CN101810888B - Preparation method for material with high density fixed biologically functional molecule - Google Patents
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Abstract
The invention relates to a preparation method for material with bioactivity functional surface, which comprises the steps of: grafting polymethylacrylic acid oligomerization gylcol ester (POEGMA) with excellent rejecting non-specific protein adsorption capacity on the surface of the material by an atom transfer radical polymerization (ATRP) technique; then grafting polymethylpentene acryloyl oxyl succinimide at the tail end of the POEGMA by using a secondary initiation of ATRP; and fixing biological molecules containing amino in a high-density way by using a larger number of active ester group contained in the side chain of PNHSMA. The bioactivity functional surface provided by the method can obviously increase the grafting density of the surfaces of the biological molecules, simultaneously reduces the undesirable influence caused by non-specific protein adsorption, effectively keeps the activity of the fixed biological molecules and can fix various biological molecules and is suitable for more extensive biomedical fields.
Description
Technical field
The present invention relates to biological detection, organizational project and polymeric material field, particularly relate to a kind of energy high density fixed biologically molecule and repel simultaneously the preparation method on the biological function surface of non-specific protein adsorption.
Background technology
Utilize Biological Principles that the bioactive substances such as protein, cell growth factor, enzyme, polypeptide are fixed on the material surface, various biological function that can the Effective Raise material (such as anticoagulation function, with the active of antibodies and to the adhesion of cell etc.), this has important using value (Pascal J.et al.Angew.Chem.Int.Ed. in the multiple bio-medical fields such as biological detection, organizational project, protein separation, Artificial Intervention material, 2008,47:9618-9647; Chen H.et al.Prog.Polym.Sci., 2008,33:1059-1087).For example: fixing heparin can be given the surface anticoagulant function to improve its blood compatibility; Fixedly the extracellular matrix protein such as fibronectin, collagen protein can effectively promote sticking of superficial cell and breed.But when making the fixing many as far as possible bioactive molecules of material surface, the surface also must have the ability of the absorption of repelling nonspecific proteins matter.This is because in field of biological detection such as biosensor, biochips, and the background noise that is caused by nonspecific proteins matter is the principal element that hinders detection accuracy; And at the Artificial Intervention material, the untoward reaction such as thrombosis, bacterial adhesion, inflammation that non-specific protein absorption causes also must be reduced as far as possible in the fields such as tissue engineering bracket.
The preparation strategy on this class biological function surface generally is that the biologically inert surface is combined with the bioactive molecule immobilization at present.Such as the people such as Xu (Xu et al.Biomacromolecules, 2009,10:1665-1674) at surface grafting have an excellent POEGMA that repels the non-specific protein absorption function, and the hydroxyl of its side chain terminal activated, and then fixed the biosensor of immunoglobulin (IgG) for the preparation of high s/n ratio.The people such as Tugulu (Tugulu et al.Biomaterials, 2007,28:2536-2546) at surface grafting POEGMA, after perhydroxyl radical activation, fixed the cell adhesion polypeptide, effectively promoted cell to sprawl in sticking of surface.Yet these preparation methoies all need to experience the process to functional group's activation, direct fixing biological molecules, course of reaction more complicated; The transformation efficiency of active group is not high, and then to cause the quantity of fixing biological molecules be not a lot, can not at utmost realize its biological function.
Summary of the invention
Technical problem to be solved by this invention is: for the problem that the existing course of reaction of present bioactivity surface preparation method is complicated, fixing biological molecules density is not high, provide a kind of simple to operate, can the high density fixed biologically molecule and repel simultaneously the surface modifying method of nonspecific proteins absorption.
