule not compound in liquid phase, obtain fluorescence molecule HPS and the compound two fluorescent core shell structure polymer nano-microspheres of CdTe.The fluorescent nanometer microsphere obtaining is dissolved in 350mL water.
(4) in the subcutis of nude mice, inoculate tongue squamous cell carcinoma, after 7 days, cell forms after tumor tissues through diffusion propagation, two fluorescent core shell polymeric Nano microspheres that step (3) is obtained are mixed with the solution that concentration is 3mg/mL, measure 30 μ L and inject respectively tumor tissues and the normal subcutis of the nude mice of tumour, after 24h, carry out respectively slicing treatment, then carry out imaging by laser confocal microscope.
Embodiment 3:
(1) the NIPAM monomer that takes 5mmol is dissolved in 190mL deionized water, joins in the three-necked bottle of 500mL, adds 2 × 10
-6the RhB of mol; the vinylbenzene (St) of 5mL; under room temperature and nitrogen protection; mechanical stirring (400rpm) 30min; then be warming up to gradually 70 DEG C; add the aqueous solution that 10mL contains initiator ammonium persulfate (APS) 0.3mmol in system, initiated polymerization, reaction is carried out 12h and is finished.The polymer seeds microballoon containing RhB obtaining.Remove the impurity such as liquid phase unconverted monomer, initiator by high speed centrifugation (18500r/min), then be dissolved in 100mL deionized water stand-by.
(2) seed microspheres solution step (1) being obtained is slowly poured in the three-necked bottle of 500mL; and as seed; synthesize RhB-PS/PNIPAM-PMAA core-shell particles by seeded emulsion polymerization; in system, add 40mmol NIPAM; the MAA of 3.2mmol; under room temperature and nitrogen protection; mechanical stirring (300rpm) 30min; then be warming up to gradually 70 DEG C; add the aqueous solution that 15mL contains initiator ammonium persulfate (APS) 0.6mmol in system, initiated polymerization.Reaction is carried out 12h and is finished, and obtains the nucleocapsid structure polymer nano-microspheres containing RhB.Remove the impurity such as liquid phase unconverted monomer, initiator by high speed centrifugation (18800r/min), be dissolved in 100mL deionized water stand-by.
(3) measuring the RhB-PS/PNIPAM-PMAA Nano microsphere that 10mL step (2) obtains pours in the three-necked bottle of 100mL; take micro-d-TPE molecule 5.2 μ mol and put into core-shell nano microballoon emulsion; at 35 DEG C, under the condition of nitrogen protection, magnetic agitation reaction 5h.By high speed centrifugation processing, remove the not compound TTAPE molecule of liquid phase, obtain fluorescence molecule TTAPE and the compound two fluorescent core shell polymeric Nano microspheres of RhB.The fluorescent nanometer microsphere obtaining is dissolved in 30mL water.
(4) in the subcutis of nude mice, inoculate cervical cancer cell, after 7 days, cell forms after tumor tissues through diffusion propagation, two fluorescent core shell polymeric Nano microspheres that step (3) is obtained are mixed with the solution that concentration is 5mg/mL, measure 10 μ L and inject respectively tumor tissues and the normal subcutis of the nude mice of tumour, after 24h, carry out respectively slicing treatment, then carry out imaging by laser confocal microscope.
