CN107899066A - Cation polyhydroxylated polymer embolism microball and preparation method thereof - Google Patents
Cation polyhydroxylated polymer embolism microball and preparation method thereof Download PDFInfo
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Abstract
The present invention relates to a kind of cation polyhydroxylated polymer embolism microball and preparation method thereof, belong to biological medical polymer material technical field.It is formed for the functionalization macromolecular with biocompatibility by crosslinking agent amino compound, alkyl gadoleic acid derivative and aminoalkyl gadoleic acid derivative or its ammonium salt cross-linked polymeric；There is 1,2 glycol or 1,3 diol structure functional groups, are aminoalkyl gadoleic acid derivative also with amido-acetal or esters structure, side chain on its main chain.Of the invention the microballoon enormously simplify the species of raw material compared with existing polyvinyl alcohol cationic microspheres, reduces purchasing of raw materials cost, simplifies production technology, while avoids environmental pollution caused by a large amount of dispersants and organic solvent emission.
Description
Technical field
The present invention relates to a kind of cation polyhydroxylated polymer embolism microball and preparation method thereof, belong to bio-medical high score
Sub- field of material technology.
Background technology
Traditional tumor therapeuticing method includes chemotherapy, radiotherapy and operative treatment.In recent years, minimally invasive interventional therapy is because of its tool
There are small wound, high selectivity, patient's better tolerance and the advantages such as control administration can be targeted and developed rapidly as a kind of important
Oncotherapy means, have significant effect in the treatment of the rich vascular solid tumor such as liver cancer, kidney, fibroid.Intervention
Treatment is by under the auxiliary of medical imaging device, and doctor is by the blood supply blood for importeding into tumor focus position of microtubular selectivity
Pipe, then Reperfu- sion suppository is to achieve the purpose that to cut off tumor locus blood supply so that tumour is because enough battalion can not be obtained
Support and supply and " hungry to death ".Therefore it is most important for the interventional treatment of tumour, the selection of suppository.
Traditional suppository preparation process is complicated, and particle diameter distribution is wide, and elastic deformation is poor, then so that embolization effect is inadequate
Ideal, the problems such as there is bolt, drift by mistake and be difficult to block target blood completely.In recent years by improving preparation process and right
The stringent control screening of appearance, these problems are greatly taken on a new look.In the evolution of technical recipe, occur some new
Chemotherapeutics can be used in combination with suppository for the suppository of type, greatly improve the effect of interventional treatment, while also drop
The low general toxicity of chemotherapeutics.
In all suppositories, a kind of medicament elution microballoon has realized containing and releasing to many antineoplastic chemotherapy medicines
Put.These microballoons are obtained by being chemically synthesized by the monomer or high molecular material of biocompatibility.Clinic makes at present
Most of antitumor drug such as adriamycin, Irinotecan, oxaliplatin etc. are to carry electric charge, by being tied in microballoon chemistry
Electrically charged functional group, such as carboxyl, amino, sulfonic group etc. are introduced in structure design, both realize efficiently under electrostatic interaction
Ground combines.Carry the microballoon after medicine to imported into target blood, can realize the slow release to medicine in neoplasm in situ, reduce
The toxic side effect of Formulations for systemic administration, while medicine is constantly discharged in tumor locus, and enduringly directly tumour cell can be played
Effect, with reference to the effect of the blocking blood supply of microballoon in itself, collaboration inhibits the malignant proliferation of tumour cell, shows and preferably control
Therapeutic effect.