The present invention solves its technical problem and adopts following technical scheme:
High density fixed biologically functional molecule material preparation method provided by the invention, it may further comprise the steps:
(1) preparation of POEGMA modified surface:
To be fixed with the material surface of initiator, place the solution that contains catalyst/ligand system and OEGMA monomer to carry out the ATRP reaction under nitrogen protection, reaction temperature is 0~45 ℃, and the response time is 0.5~6 hour, obtains the POEGMA modified surface; POEGMA is the english abbreviation of polymethylacrylic acid oligomeric ethylene glycol ester, OEGMA be methacrylic acid oligomeric ethylene glycol ester english abbreviation, ATRP is the english abbreviation of atom transfer radical polymerization.
The described material that is fixed with initiator can adopt monocrystal silicon or glass; This initiator is α-bromine butyryl bromide, alpha-brominated isobutyl acylbromide, or alpha-brominated propionyl bromide.
Described catalyst/ligand system can adopt cuprous bromide/five methyl diethylentriamine, or copper bromide/ascorbic acid.
Described OEGMA monomer solution is aqueous solution, methanol solution, or the mixed solution of water and methanol.
(2) preparation of NHSMA:
In reaction unit, methacrylic chloride is slowly splashed in the solution of NHS by 1: 1~1.2: 1 mol ratio first, stirring reaction under the condition that triethylamine exists, reaction temperature is 0~35 ℃, response time is 1~12 hour, obtains the monomer solution of NHSMA; Again this monomer solution is obtained white crystal NHSMA through recrystallization; Described NHSMA is the english abbreviation of methacryloxy butanimide, and described NHS is the english abbreviation of N-hydroxy-succinamide.
Described NHS solution is the chloroform soln of N-hydroxy-succinamide, and by W/V, the triethylamine consumption is 10~25% of described solution.
(3) preparation of POEGMA-PNHSMA modified surface:
Place the monomer solution of the NHSMA that contains catalyst/ligand system and gained to carry out secondary ATRP reaction the POEGMA modified surface of gained, reaction temperature is 70~100 ℃, and the response time is 2~6 hours, obtains the POEGMA-PNHSMA modified surface.
Described catalyst/ligand system can adopt copper bromide/five methyl diethylentriamine, or cuprous bromide/five methyl diethylentriamine.
Described NHSMA monomer solution is methyl phenyl ethers anisole solution or dimethyl sulphoxide solution.
(4) POEGMA-PNHSMA modified surface immobilizing biologically active molecule:
Place the solution that contains bioactive molecule to react the POEGMA-PNHSMA modified surface of gained, temperature is controlled at 0~40 ℃, and the response time is 2~24 hours, and reaction places passivator (EG) with described surface after finishing
2NH
2Solution in unreacted NHS group is carried out passivation, passivation temperature is room temperature, the response time is 2~12 hours.After this step is finished, the POEGMA-PNHSMA modified surface is taken out from solution, clean with ethanol or aqueous solvent respectively, be fixed the biological function surface of biotin, collagen protein and heparin bioactive molecule.
Described bioactive molecule is that biotin acyl trap, fibronectin, collagen protein, heparin, lysine or other contain amino biomolecule.The solution of described bioactive molecule is that alcoholic solution, acetic acid solution, phosphate buffered solution or other can dissolve the solution of corresponding bioactive molecule.
Described (EG)
2NH
2Solution be alcoholic solution.
Through above-mentioned steps, finally obtain the high density fixed biologically functional molecule material, this material surface has the function of not adsorbing non-specific albumen.
The present invention compared with prior art has advantages of following main:
Method provided by the invention is the method that the direct surface initiated polymerization prepares bioactivity surface, the group activation process in the middle of not needing.Compared with prior art, the present invention has following outstanding feature:
1. be beneficial to the activity that keeps fixing biological molecules: with traditional activation functional group then the method for fixing biological molecules compare, this method can be fixed more highdensity bioactive molecule, POEGMA namely can repel nonspecific proteins absorption as the existence of wall simultaneously, a hydrophilic environment can be provided again, thereby be conducive to keep the activity of fixing biological molecules.
2. simple to operate, easy row: can be by changing the polymerizing condition of secondary ATRP, with the physics and chemistry characteristic on controlled material surface easily.
