CN101450996B - Glucose responding type polyphosphazene hydrogel - Google Patents
Glucose responding type polyphosphazene hydrogel Download PDFInfo
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- CN101450996B CN101450996B CN2007101789166A CN200710178916A CN101450996B CN 101450996 B CN101450996 B CN 101450996B CN 2007101789166 A CN2007101789166 A CN 2007101789166A CN 200710178916 A CN200710178916 A CN 200710178916A CN 101450996 B CN101450996 B CN 101450996B
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Abstract
The invention relates to a glucose-responsive nitrile polyphosphine hydrogel and a method for preparing the same. The method utilizes interaction between nitrile polyphosphine containing glucose side groups and lectin concanavalin A (Concanavalin A, Con A) to obtain a hydrogel system with different crosslinking degrees and water contents through the proportion increase of the glucose side groups and the selection of a second proper substituting group and a third proper substituting group and other means; and the nitrile polyphosphine hydrogel system has glucose responsiveness, biocompatibility and biodegradability, and can be used for intelligent release of insulin.
Description
Technical field:
The present invention relates to a kind of glucose responding type polyphosphazene hydrogel.
Background technology:
Diabetes are to be a kind of syndrome of basic biochemical character to continue hyperglycemia, at present mainly based on pharmacological agent.Insulinize mainly is hyperglycemia medication after having meal at the patient, the hypoglycemic effect is obvious after being usually expressed as medication, the phenomenon that drug effect forfeiture back blood sugar concentration raises again, and Regular Insulin can only take the injection system administration at present, and the every day of injection has repeatedly brought great inconvenience for patient's daily life.Owing to the influence of other factors of individual diversity XOR, long-term injection of insulin also causes side effects such as hypoglycemic reaction, insulin resistant, hyperinsulinemia and insulin allergy and oedema easily in addition.Therefore, medical circle is always all in the better approach that strives to find the treatment diabetes.For example, the research of pancreatic islets transplantation, artificial pancreas etc. has all obtained gratifying achievement.Can simulate the research and development of the intelligent Regular Insulin sustained release system of pancreas, also be a kind of potential, diabetes remedy with application prospect.
For a long time, medical circle expects to find ideal medicine sustained release solid support material always, these materials can the perception physiological environment variation, adjust the release behavior of entrained medicine, thereby reach fast effectively the treatment disease and reduce the side effect that medicine brings human body as far as possible.Discover that the polymer intelligent hydrogel can satisfy above-mentioned requirements to a great extent.At present, in the document report more glucose responding type hydrogel mainly contain three kinds of response mechanisms (Advanced Drug Delivery Reviews, 2002,54:79-98): (1) glucolase-pH response type aquogel system; (2) phytohemagglutinin-contain glucosyl group macromolecule hydrogel system; (3) based on phenyl-boron dihydroxide and the interactional macromolecule hydrogel system of polyhydroxy substance.
If be used to prepare the polymeric main polyacrylamide and polyacrylic acid (ester) class of above-mentioned glucose responding type hydrogel at present, but these materials are mostly to select different monomers to carry out homopolymerization or final polymer properties is regulated and controlled in copolymerization, so performance is adjustable or controlled range is narrower, be difficult to satisfy the needs of drug release, do not reach the best effect of pharmacological agent; And the degradation property of most materials is relatively poor.But in the clinical application of glucose responding type hydrogel, heeling-in mold base formula pharmaceutical dosage form is than a kind of mode that is easier to implement, after finishing in drug release, carry out the operation second time macromolecule matrix is taken out, so the degradation property of polymeric matrix is a crucial index.So it is very necessary that the degradable macromolecule gelling system of development biocompatibility is used for intelligent drug release.