By the search to existing patent, China Patent Publication No. is CN 101029109A, publication date 2007.09.05
Patent of invention propose a kind of preparation method of cationic microsphere with crosslinked swelling function.Using persulfate and sulfurous acid
Salt, or persulfate and azodiisobutyronitrile (AIBN) binary complex are initiator, dispersant and crosslinking agent are added, in ring
In the blending agents such as hexane-water, trigger cationic monomer MethacryloyloxyethylTrimethyl Trimethyl Ammonium Chloride (DMC) and acryloyl
Amine (AM) monomer carries out inverse suspension polymerization, and cationic microsphere with crosslinked swelling function is made；Dispersant used is：Sorbitan
The binary complex system of alcohol monoleate and polyoxyethylene 20 sorbitan monostearate composition, crosslinking agent N, N '-methylene
Base diacrylamine.The technique is simple and convenient, but its to prepare particle smaller, can not meet clinically to different size microballoon
Requirement.And the technique has used the irritation organic solvent such as hexamethylene, and acrylamide monomer residual has neurotoxicity,
Biocompatibility itself has to be tested.
It is CN 101143906B in China Patent Publication No., publication date is in 2010.05.19 inventions, it is proposed that one kind system
The method of standby monodisperse cation type polymer micro-sphere.By cationic monomer diallyldimethylammonChloride Chloride, vinyl monomer
Methyl methacrylate, polyethylene of dispersing agent base pyrrolidones K30, initiator azodiisobutyronitrile, decentralized medium deionized water
With methanol add reactor in, be stirred continuously down and be warming up to 75 DEG C of constant temperature, the reaction was continued 4 it is small when after reaction was completed；Then by institute
Obtain lotion to be washed, centrifuged with methanol, repeatedly for three times, then be washed with deionized, centrifuge, repeatedly for three times, you can obtain single dispersing
Cation type polymer micro-sphere.The method nucleation rate is fast, and scattered homogeneous polymer microballoon is easily made.But in preparation process
Substantial amounts of dispersant and methanol are used, cleaning process is cumbersome, complicated, and the environment for being not suitable for large-scale production and producing is dirty
It is more to contaminate thing.
It is 8673266 B2 of US in U.S. Patent Publication No., publication date is in the invention of 2014.03.18, there is provided a kind of
The method for preparing polyvinyl alcohol cationic microspheres.Diethylin ethyl is added into sulfuric acid-sodium-chloride water solution of polyvinyl alcohol
Dextran solution and collagen solution, then add glutaraldehyde solution and form homogeneous mixed solution.Finally this is mixed
Solution is dispersed in rapidly in the paraffin oil containing sorbitan monooleate, by 6 it is small when heat cross-linking be solidified into microballoon
Particle, finally by the cleaning of dichloromethane, removes unreacted crosslinking agent and auxiliary agent, forms final product microballoon.Should
Method technique is relatively simple, but used supplementary material is complex, and of high cost, reaction yield is relatively low.
The antitumor drug of Clinical practice at present, while being directly used in kill cancer cell, also produces normal cell
Same lethal effect, causes that side reaction is more, bioavilability is low, a large amount of is used so as to limit its.Under given conditions,
Carry negative electrical charge using many antitumor drugs, by electrostatic adsorption be wrapped in it is microsphere supported in, ideally solve this
A problem.The purpose of the present invention is by introducing positive functional groups in microballoon chemical constitution, prepare a kind of novel cation
Type polymer plug microballoon, and antineoplastic targeting is rapidly and efficiently contained by electrostatic interaction and is delivered to tumor locus,
The dosage of medicine is greatly reduced, reduces use cost, while improves the bioavailability of medicine.Pass through microballoon
Blocking the effect of blood supply, the therapeutic effect of tumour is obviously improved with reference to the antitumor activity of medicine.
In the microspheres product of existing clinical listing, lack medicine-carried functional group or medicine-carried part in whole microballoon chemistry
Accounting is relatively low in structure, and generally existing carries the problem of medicine is slow, efficiency is low and drug encapsulation is unstable, just has phase before human body is implanted into
When a part of medicine " burst release ", cause the sustained release drugs time shorter, be unable to maintain that the higher blood medicine at cancer target position
Concentration.More important point, at present the overwhelming majority drug bearing microspheres have been carried out containing chemicals, once be unable to maintain that compared with
High blood concentration, tumour under the action of low concentration medicine, easily produce drug resistance for a long time, this will greatly increase controlling for tumour
Treat difficulty and treatment cost, the therapeutic effect that cannot be got well on the contrary.