3. the suitability is wider: can be used for fixing any bioactive molecule that contains amino and also effectively realize its biological function, be applicable to such as many bio-medicals fields such as biological detection, organizational project, protein separations.For example, behind the active surface fixed biologically element that utilizes this method to obtain, can the selective binding Avidin; Phenomenon (seeing Fig. 1) do not occur sticking at POEGMA modified surface cell, and fixedly behind the collagen protein, can effectively promote cell adhesion to sprawl (seeing Fig. 2) on the surface; Behind surperficial fixing heparin, can specific binding anticoagulant factor ATIII (seeing Fig. 3), obtain surface that has anticoagulant functions etc.As can be seen from Figure 3, the ATIII adsorbance of POEGMA modified surface is 0.0129ug/cm
2, and the ATIII adsorbance of fixing heparin rear surface is 0.0942ug/cm
2, the surface A TIII adsorbance after namely fixing has increased by 10 times.
Description of drawings
Fig. 1 be POEGMA modified surface cell stick growing state.
Fig. 2 be fixed the collagen protein superficial cell stick growing state.
Fig. 3 is the POEGMA modified surface and has fixed the absorption situation of heparin rear surface to anticoagulant factors A TIII.
The specific embodiment
The invention provides the preparation method that a kind of high density fixed biologically functional molecule repels the biological function surface of non-specific protein absorption simultaneously.Fixedly behind the initiator, in the presence of part/catalyst and monomer OEGMA, at material surface grafting POEGMA, then utilize secondary to cause ATRP at the terminal grafting PNHSMA of POEGMA by the ATRP technology at material surface.Utilize the contained a large amount of NHS groups of PNHSMA fixedly to contain to high-density amino bioactive molecule (such as protein, polysaccharide, enzyme etc.), finally realize its physiological function.
Below by embodiment, the present invention is further elaborated, but do not limit the present invention.
Embodiment 1
The 10mL chloroform of 2.2mL methacrylic chloride is added drop-wise in 0 ℃ the 20mL chloroform soln that contains 2.3gNHS and 3.3mL triethylamine.After dropwising, at room temperature reacted 4 hours.Reactant liquor cleans with saturated brine ice, and with anhydrous magnesium sulfate organic facies is carried out drying.Filtering-depositing, solvent is concentrated after in the mixed solution of 0.8mL ethyl acetate and 6mL normal hexane recrystallization obtain monomer NHSMA.
Under nitrogen atmosphere, with 7.93g OEGMA, 2 of 312mg, 2-bipyridyl and 143mg cuprous bromide are dissolved in the mixed solution of 15mL first alcohol and water (4: 1).To transfer to the surface behind the ultrasonic 5min of mentioned solution and be fixed with the silicon chip of α-bromine butyryl bromide initiator, use copper bromide/bipyridyl stopped reaction behind the reaction 2h under the room temperature, and clean with a large amount of water and ethanol effects on surface, drying up with nitrogen afterwards, POEGMA has been fixed on the surface after the processing.Above-mentioned surface placed contain the 14mg cuprous bromide, 0.92g NHSMA, in the 6mL methyl phenyl ethers anisole of 42 μ L PMDETA, reaction is carried out silicon chip being cleaned and drying in vacuum tank with a large amount of DMF (DMF) after the 2h. reaction finishes under 90 ℃.
Above-mentioned surface is placed in the middle of the sodium acetate solution (pH 5.5) of 1mg/mL biotin hydrazides, and at room temperature reaction is spent the night.Use sodium acetate solution, water, ethanol clean surface after reaction finishes, and this diaphragm is placed 0.1M (EG)
2NH
2Alcoholic solution in carry out passivation with the active ester group that the surface is remaining.Can obtain the bioactivity surface of high density fixed biologically element.