Claims (5)
1. two fluorescent emission polymer nano-microspheres for pH response, is characterized in that: prepared by following steps:
(1) the N-isopropylacrylamide NIPAM monomer that takes 2-10mmol is dissolved in the deionized water of 100-200mL, then adds the polymerization single polymerization monomer 1,1 × 10 of 10-50mmol
-6-5 × 10
-6the fluorescence molecule A of mol, under room temperature and nitrogen protection, mechanical stirring 30-60min; Then be warming up to gradually 60-70 DEG C, add 5-15mL to contain the aqueous solution of 0.3-0.6mmol initiator, initiated polymerization, obtains the polymer seeds microballoon containing fluorescence molecule A after reaction 12-24h; Finally remove the impurity such as unconverted monomer, initiator in liquid phase by high speed centrifugation, the more centrifugal polymer seeds microballoon containing fluorescence molecule A obtaining is dissolved in 50-100mL deionized water stand-by;
(2) in the polymer seeds microspheres solution of step (1), add the polymerization single polymerization monomer 1 of 10-60mmol and the pH responsiveness polymerization single polymerization monomer 2 of 1-5mmol, under room temperature and nitrogen protection, mechanical stirring 30-60min, then be warming up to gradually 70-85 DEG C, add 15mL to contain the aqueous solution of 0.5 – 1.5mmol initiator, initiated polymerization, reaction obtains the polymer nano-microspheres of nucleocapsid structure after 12-24h; Finally remove the impurity such as unconverted monomer, initiator in liquid phase by high speed centrifugation, the more centrifugal nucleocapsid structure polymer nano-microspheres obtaining is dissolved in 50-100mL deionized water stand-by;
(3) measure the core-shell nano microballoon emulsion that 10-30mL step (2) obtains, the fluorescence molecule B that takes 2-10 μ mol joins in this core-shell nano microballoon emulsion, at 30-40 DEG C, under the condition of nitrogen protection, under magnetic agitation, reacts 3-8h; Finally remove the not compound fluorescence molecule B of liquid phase by high speed centrifugation, obtain fluorescence molecule A and the compound two fluorescent core shell polymeric Nano microspheres of B;
Wherein, polymerization single polymerization monomer 1 is vinylbenzene, fluorostyrene, methyl methacrylate or glycidyl methacrylate; PH responsiveness polymerization single polymerization monomer 2 is that vinylformic acid, methacrylic acid, methyl acrylate, methacrylic acid are received or dimethylaminoethyl methacrylate;
Fluorescence molecule A is rare earth compounding RaXnYm, semiconductor nano, rhodamine B or metal nanometre cluster; Wherein, Ra is europium, terbium, thulium, lanthanum, erbium or ytterbium; The first X ligand is thenoyltrifluoroacetone, methyl ethyl diketone, diphenylpropane-1,3-dione(DPPO) or Whitfield's ointment, n=1-3; Ligands Y is 1,10-phenanthroline, m=0-1;
Fluorescence molecule B is bromination (N, N, N-triethyl-3-(4-(1, 2-phenylbenzene-2-(4-(2-triethylamine) oxyethyl group) vinyl) vinyl) phenyl) propyl group amine, bromination 2, 2 ', 2 ' '-(4, 4 ', 4 ' '-(2-(4-(3-s triethylamine) propyl group) phenyl) 1, 1, 2-triphenyl vinyl three oxygen) three (N, N, N-triethyl ethamine), hexaphenyl thiophene is coughed up, Silole, 1, 1-bis-[p-(diethyl amino methyl) benzene]-2, 3, 4, 5-tetra-benzo Siloles or 3-(4-(1, 2-phenylbenzene-2-(4-sulfo group oxyethyl group) phenyl) vinyl) propyl group-1-sodium sulfonate.
2. two fluorescent emission polymer nano-microspheres for pH response, is characterized in that: semiconductor nano is CdTe, CdSe, CdS, PbS, PbSe or PbTe.
3. two fluorescent emission polymer nano-microspheres for pH response, is characterized in that: metal nanometre cluster is Au nano-cluster or Ag nano-cluster.
4. two fluorescent emission polymer nano-microspheres for pH response, is characterized in that: initiator is Potassium Persulphate K
2s
2o
8, ammonium persulphate (NH
4)
2s
2o
8, Sodium peroxoborate NaBO
34H
2o, Sodium Persulfate Na
2s
2o
8or azo-bis-isobutyl cyanide AIBN.
5. a fluorescent material for application in tumor tissues detects, is characterized in that: be that the two fluorescent core shell polymeric Nano microspheres described in any one prepare by claim 1～4.
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| CN109613266A (en) * | 2018-12-30 | 2019-04-12 | 吉林大学 | It is a kind of detection glycosylated albumin and its concentration method, detection glycated amino acid oxidizing ferment -one amine oxidase and its concentration method |
| CN109613266B (en) * | 2018-12-30 | 2021-11-05 | 吉林大学 | Method for detecting glycated albumin and concentration thereof, and method for detecting glycated amino acid oxidase-ketoamine oxidase and concentration thereof |
| CN112342014A (en) * | 2020-10-28 | 2021-02-09 | 安徽为臻生物工程技术有限公司 | Preparation method of monodisperse polymer fluorescent microspheres |
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