And the cation type polymer medicine carrying material that existing literature report is more, such as polyethyleneimine, polyacrylamide,
There is serious cytotoxicity.In order to reduce its cytotoxicity, the degree of polymerization is often reduced in design of material, reduces cation base
The density of group, so reduces its drug carrying ability again, greatly limit its application development.
The content of the invention
There is good biocompatibility and structural stability, higher carrier medicine carrying efficiency the object of the present invention is to provide a kind of
And the preparation method of the novel cation polyhydroxylated polymer embolism microball of preferable sustained release performance.
By polymer plug microballoon made from this method, inside has positively charged cross-linked structure, makes its right
Antitumor drug with negative electrical charge group has extremely strong affinity, and medicine can be extremely stably wrapped in microballoon,
After being implanted into human body, release that can be steady in a long-term remains that medicine under required dosage, both avoids this series antineoplastic medicament
The injury of normal tissue, and improve the therapeutic effect of medicine.
Technical scheme, cation polyhydroxylated polymer embolism microball, it is to have the function of biocompatibility
Change macromolecular to be crosslinked by crosslinking agent amino compound, alkyl gadoleic acid derivative and aminoalkyl gadoleic acid derivative or its ammonium salt
It is polymerized；There is 1,2- glycol or 1,3- diol structure functional group, also with amido-acetal or esters structure, side on its main chain
Chain is aminoalkyl gadoleic acid derivative；
Wherein amino compound is amido aldehyde or acetal compound, carbon number 1-20；Alkyl gadoleic acid derivative is alkyl
The acetal or aldehyde compound of olefin(e) acid ester, acid amides, carbon number 1-20；Aminoalkyl gadoleic acid derivative or its ammonium salt are amino
（Ammonium salt）Alkyl olefin(e) acid ester or amides compound, carbon number 1-40.
The amido aldehyde or acetal are specially aminoacetaldehyde dimethyl acetal, aminoacetaldehyde diethyl acetal, 4- amino fourths
Aldehyde dimethylacetal, 4- aminobutyraldehyde diethyl acetals etc.；Alkyl gadoleic acid derivative is specially N acrylamide base dimethyl second
Acetal, N-2- propylacrylamide bases dimethyl-acetal, N- ethyl acrylamide base dimethyl butyrate acetals etc.；Aminoalkyl alkene
Acid derivative is dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, 3-（Methacrylamide）Propyl group three
Ammonio methacrylate or n-isopropyl acrylamide.
The function macromolecular is polyhydroxylated polymer, is specially polyvinyl alcohol, polyethylene glycol or polysaccharide macromolecular.
The polysaccharide macromolecular is using amylose, chitosan or hydroxymethyl cellulose as raw material.