Embodiment 2
The 10mL chloroform of 2.2mL methacrylic chloride is added drop-wise in 0 ℃ the 20mL chloroform soln that contains 2.3g NHS and 3.3mL triethylamine.After dropwising, at room temperature reacted 4 hours.Reactant liquor cleans with saturated brine ice, and with anhydrous magnesium sulfate organic facies is carried out drying.Filtering-depositing, solvent is concentrated after in the mixed solution of 0.8mL ethyl acetate and 6mL normal hexane recrystallization obtain monomer NHSMA.
Under nitrogen atmosphere, with 7.93g OEGMA, 2 of 312mg, 2-bipyridyl and 143mg cuprous bromide are dissolved in the mixed solution of 15mL first alcohol and water (1: 1).Will transfer to behind the ultrasonic 5min of mentioned solution the fixing silicon chip of α-bromine butyryl bromide initiator in surface, also clean with a large amount of water and ethanol effects on surface behind the reaction 2h under the room temperature, dry up with nitrogen afterwards.Above-mentioned surface placed contain the 14mg cuprous bromide, 0.92g NHSMA, in the 6mL methyl phenyl ethers anisole of 42 μ L PMDETA, reaction is carried out silicon chip being cleaned and drying in vacuum tank with a large amount of DMF after the 3h. reaction finishes under 70 ℃.
The acetic acid solution of 4wt% collagen protein is transferred to 8.0 with the 2.0M sodium hydroxide solution with pH obtain collagen solution.Place collagen solution to spend the night in 4 ℃ of reactions on above-mentioned surface.Reaction finishes rear water, ethanol clean surface, and this diaphragm is placed 0.1M (EG)
2NH
2Alcoholic solution in carry out passivation with the active ester group with remnants.Can obtain the fixedly bioactivity surface of collagen protein of high density.
Embodiment 3
The 10mL chloroform of 2.2mL methacrylic chloride is added drop-wise in 0 ℃ the 20mL chloroform soln that contains 2.3g NHS and 3.3mL triethylamine.After dropwising, at room temperature reacted 4 hours.Reactant liquor cleans with saturated brine ice, and with anhydrous magnesium sulfate organic facies is carried out drying.Filtering-depositing, solvent is concentrated after in the mixed solution of 0.8mL ethyl acetate and 6mL normal hexane recrystallization obtain monomer NHSMA.
Under nitrogen atmosphere, with 7.93g OEGMA, 2 of 312mg, 2-bipyridyl and 143mg cuprous bromide are dissolved in the mixed solution of 15mL first alcohol and water (2: 1).Will transfer to behind the ultrasonic 5min of mentioned solution the fixing silicon chip of α-bromine butyryl bromide initiator in surface, clean with a large amount of water and ethanol effects on surface after reacting 2h under the room temperature, dry up with nitrogen afterwards.Above-mentioned surface placed contain the 14mg cuprous bromide, 0.92g NHSMA, in the 6mL methyl phenyl ethers anisole of 42 μ L PMDETA, 4h is carried out in reaction under 100 ℃.Reaction is cleaned silicon chip and is dried in vacuum tank with a large amount of DMF after finishing.
Diaphragm is placed phosphate buffered solution (pH=8.0) the room temperature reaction 24h of the heparin of 10mg/mL.Use phosphate buffered solution, water, ethanol clean surface after reaction finishes, and this diaphragm is placed 0.1M (EG)
2NH
2Alcoholic solution in carry out passivation with the active ester group with remnants.Can obtain the bioactivity surface of high density fixing heparin.
Embodiment 4
The 10mL chloroform of 2.2mL methacrylic chloride is added drop-wise in 0 ℃ the 20mL chloroform soln that contains 2.3gNHS and 3.3mL triethylamine.After dropwising, at room temperature reacted 4 hours.Reactant liquor cleans with saturated brine ice, and with anhydrous magnesium sulfate organic facies is carried out drying.Filtering-depositing, solvent is concentrated after in the mixed solution of 0.8mL ethyl acetate and 6mL normal hexane recrystallization obtain monomer NHSMA.