Though, Biodegradable high-molecular such as polyester, polyamino acid, poly-acid anhydrides, poe and polycarbonate etc. also have been widely used in the research of medicine sustained release, but because the restriction of polymer molecular structure, be used to prepare the research of aquogel system and few, therefore, another kind of drug release material-poly phosphazene just more and more causes people's interest.Polyphosphonitrile is meant the inorganic main chain polymer that a class main chain is formed by connecting with the single, double key of alternative by the phosphorus nitrogen-atoms, and the both sides of phosphorus atom are easy to introduce different functional groups in its main chain, thereby makes the macromolecular material of high molecular functionalization with the preparation different performance.Owing to can on same main polymer chain, introduce two or more function side group simultaneously, so the poly phosphazene polymer is that other polymkeric substance are incomparable in the diversity and the controllability of structure and aspect of performance.And the degraded of poly phosphazene belongs to the side chain mechanism of degradation, it is the high molecular degradability of biodegradability decision poly phosphazene of side chain, therefore the singularity that structurally had of poly phosphazene makes it have special advantages as drug release carrier and tissue engineering cell scaffold material.
Summary of the invention:
The purpose of this invention is to provide a kind of glucose responding type polyphosphazene hydrogel, employing contains the interaction of the poly phosphazene and the Con A of glucose side group, the aquogel system that ratio by improving the glucose side group and the suitable means such as second substituting group of selection can obtain to have different degree of crosslinking and different moisture content, this polyphosphazene hydrogel system has glucose responding, and have biocompatibility, biodegradability, can be used for the intelligence of Regular Insulin is discharged.
Glucose responding type polyphosphazene hydrogel of the present invention, by the poly phosphazene polymer aqueous solution and phytohemagglutinin concanavalin A (ConcanavalinA, ConA) aqueous solution forms, wherein the high molecular chemical structural formula of poly phosphazene is as follows:
Wherein x+y≤2 and x can not be 0, n=10-5000;
R is a glucosyl group, and its ratio can be 1～100% of side group sum, and optimum proportion is 5～95%, and the binding site with Con A effect is provided.
R ' is any in the groups such as amino acid ester, methylamine, imidazoles, alkyloxy-ethers, methoxy poly (ethylene glycol) ether or their combination; Its ratio can be 0～99% of side group sum, and optimum proportion is 5～95%, in order to the hydrophilic and hydrophobic of telomerized polymer and biodegradability etc.
Above-mentioned poly phosphazene polymer, needs according to concrete application, can also control the ratio of R and R ' by feed ratio, when x+y＜2, suitably introduce the third substituting group, can be the group that hydroxyethyl methylacrylate, vinyl carbinol, allylamine etc. contain unsaturated double-bond, also can be that amino ethoxy, hydroxyl-oxethyl etc. contain one of group of amino or hydroxy functional group, for the formation of hydrogel provides the point of chemically crosslinked to a certain degree.The ratio that this substituting group accounts for the substituting group total amount can be 1～30%, and optimum proportion is 1～10%.
The high molecular preparation method of poly phosphazene, be earlier by 1,2:5, the an alkali metal salt of 6-di-O-isopropylidene-alpha-D-glucose and linear poly-dichlorides phosphorus nitrile carry out substitution reaction and prepare in tetrahydrofuran (THF), dioxane, benzene or toluene, temperature of reaction is 40-100 ℃, and the reaction times is 12～84 hours, 1,2:5, the substitute proportion of 6-di-O-isopropylidene-alpha-D-glucose are 1～100%.
Subsequently, add and contain the compound of R ' group and unsubstituted P-Cl continuation reaction still, obtain mixing the polymkeric substance of replacement.This polymkeric substance promptly gets subject polymer slough the protecting group of glucose with trifluoroacetic acid solution after.
When the compound that contains R ' group is the compound that contains terminal hydroxy group, during as ethanol, methyl cellosolve or methoxy poly (ethylene glycol) ether, to carry out the temperature of reaction of nucleophilic substitution be 40-100 ℃ to P-Cl on itself and the phosphonitrile main chain, and the reaction times is 12～84 hours.
When the compound that contains R ' group is to contain the amino compound of end, during as methylamine or amino acid ester, to carry out the temperature of reaction of nucleophilic substitution be 0-50 ℃ to P-Cl on itself and the phosphonitrile main chain, and the reaction times is 12～84 hours.