The preparation method of the cation polyhydroxylated polymer embolism microball, step are as follows：
（1）The synthesis of small molecule crosslinking agent：Sodium hydroxide is added in four-hole boiling flask and water stirs to form solution, is then slowly added
Enter the amino compound of ormal weight, the acryloyl chloride or acryloyl chloride derivative of equivalent are slowly added dropwise after stirring evenly, drip
Continue to stir half an hour after adding；Saturated nacl aqueous solution washing is added to the solution after reaction, is extracted with methyl tertiary butyl ether(MTBE)
Take, extract purifies to obtain required small molecule crosslinking agent alkyl olefin(e) acid derivative after removing water, filter, concentrate by column chromatography
Thing；
（2）The synthesis of functionalization polyhydroxylated polymer intermediate：Added in function macromolecular in the flask containing purified water, heating
Stirring and dissolving, concentration 80-250g/L.After homogeneous solution system is formed after it, 15-25 DEG C is cooled to, then press function respectively
The 0.5%-10% of macromolecular quality adds step（1）The crosslinking agent alkyl gadoleic acid derivative and increase main chain positive charge density of synthesis
Amino compound, stir 1-30min, then the hydrochloric acid of 10%-80% function macromolecular quality be added dropwise（Mass fraction 36%）, drop
When 10-30 DEG C of stirring 3-7 of insulation is small after adding, after reaction with the sodium hydroxide solution regulation system of 0.5-10mol/L
PH value is finally concentrated into viscosity and reaches 1500cps required function polyhydroxylated polymer intermediates produced above to 6.5-8.0；
（3）The synthesis of cation polyhydroxylated polymer embolism microball：Water is added to stir aminoalkyl gadoleic acid derivative or its ammonium salt,
Add 15-25 DEG C of stirring fully dissolving, then this solution is slowly added into step of persulfate（2）It is more to prepare gained functionalization
Viscosity is adjusted in hydroxy polymer intermediate, after stirring evenly to 250-400cps, it is spare to obtain polymer monomer homogeneous phase solution；
Butyl acetate is separately added in four-hole boiling flask, adjusts rotating speed 200-400rpm, adds acetylbutyrylcellulose and purified water,
Start to be passed through N2, heating systems temperature is to 40-80 DEG C, and then dropwise addition polymer monomer homogeneous phase solution, is added dropwise, 1-20min
Interior addition tetramethylethylenediamine TMEDA, forms oil mixing with water system, 50 ~ 80 DEG C of control system reaction temperature, when insulation 2-6 is small；
After reaction, solid particle is collected, is cleaned successively with butyl acetate, ethyl acetate and acetone, then it is true by 50-70 DEG C
Sky is dried to obtain cation polyhydroxylated polymer embolism microball.
In above-mentioned oil mixing with water system, polymer monomer total concentration is controlled in 50-100g/L, wherein functionalization polyhydroxy
Intermediate polymer accounts for the 70%-95% of polymer monomer gross mass, and aminoalkyl gadoleic acid derivative or its ammonium salt account for polymer list
The 5%-30% of body gross mass, persulfate concentration are 1-10g/L, and the concentration of tetramethylethylenediamine is 1-10g/L, and acetate butyrate is fine
The concentration of dimension element is 1-8g/L.
The present invention is compared compared with product, except retaining the elastic good of original medicament elution microballoon, the advantages of medicine-carried outside,
Also several big innovative points need emphasis to refer to：
（1）Main polymer chain introduces the part material amido-acetal of synthetic cross-linking agent, reduces purchasing of raw materials cost, Er Qietong
Cross the positive ion density that the method dexterously adds final microspheres product；
（2）The polyhydroxylated polymer microballoon that the present invention synthesizes, the microballoon charge concentration synthesized compared with prior art are distributed in crosslinking
On side chain, evenly, the stronger problem of cytotoxicity brought so as to avoid higher positive ion density, has distribution of charges
Preferable biocompatibility；
（3）The present invention uses aminoalkyl gadoleic acid derivative as monomer crosslinked synthesizing cationic polyhydroxylated polymer microballoon, can be with
Many negatively charged active antineoplastic agents are efficiently contained, such as chemicals methotrexate (MTX), pemetrexed and biological medicament
Some monoclonal antibodies of class, small molecules interference RNA etc., applicable surface is extremely extensive.Medicine and microballoon can be in tumour portions when being used in combination
Position produces higher drug concentration, avoids the generation of multi-drug resistance of the tumor, greatly promotes the effect of existing interventional treatment.
（4）The relatively easy convenience of synthesis technique of the present invention, avoids traditional cation polymer microballoon emulsion polymerization work
The shortcomings that skill needs substantial amounts of emulsifying agent, dispersant and produces a large amount of poisonous organic solvent pollution things excitatory, can
Reduce the pollution to environment and the injury to operating personnel's body.