Under nitrogen atmosphere, with 7.93g OEGMA, 2 of 312mg, 2-bipyridyl and 143mg cuprous bromide are dissolved in the mixed solution of 15mL first alcohol and water (2: 1).Will transfer to behind the ultrasonic 5min of mentioned solution the fixing silicon chip of α-bromine butyryl bromide initiator in surface, clean with a large amount of water and ethanol effects on surface after reacting 4h under the room temperature, dry up with nitrogen afterwards.Above-mentioned surface placed contain the 14mg cuprous bromide, 0.92gNHSMA, in the 6mL methyl phenyl ethers anisole of 42 μ L PMDETA, 6h is carried out in reaction under 100 ℃.Reaction is cleaned silicon chip and is dried in vacuum tank with a large amount of DMF after finishing.
Diaphragm is placed citrate buffer solution (pH=8.0) the room temperature reaction 24h of the rgd peptide of 0.1mg/mL.Use citrate buffer solution, water, ethanol clean surface after reaction finishes, and this diaphragm is placed 0.1M (EG)
2NH
2Alcoholic solution in carry out passivation with the active ester group with remnants.Can obtain the fixedly bioactivity surface of RGD of high density.
Embodiment 5
The 10mL chloroform of 2.2mL methacrylic chloride is added drop-wise in 0 ℃ the 20mL chloroform soln that contains 2.3g NHS and 3.3mL triethylamine.After dropwising, at room temperature reacted 4 hours.Reactant liquor cleans with saturated brine ice, and with anhydrous magnesium sulfate organic facies is carried out drying.Filtering-depositing, solvent is concentrated after in the mixed solution of 0.8mL ethyl acetate and 6mL normal hexane recrystallization obtain monomer NHSMA.
Under nitrogen atmosphere, with 7.93g OEGMA, 2 of 312mg, 2-bipyridyl and 143mg cuprous bromide are dissolved in the mixed solution of 15mL first alcohol and water (1: 1).Will transfer to behind the ultrasonic 5min of mentioned solution the fixing silicon chip of α-bromine butyryl bromide initiator in surface, clean with a large amount of water and ethanol effects on surface after reacting 3h under the room temperature, dry up with nitrogen afterwards.Above-mentioned surface placed contain the 14mg cuprous bromide, 0.92g NHSMA, in the 6mL methyl phenyl ethers anisole of 42 μ L PMDETA, 4h is carried out in reaction under 90 ℃.Reaction is cleaned silicon chip and is dried in vacuum tank with a large amount of DMF after finishing.
Diaphragm is placed citrate buffer solution (pH=8.0) the room temperature reaction 24h of the rgd peptide of 0.1mg/mL.Use citrate buffer solution, water, ethanol clean surface after reaction finishes, and this diaphragm is placed 0.1M (EG)
2NH
2Alcoholic solution in carry out passivation with the active ester group with remnants.Can obtain the fixedly bioactivity surface of RGD of high density.
Embodiment 6
The 10mL chloroform of 2.2mL methacrylic chloride is added drop-wise in 0 ℃ the 20mL chloroform soln that contains 2.3g NHS and 3.3mL triethylamine.After dropwising, at room temperature reacted 4 hours.Reactant liquor cleans with saturated brine ice, and with anhydrous magnesium sulfate organic facies is carried out drying.Filtering-depositing, solvent is concentrated after in the mixed solution of 0.8mL ethyl acetate and 6mL normal hexane recrystallization obtain monomer NHSMA.
Under nitrogen atmosphere, with 7.93g OEGMA, 2 of 312mg, 2-bipyridyl and 143mg cuprous bromide are dissolved in the mixed solution of 15mL first alcohol and water (2: 1).Will transfer to behind the ultrasonic 5min of mentioned solution the fixing silicon chip of α-bromine butyryl bromide initiator in surface, clean with a large amount of water and ethanol effects on surface after reacting 4h under the room temperature, dry up with nitrogen afterwards.Above-mentioned surface placed contain the 14mg cuprous bromide, 0.92g NHSMA, in the 6mL methyl phenyl ethers anisole of 42 μ LPMDETA, 6h is carried out in reaction under 100 ℃.Reaction is cleaned silicon chip and is dried in vacuum tank with a large amount of DMF after finishing.