Preparation glucose side group replaces the main raw material 1 of poly phosphazene, 2:5,6-di-O-isopropylidene-alpha-D-glucose can be buied, and also can react by alpha-D-glucose and excessive propanone to obtain under zinc chloride and phosphoric acid catalyzed, temperature of reaction 20-40 ℃, reaction times 24-48 hour.
The preparation of linear polydichlorophosphazenes be by the hexachlorocyclotriphosphazene monomer under the anhydrous and oxygen-free condition, 220-280 ℃ ring-opening polymerization 10-96 hour and get, the polymerization degree 10～5000, best polymer scope are 100～2000, molecular weight 1～200,000.
Be a simple procedure signal of poly phosphazene preparation process below:
R
1Group can come from one or more in amino acid ester, first ammonia, imidazoles, alkyloxy-ethers, the methoxy poly (ethylene glycol) ether;
R
2Group can come from one or more in hydroxyethyl methylacrylate, vinyl carbinol, allylamine, the monoethanolamine.
The preparation method of glucose responding type polyphosphazene hydrogel of the present invention is: with concentration is the poly phosphazene polymer aqueous solution of 0.1～0.5mg/L and phytohemagglutinin concanavalin A (the Concanavalin A that concentration is 0.5～2.0mg/L, Con A) aqueous solution mixed, leaves standstill 5-30 minute with 1: 1 volume ratio, removed unreacted Con A and made.
The invention effect: polyphosphazene hydrogel of the present invention is based on the poly phosphazene that contains the glucose side group and the interaction of Con A, the aquogel system that ratio by improving the glucose side group and the suitable means such as second substituting group of selection can obtain to have different degree of crosslinking and different moisture content, this system has glucose responding, and have good biocompatibility, can simulate pancreas function and be used for the intelligence of Regular Insulin is discharged.
Embodiment:
Embodiment 1:
(1) preparation of polydichlorophosphazenes: the 2g hexachlorocyclotriphosphazene is encapsulated in the glass tube with vacuum, places 260 ℃ of reactions 48 hours.To be cooled to room temperature, remove the big ring phosphonitrile by product of unreacted monomer and generation with the dry sherwood oil repetitive scrubbing of heat, use the abundant dissolution residual substance of exsiccant benzene then, remove by filter insolubles after, with behind the petroleum ether precipitation, vacuum-drying polydichlorophosphazenes is stand-by.
(2) 1,2:5, the preparation of 6-di-O-isopropylidene-alpha-D-glucose: anhydrous alpha-D-glucose of 5g and 57ml anhydrous propanone are placed the dry there-necked flask that has mechanical stirrer, the phosphoric acid 0.23ml that successively adds 3.79g Zinc Chloride Anhydrous and 85%, behind the room temperature reaction 30 hours, filter, dropping sodium (25mol/L) solution is up to neutrality in the filtrate.Refilter, the filtrate decompression distillation obtains thick liquid after removing and desolvating.Viscous fluid chloroform extraction three times merge chloroform extraction liquid with after the less water washing, remove solvent and get white crystal, and (1: 2v/v) recrystallization is 2 times, gets 1 of purifying, 2:5,6-di-O-isopropylidene-alpha-D-glucose after the drying through chloroform-normal hexane.
(3) preparation of poly phosphazene:
100ml exsiccant tetrahydrofuran solution is placed the there-necked flask that has mechanical stirrer, add 10.4g (0.04mol) 1 subsequently, 2:5,6-di-O-isopropylidene-alpha-D-glucose and 1.0g (0.043mol) metal is received, behind the room temperature reaction 24 hours, the tetrahydrofuran solution (100ml) of 1.16g (0.01mol) polydichlorophosphazenes slowly is added drop-wise in the above-mentioned solution, and heating reflux reaction 96 hours.Centrifugal remove insolubles after, rotary evaporation is removed most of solvent and is obtained viscous liquid, and this thick liquid is precipitated with deionized water, the throw out that obtains is in 40 ℃ of following drying under reduced pressure.Then the exsiccant polymkeric substance is placed the single port bottle that has magnetic agitation,, be stirred to polymkeric substance and dissolve back continuation reaction 4 hours fully to the trifluoroacetic acid 20ml that wherein drips 90%.With in the supersaturation sodium hydrogen carbonate solution and after, place dialysis tubing (molecular weight cut-off 12000) with deionized water dialysis purifying 3 days, rotary evaporation is removed and can be got 100% glucose in 40 ℃ of following vacuum-dryings behind the moisture content and replace poly phosphazene (polymkeric substance 1).