For the present invention to derive from a wealth of sources, stable structure is reliable, and polyhydroxy of the human body without any poison pair and stimulation is polymerize
Thing is primary raw material, preferred polyvinyl alcohol.Ethylidene ether structure to contain acrylic acid or derivatives thereof is used as crosslinking agent, multiple crosslinkings
1,2- glycol or 1,3- diol structure in agent molecule and polyvinyl alcohol chain structure are connected in the form of covalent bond, then with ammonia
Base esters of acrylic acid or its ammonium salt occur radical polymerization and form the aquogel polymer with crosslinking net jointly.It is in addition, poly-
Remaining 1,2- glycol or 1,3 glycol structure can be optionally with amino ethylidene ether structure with altogether on vinyl alcohol main chain
The form of valence link is connected, and further increases the positive charge density inside polymer microballoon, and lifting carries drug effect fruit.The system passes through anti-
The microsphere type embolic agent that phase suspension radical polymerization is prepared has more perfect ball shape, and inside carries knot containing positive charge
The amino or ammonium salt structure of structure, and creatively positive charge is evenly distributed on main chain and side chain, both improve positive electricity
Lotus density, and it is unlikely to that local density is excessive to cause serious cytotoxicity, there is good adsorption energy to bioactive substance
Power, and the microballoon carried after medicine is highly stable, the ability with lasting slow release.
Beneficial effects of the present invention：Compared with existing medicament elution microballoon, microballoon institute is electrically charged in main chain and crosslinking side
Chain is distributed, and charge density is more uniform, carries medicine speed and efficiency greatly promotes, the medicine for improving cancer target position is dense
Degree.In addition, it can also contain a variety of electronegative chemotherapeutics and biological medicament, medicine is applied widely, effectively avoids chemotherapeutic
Thing is also easy to produce the problem of drug resistance；
Compared with existing cation type polymer micro-sphere, which greatly reduces cytotoxicity, solves cationic microspheres
The problem of easily leading to toxicity；
Compared with existing polyvinyl alcohol cationic microspheres, which enormously simplify the species of raw material, reduce the purchasing of raw materials into
This, simplifies production technology, while avoid environmental pollution caused by a large amount of dispersants and organic solvent emission.
Embodiment
The synthesis of small molecule crosslinking agent
Embodiment 1
40g NaOH are dissolved in 300 mL purified waters, after 250 rpm stirring and dissolvings, 1 DEG C is cooled to ice salt bath.Then
It is slowly added to 147.3 g aminoacetaldehyde diethyl acetals.After system is uniform, 99.5 g acryloyl chlorides are slowly added dropwise, drip
5 DEG C of 30 min of insulation reaction after finishing.Solution is stated then up and adds 150 mL saturated nacl aqueous solutions, and first is added after stirring completely
Base tertbutyl ether extracts.Upper strata oily liquids is collected, the crude product obtained after concentration purifies to obtain colorless transparent oil through column chromatography
Shape product N acrylamide base diethoxy acetal（95.7g）.
Embodiment 2
30g NaOH are dissolved in 300 mL purified waters, after 280 rpm stirring and dissolvings, 10 DEG C are cooled to ice salt bath.Then
It is slowly added to 100.2g 4- aminobutyl aldehyde dimethylacetals.After system is uniform, 67.5g acryloyl chlorides are slowly added dropwise, drip
10 DEG C of 30 min of insulation reaction after finishing.Solution is stated then up and adds 100 mL saturated nacl aqueous solutions, is added after stirring completely
Methyl tertiary butyl ether(MTBE) extracts.Upper strata oily liquids is collected, the crude product obtained after concentration purifies to obtain water white transparency through column chromatography
Oily product N acrylamide base dimethoxy butyral（64.2g）.