Diaphragm is placed 0 ℃ of reaction of phosphate buffered solution (pH=7.4) 24h of the fibronectin of 0.1mg/mL.Use phosphate buffered solution, water, ethanol clean surface after reaction finishes, and this diaphragm is placed 0.1M (EG)
2NH
2Alcoholic solution in carry out passivation with the active ester group with remnants.Can obtain the fixedly bioactivity surface of fibronectin of high density.
Claims (5)
1. the material preparation method of a high density fixed biologically functional molecule is characterized in that may further comprise the steps:
(1) preparation of POEGMA modified surface:
To be fixed with the material surface of initiator, place the solution that contains catalyst/ligand system and OEGMA monomer to carry out the ATRP reaction under nitrogen protection, reaction temperature is 0~45 ℃, and the response time is 0.5~6 hour, obtains the POEGMA modified surface; The described material that is fixed with initiator is monocrystal silicon or glass; This initiator is α-bromine butyryl bromide, alpha-brominated isobutyl acylbromide or alpha-brominated propionyl bromide; Described catalyst/ligand system is cuprous bromide/five methyl diethylentriamine or copper bromide/ascorbic acid; POEGMA is the english abbreviation of polymethylacrylic acid oligomeric ethylene glycol ester, and OEGMA is the english abbreviation of methacrylic acid oligomeric ethylene glycol ester, and ATRP is the english abbreviation of atom transfer radical polymerization;
(2) preparation of NHSMA:
In reaction unit, methacrylic chloride is slowly splashed in the solution of NHS by 1: 1~1.2: 1 mol ratio first, stirring reaction under the condition that triethylamine exists, reaction temperature is 0~35 ℃, response time is 1~12 hour, obtains the monomer solution of NHSMA; Again this monomer solution is obtained white crystal NHSMA through recrystallization; Described NHSMA is the english abbreviation of methacryloxy butanimide, and described NHS is the english abbreviation of N-hydroxy-succinamide;
(3) preparation of POEGMA-PNHSMA modified surface:
Place the monomer solution of the NHSMA that contains catalyst/ligand system and gained to carry out secondary ATRP reaction the POEGMA modified surface of gained, reaction temperature is 70~100 ℃, and the response time is 2~6 hours, obtains the POEGMA-PNHSMA modified surface; Described catalyst/ligand system is copper bromide/five methyl diethylentriamine, or cuprous bromide/five methyl diethylentriamine;
(4) POEGMA-PNHSMA modified surface immobilizing biologically active molecule:
Place the solution that contains bioactive molecule to react the POEGMA-PNHSMA modified surface of gained, temperature is controlled at 0~40 ℃, and the response time is 2~24 hours, and reaction places passivator (EG) with described surface after finishing
2NH
2The solution of ethanol in unreacted NHS group is carried out passivation, passivation temperature is room temperature, the response time is 2~12 hours; Described bioactive molecule is that biotin hydrazides, lysine or other contain amino bioactive molecule;
Through above-mentioned steps, finally obtain the high density fixed biologically functional molecule material, this material surface has the function of not adsorbing non-specific albumen.
2. method according to claim 1, it is characterized in that: described OEGMA monomer solution is aqueous solution, methanol solution, or the mixed solution of water and methanol.
3. method according to claim 1, it is characterized in that: described NHS solution is the chloroform soln of N-hydroxy-succinamide, by W/V, the triethylamine consumption is 10~25% of described solution.
4. method according to claim 1, it is characterized in that: the described NHSMA monomer solution of step (3) is methyl phenyl ethers anisole solution or dimethyl sulphoxide solution.
5. method according to claim 1 is characterized in that: the solution of described bioactive molecule is that alcoholic solution, acetic acid solution, phosphate buffered solution or other can dissolve the solution of corresponding bioactive molecule.
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