(4) preparation of hydrogel:
Polymkeric substance 1 is mixed with the aqueous solution that concentration is 0.2g/mL, with concentration be the ConA aqueous solution of 2.0g/mL, mix with 1: 1 volume ratio, leave standstill after 5 minutes and form hydrogel.Remove the Con A that has neither part nor lot in reaction in the gel with the deionized water extraction.
Embodiment 2:
Step (1), (2) are with embodiment 1
(3) preparation of poly phosphazene:
100ml exsiccant tetrahydrofuran solution is placed the there-necked flask that has mechanical stirrer, add 7.80g (0.03mol) 1 subsequently, 2:5,6-di-O-isopropylidene-alpha-D-glucose and 0.75g (0.033mol) metal is received, room temperature reaction 24 hours.The polydichlorophosphazenes solution of 1.16g (0.01mol) slowly is added drop-wise in the above-mentioned solution, and refluxed 96 hours.Tetrahydrofuran solution (100ml) (the room temperature reaction preparation in 24 hours in tetrahydrofuran (THF) by 0.80ml (0.01mol) methyl cellosolve and 0.25g (0.011mol) sodium Metal 99.5) with methyl ethanol sodium slowly is added drop-wise in the above-mentioned solution then, reaction was warming up to 50 ℃ and continues reaction 24 hours after 24 hours under the room temperature.Centrifugal remove insolubles after, rotary evaporation is removed most of solvent and is obtained viscous liquid, with oil mystery precipitation, methyl alcohol dialysis (dialysis tubing molecular weight cut-off 12000) purifying after 3 days, rotary evaporation is removed solvent, in 40 ℃ of following vacuum-dryings with this thick liquid.Then the exsiccant polymkeric substance is placed the single port bottle that has magnetic agitation,, be stirred to polymkeric substance and dissolve back continuation reaction 4 hours fully to the trifluoroacetic acid 20ml that wherein drips 90%.With in the supersaturation sodium hydrogen carbonate solution and after, place dialysis tubing (molecular weight cut-off 12000) with deionized water dialysis purifying 3 days, rotary evaporation is removed behind the moisture content in 40 ℃ of following vacuum-dryings can get 80% glucose and 20% methyl cellosolve replaces poly phosphazene (polymkeric substance 2) altogether.
(4) preparation of hydrogel:
Polymkeric substance 2 is mixed with the aqueous solution that concentration is 0.25g/mL, with concentration be the Con A aqueous solution of 1.6g/mL, mix with 1: 1 volume ratio, leave standstill after 10 minutes and form hydrogel.Remove the Con A that has neither part nor lot in reaction in the gel with the deionized water extraction.