The synthesis of functionalization polyhydroxylated polymer intermediate
Embodiment 3
180 g of polyvinyl alcohol is measured, 1000 mL purified waters are added in 2 L reaction flasks, are turned with 90 DEG C of temperature, 200 rpm of rotating speed
Fast stirring and dissolving.After solid is completely dissolved, after system is cooled to room temperature, 2.93g small molecule crosslinking agents N- third is added thereto
Acrylamide base diethoxy acetal and 13.3 g aminoacetaldehyde diethyl acetals, after stirring 10min, then are added dropwise 100mL 36%
The hydrochloric acid of mass fraction.When 15 DEG C of insulation reactions 6 are small after dripping.After reaction with the hydroxide that concentration is 1.5 mol/L
Sodium solution regulation system to pH value is 7.0, and is stablized 10 minutes.Then crude product is collected, institute is obtained after filtering removal of impurities, concentration
Functionalization polyhydroxylated polymer intermediate is needed, viscosity is controlled in 1500 cps.
Embodiment 4
100 g of polyvinyl alcohol is measured, 850 mL purified waters are added in 1 L reaction flasks, are turned with 96 DEG C of temperature, 250 rpm of rotating speed
Fast stirring and dissolving.After solid is completely dissolved, after system is cooled to room temperature, 1.95g small molecule crosslinking agents N- is added thereto
Acrylamido dimethoxy butyral and 8.87g 4- aminobutyl aldehyde dimethylacetals, after stirring 10min, then are added dropwise 66mL
The hydrochloric acid of 36% mass fraction.When 30 DEG C of insulation reactions 3 are small after dripping.After reaction with the hydrogen-oxygen that concentration is 2.0 mol/L
It is 7.8 to change sodium solution regulation system to pH value, and is stablized 15 minutes.Then crude product is collected, is obtained after filtering removal of impurities, concentration
Required function polyhydroxylated polymer intermediate, viscosity are controlled in 1600 cps.
Embodiment 5
180 g of polyvinyl alcohol is measured, 1000 mL purified waters are added in 1 L reaction flasks, are turned with 90 DEG C of temperature, 250 rpm of rotating speed
Fast stirring and dissolving.After solid is completely dissolved, after system is cooled to room temperature, 3.2g small molecule crosslinking agents N- third is added thereto
Acrylamide base dimethoxy butyral and 11.1g 4- aminobutyl aldehyde dimethylacetals, after stirring 10min, then are added dropwise 100mL
The hydrochloric acid of 36% mass fraction.When 20 DEG C of insulation reactions 5 are small after dripping.The hydrogen-oxygen for being after reaction 2.0mol/L with concentration
It is 7.2 to change sodium solution regulation system to pH value, and is stablized 30 minutes.Then crude product is collected, is obtained after filtering removal of impurities, concentration
Required function polyhydroxylated polymer intermediate, viscosity are controlled in 1700 cps.
The synthesis of cation polyhydroxylated polymer embolism microball
Embodiment 6
（1）32.89g dimethylaminoethyl methacrylates, 185g purified waters and 14.9g mistakes are sequentially added in beaker
Potassium sulfate and the stirring and dissolving under the conditions of 15 DEG C.After treating that potassium peroxydisulfate is completely dissolved, this solution is added to 500g embodiments 3
Viscosity is adjusted in the functionalization polyhydroxylated polymer intermediate of preparation, after stirring evenly, and to 280 cps to obtain polymer monomer equal
Phase liquid, it is spare；
（2）3000mL butyl acetates are added in 5L four-hole boiling flasks as solvent, stirring is started, adjusts speed of agitator 250rpm.
50g acetylbutyrylcelluloses homogeneous phase solution is weighed as stabilizer, 25 g purified waters are as dispersed phase；It is passed through nitrogen, system temperature
Degree is added dropwise step (1) after rising to 60 DEG C and prepares the homogeneous liquid of resulting polymers monomer, and 10mL tetramethylethylenediamines, is consequently formed oil
The inverse suspension polymerization reaction system of Bao Shui, system continue under the conditions of 60 DEG C stirring reaction 4 it is small when;
（3）After reaction, reaction dissolvent is filtered and collects microballoon, then use 1000mL butyl acetates, 1000mL second successively
Acetoacetic ester and the washing of 1000mL acetone, then by 56 DEG C of vacuum drying, obtain cation polyhydroxylated polymer embolism microball crude product.