Embodiment 3:
Step (1), (2) are with embodiment 1
(3) preparation of poly phosphazene:
100ml exsiccant tetrahydrofuran solution is placed the there-necked flask that has mechanical stirrer, add 5.20g (0.02mol) 1 subsequently, 2:5,6-di-O-isopropylidene-alpha-D-glucose and 0.50g (0.022mol) metal is received, room temperature reaction 24 hours.The polydichlorophosphazenes solution of 1.16g (0.01mol) slowly is added drop-wise in the above-mentioned solution, and refluxed 96 hours.Tetrahydrofuran solution (100ml) (the room temperature reaction preparation in 24 hours in tetrahydrofuran (THF) by 1.60ml (0.02mol) methyl cellosolve and 0.50g (0.022mol) sodium Metal 99.5) with methyl ethanol sodium slowly is added drop-wise in the above-mentioned solution then, reaction was warming up to 50 ℃ and continues reaction 24 hours after 24 hours under the room temperature.Centrifugal remove insolubles after, rotary evaporation is removed most of solvent and is obtained viscous liquid, with oil mystery precipitation, methyl alcohol dialysis (dialysis tubing molecular weight cut-off 12000) purifying after 3 days, rotary evaporation is removed solvent, in 40 ℃ of following vacuum-dryings with this thick liquid.Then the exsiccant polymkeric substance is placed the single port bottle that has magnetic agitation,, be stirred to polymkeric substance and dissolve back continuation reaction 4 hours fully to the trifluoroacetic acid 20ml that wherein drips 90%.With in the supersaturation sodium hydrogen carbonate solution and after, place dialysis tubing (molecular weight cut-off 12000) with deionized water dialysis purifying 3 days, rotary evaporation is removed behind the moisture content in 40 ℃ of following vacuum-dryings can get 50% glucose and 50% methyl cellosolve replaces poly phosphazene (polymkeric substance 3) altogether.
(4) preparation of hydrogel:
Polymkeric substance 3 is mixed with the aqueous solution that concentration is 0.3g/mL, with concentration be the ConA aqueous solution of 1.6g/mL, mix with 1: 1 volume ratio, leave standstill after 10 minutes and form hydrogel.Remove the Con A that has neither part nor lot in reaction in the gel with the deionized water extraction.
Embodiment 4:
Step (1), (2) are with embodiment 1
(3) preparation of poly phosphazene:
100ml exsiccant tetrahydrofuran solution is placed the there-necked flask that has mechanical stirrer, add 2.60g (0.01mol) 1 subsequently, 2:5,6-di-O-isopropylidene-alpha-D-glucose and 0.25g (0.011mol) metal is received, room temperature reaction 24 hours.The polydichlorophosphazenes solution of 1.16g (0.01mol) slowly is added drop-wise in the above-mentioned solution, and refluxed 96 hours.Tetrahydrofuran solution (100ml) (the room temperature reaction preparation in 24 hours in tetrahydrofuran (THF) by 2.40ml (0.03mol) methyl cellosolve and 0.75g (0.011mol) sodium Metal 99.5) with methyl ethanol sodium slowly is added drop-wise in the above-mentioned solution then, reaction was warming up to 50 ℃ and continues reaction 24 hours after 24 hours under the room temperature.Centrifugal remove insolubles after, rotary evaporation is removed most of solvent and is obtained viscous liquid, with oil mystery precipitation, methyl alcohol dialysis (dialysis tubing molecular weight cut-off 12000) purifying after 3 days, rotary evaporation is removed solvent, in 40 ℃ of following vacuum-dryings with this thick liquid.Then the exsiccant polymkeric substance is placed the single port bottle that has magnetic agitation,, be stirred to polymkeric substance and dissolve back continuation reaction 4 hours fully to the trifluoroacetic acid 20ml that wherein drips 90%.With in the supersaturation sodium hydrogen carbonate solution and after, place dialysis tubing (molecular weight cut-off 12000) with deionized water dialysis purifying 3 days, rotary evaporation is removed behind the moisture content in 40 ℃ of following vacuum-dryings can get 30% glucose and 70% methyl cellosolve replaces poly phosphazene (polymkeric substance 4) altogether.
(4) preparation of hydrogel:
Polymkeric substance 4 is mixed with the aqueous solution that concentration is 0.4g/mL, with concentration be the ConA aqueous solution of 1.2g/mL, mix with 1: 1 volume ratio, leave standstill after 20 minutes and form hydrogel.Remove the Con A that has neither part nor lot in reaction in the gel with the deionized water extraction.
Embodiment 5:
Step (1), (2) are with embodiment 1
(3) preparation of poly phosphazene:
100ml exsiccant tetrahydrofuran solution is placed the there-necked flask that has mechanical stirrer, add 7.80g (0.03mol) 1 subsequently, 2:5,6-di-O-isopropylidene-alpha-D-glucose and 0.75g (0.033mol) metal is received, room temperature reaction 24 hours.The polydichlorophosphazenes solution of 1.16g (0.01mol) slowly is added drop-wise in the above-mentioned solution, and refluxed 96 hours.Under 0 ℃, slowly be added drop-wise to tetrahydrofuran solution of glycine ethyl ester (remove triethylamine hydrochloride and obtain) and 1.38ml (0.01mol) triethylamine in the above-mentioned solution then by 1.38g (0.01mol) glycine ethyl ester hydrochloride and 1.38ml (0.01mol) the triethylamine 6 hours after-filtration that in tetrahydrofuran solution, reflux, reaction continued reaction 18 hours after 6 hours in the ice bath under room temperature.Centrifugal remove insolubles after, rotary evaporation removes most of solvent and unreacted triethylamine obtains viscous liquid, and this thick liquid is precipitated with deionized water, the throw out that obtains is in 40 ℃ of following drying under reduced pressure.Then the exsiccant polymkeric substance is placed the single port bottle that has magnetic agitation,, be stirred to polymkeric substance and dissolve back continuation reaction 4 hours fully to the trifluoroacetic acid 20ml that wherein drips 90%.With in the supersaturation sodium hydrogen carbonate solution and after, place dialysis tubing (molecular weight cut-off 12000) with deionized water dialysis purifying 3 days, rotary evaporation is removed behind the moisture content in 40 ℃ of following vacuum-dryings can get 80% glucose and 20% glycine ethyl ester replaces poly phosphazene (polymkeric substance 5) altogether.
(4) preparation of hydrogel:
Polymkeric substance 5 is mixed with the aqueous solution that concentration is 0.25g/mL, with concentration be the Con A aqueous solution of 1.6g/mL, mix with 1: 1 volume ratio, leave standstill after 10 minutes and form hydrogel.Remove the Con A that has neither part nor lot in reaction in the gel with the deionized water extraction.
Embodiment 6:
Step (1), (2) are with embodiment 1
(3) preparation of poly phosphazene:
100ml exsiccant tetrahydrofuran solution is placed the there-necked flask that has mechanical stirrer, add 5.20g (0.02mol) 1 subsequently, 2:5,6-di-O-isopropylidene-alpha-D-glucose and 0.50g (0.022mol) metal is received, room temperature reaction 24 hours.The polydichlorophosphazenes solution of 1.16g (0.01mol) slowly is added drop-wise in the above-mentioned solution, and refluxed 96 hours.Under 0 ℃, slowly be added drop-wise to tetrahydrofuran solution of glycine ethyl ester (remove triethylamine hydrochloride and obtain) and 2.76ml (0.02mol) triethylamine in the above-mentioned solution then by 2.76g (0.02mol) glycine ethyl ester hydrochloride and 2.76ml (0.02mol) the triethylamine 6 hours after-filtration that in tetrahydrofuran solution, reflux, reaction continued reaction 18 hours after 6 hours in the ice bath under room temperature.Centrifugal remove insolubles after, rotary evaporation removes most of solvent and unreacted triethylamine obtains viscous liquid, and this thick liquid is precipitated with deionized water, the throw out that obtains is in 40 ℃ of following drying under reduced pressure.Then the exsiccant polymkeric substance is placed the single port bottle that has magnetic agitation,, be stirred to polymkeric substance and dissolve back continuation reaction 4 hours fully to the trifluoroacetic acid 20ml that wherein drips 90%.With in the supersaturation sodium hydrogen carbonate solution and after, place dialysis tubing (molecular weight cut-off 12000) with deionized water dialysis purifying 3 days, rotary evaporation is removed behind the moisture content in 40 ℃ of following vacuum-dryings can get 50% glucose and 50% glycine ethyl ester replaces poly phosphazene (polymkeric substance 6) altogether.
(4) preparation of hydrogel:
Polymkeric substance 6 is mixed with the aqueous solution that concentration is 0.3g/mL, with concentration be the ConA aqueous solution of 1.6g/mL, mix with 1: 1 volume ratio, leave standstill after 10 minutes and form hydrogel.Remove the Con A that has neither part nor lot in reaction in the gel with the deionized water extraction.
Embodiment 7:
Step (1), (2) are with embodiment 1
(3) preparation of poly phosphazene:
100ml exsiccant tetrahydrofuran solution is placed the there-necked flask that has mechanical stirrer, add 2.60g (0.01mol) 1 subsequently, 2:5,6-di-O-isopropylidene-alpha-D-glucose and 0.25g (0.011mol) metal is received, room temperature reaction 24 hours.The polydichlorophosphazenes solution of 1.16g (0.01mol) slowly is added drop-wise in the above-mentioned solution, and refluxed 96 hours.Under 0 ℃, slowly be added drop-wise to tetrahydrofuran solution of glycine ethyl ester (remove triethylamine hydrochloride and obtain) and 4.14ml (0.03mol) triethylamine in the above-mentioned solution then by 4.14g (0.03mol) glycine ethyl ester hydrochloride and 4.14ml (0.03mol) the triethylamine 6 hours after-filtration that in tetrahydrofuran solution, reflux, reaction continued reaction 18 hours after 6 hours in the ice bath under room temperature.Centrifugal remove insolubles after, rotary evaporation removes most of solvent and unreacted triethylamine obtains viscous liquid, and this thick liquid is precipitated with deionized water, the throw out that obtains is in 40 ℃ of following drying under reduced pressure.Then the exsiccant polymkeric substance is placed the single port bottle that has magnetic agitation,, be stirred to polymkeric substance and dissolve back continuation reaction 4 hours fully to the trifluoroacetic acid 20ml that wherein drips 90%.With in the supersaturation sodium hydrogen carbonate solution and after, place dialysis tubing (molecular weight cut-off 12000) with deionized water dialysis purifying 3 days, rotary evaporation is removed behind the moisture content in 40 ℃ of following vacuum-dryings can get 30% glucose and 70% glycine ethyl ester replaces poly phosphazene (polymkeric substance 7) altogether.
(4) preparation of hydrogel:
Polymkeric substance 7 is mixed with the aqueous solution that concentration is 0.4g/mL, with concentration be the ConA aqueous solution of 1.2g/mL, mix with 1: 1 volume ratio, leave standstill after 20 minutes and form hydrogel.Remove the Con A that has neither part nor lot in reaction in the gel with the deionized water extraction.
Embodiment 8:
Step (1), (2) are with embodiment 1
(3) preparation of poly phosphazene:
The thanomin of 0.30g tertbutyloxycarbonyl protection is dissolved in the 30ml exsiccant tetrahydrofuran (THF); add the 0.05g sodium Metal 99.5; behind the room temperature reaction 24 hours; mix with the polydichlorophosphazenes tetrahydrofuran solution 100ml of 1.16g (0.01mol); after the back flow reaction 6 hours; with previously prepared 1; 2:5; 6-di-O-isopropylidene-alpha-D-glucose sodium alkoxide exsiccant tetrahydrofuran solution 100ml is (by 5.20g (0.02mol) 1; 2:5; 6-di-O-isopropylidene-alpha-D-glucose and 0.50g (0.022mol) metal is received room temperature reaction 24 hours preparation) add in the above-mentioned solution, and refluxed 96 hours.Tetrahydrofuran solution (100ml) (the room temperature reaction preparation in 24 hours in tetrahydrofuran (THF) by 1.60ml (0.02mol) methyl cellosolve and 0.50g (0.022mol) sodium Metal 99.5) with methyl ethanol sodium slowly is added drop-wise in the above-mentioned solution then, reaction was warming up to 50 ℃ and continues reaction 24 hours after 24 hours under the room temperature.Centrifugal remove insolubles after, rotary evaporation is removed most of solvent and is obtained viscous liquid, with oil mystery precipitation, methyl alcohol dialysis (dialysis tubing molecular weight cut-off 12000) purifying after 3 days, rotary evaporation is removed solvent, in 40 ℃ of following vacuum-dryings with this thick liquid.Then the exsiccant polymkeric substance is placed the single port bottle that has magnetic agitation,, be stirred to polymkeric substance and dissolve back continuation reaction 4 hours fully to the trifluoroacetic acid 20ml that wherein drips 90%.With in the supersaturation sodium hydrogen carbonate solution and after, place dialysis tubing (molecular weight cut-off 12000) with deionized water dialysis purifying 3 days, rotary evaporation remove behind the moisture content in 40 ℃ of following vacuum-dryings can about 5% thanomin, 50% glucose and 45% methyl cellosolve replace poly phosphazene (polymkeric substance 8) altogether.
(4) preparation of hydrogel:
Polymkeric substance 8 is mixed with the ConA aqueous solution that the aqueous solution that concentration is 0.2g/mL and concentration are 0.16g/mL, mixes, leave standstill after 10 minutes and form hydrogel with 1: 1 volume ratio.Soaked 1 hour with 0.5% glutaraldehyde solution.Remove Con A and the glutaraldehyde that has neither part nor lot in reaction in the gel with the deionized water extraction.
Claims (2)
1. a glucose responding type polyphosphazene hydrogel is formed by the poly phosphazene polymer aqueous solution and phytohemagglutinin concanavalin A aqueous solution, and wherein the high molecular chemical structural formula of poly phosphazene is:
Wherein x+y＜2 and x can not be 0, n=10-5000;
R is a glucosyl group, and its ratio is 5～95% of a side group sum;
R ' is any in amino acid ester, methylamine, imidazoles, alkyloxy-ethers, the methoxy poly (ethylene glycol) ether group or their combination, and the ratio of R ' is 5～95% of a side group sum; And introduce following the third substituting group: hydroxyethyl methylacrylate, vinyl carbinol or allylamine, perhaps contain amino amino ethoxy, perhaps contain the hydroxyl-oxethyl of hydroxy functional group, the ratio that the third substituting group accounts for the substituting group total amount is 1～30%.
2. according to the glucose responding type polyphosphazene hydrogel of claim 1, it is characterized in that: the ratio that the third substituting group accounts for the substituting group total amount is 1～10%.
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| CN103110956B (en) * | 2013-01-06 | 2014-08-20 | 北京化工大学 | Method for preparing glucose-responsive insulin-self-regulating-release carrier |
| CN107412151B (en) * | 2017-07-25 | 2021-04-02 | 中山大学 | Phytohemagglutinin-polysaccharide hydrogel capable of intelligently regulating and controlling insulin release as well as preparation and application thereof |
| CN111440331B (en) * | 2020-03-20 | 2021-05-28 | 华南农业大学 | Chitosan-based cell targeted adhesion controlled-release hydrogel and preparation method and application thereof |
| CN114404649B (en) * | 2022-01-24 | 2022-06-24 | 西安交通大学 | Hydrogel with pH/glucose dual-response metformin release function and preparation method and application thereof |
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| CN1054080A (en) * | 1990-02-13 | 1991-08-28 | 阿托化学公司 | The method for preparing poly phosphazene by the substitution reaction of polydichlorophosphazene |
| CN1613890A (en) * | 2003-11-04 | 2005-05-11 | 北京化工大学 | Biological degradable PES graft polyphosphonitrile copolymer and its preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1054080A (en) * | 1990-02-13 | 1991-08-28 | 阿托化学公司 | The method for preparing poly phosphazene by the substitution reaction of polydichlorophosphazene |
| CN1613890A (en) * | 2003-11-04 | 2005-05-11 | 北京化工大学 | Biological degradable PES graft polyphosphonitrile copolymer and its preparation |
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| CN101450996A (en) | 2009-06-10 |
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