Embodiment 7
（1）44.94g dimethylaminoethyl acrylates, 278g purified waters and 19.7g potassium peroxydisulfates are sequentially added in beaker
And the stirring and dissolving under the conditions of 25 DEG C.After treating that potassium peroxydisulfate is completely dissolved, this solution is added what is prepared to 760g embodiments 3
Viscosity, which is adjusted, in functionalization polyhydroxylated polymer intermediate, after stirring evenly obtains the homogeneous liquid of polymer monomer to 320 cps, it is standby
With；
（2）4500mL butyl acetates are added in 10L four-hole boiling flasks as solvent, stirring is started, adjusts speed of agitator 300rpm.
76.5g acetylbutyrylcelluloses homogeneous phase solution is weighed as stabilizer, 38.5g purified waters are as dispersed phase；It is passed through nitrogen, body
It is that temperature rises to after 70 DEG C and step (1) is added dropwise prepares the homogeneous liquid of resulting polymers monomer, and 30mL tetramethylethylenediamines, thus shape
Into the inverse suspension polymerization reaction system of Water-In-Oil, system continue under the conditions of 65 DEG C stirring reaction 3 it is small when;
（3）After reaction, reaction dissolvent is filtered and collects microballoon, then use 2000mL butyl acetates, 2000mL second successively
Acetoacetic ester and the washing of 2000mL acetone, then by 56 DEG C of vacuum drying, obtain cation polyhydroxylated polymer embolism microball crude product.
Embodiment 8
（1）69.3g dimethylaminoethyl acrylates are sequentially added in beaker, 370g purified waters and 26.6g potassium peroxydisulfates are simultaneously
The stirring and dissolving under the conditions of 20 DEG C.After treating that potassium peroxydisulfate is completely dissolved, this solution is added what is prepared to 1000g embodiments 3
Viscosity, which is adjusted, in functionalization polyhydroxylated polymer intermediate, after stirring evenly obtains the homogeneous liquid of polymer monomer to 300 cps, it is standby
With；
（2）4500mL butyl acetates are added in 10L four-hole boiling flasks as solvent, stirring is started, adjusts speed of agitator 300rpm.
100.0g acetylbutyrylcelluloses homogeneous phase solution is weighed as stabilizer, 48.0g purified waters are as dispersed phase；It is passed through nitrogen,
System temperature is added dropwise step (1) after rising to 65 DEG C and prepares the homogeneous liquid of resulting polymers monomer, and 32.5 mL tetramethylethylenediamines,
Be consequently formed the inverse suspension polymerization reaction system of Water-In-Oil, system continue under the conditions of 60 DEG C stirring reaction 4 it is small when;
（3）After reaction, reaction dissolvent is filtered and collects microballoon, then use 2000mL butyl acetates, 2000mL second successively
Acetoacetic ester and the washing of 2000mL acetone, then by 56 DEG C of vacuum drying, obtain cation polyhydroxylated polymer embolism microball crude product.
Claims (6)
1. cation polyhydroxylated polymer embolism microball, it is characterized in that：It leads to for the functionalization macromolecular with biocompatibility
Cross crosslinking agent amino compound, alkyl gadoleic acid derivative and aminoalkyl gadoleic acid derivative or its ammonium salt cross-linked polymeric forms；
There is 1,2- glycol or 1,3- diol structure functional group on its main chain, be amino also with amido-acetal or esters structure, side chain
Alkyl gadoleic acid derivative；
Wherein amino compound is amido aldehyde or acetal compound, carbon number 1-20；Alkyl gadoleic acid derivative is alkyl
The acetal or aldehyde compound of olefin(e) acid ester, acid amides, carbon number 1-20；Aminoalkyl gadoleic acid derivative or its ammonium salt are ammonia
Base/ammonium salt alkyl olefin(e) acid ester or amides compound, carbon number 1-40.
2. cation polyhydroxylated polymer embolism microball as claimed in claim 1, it is characterized in that：The amido aldehyde or acetal are specific
For aminoacetaldehyde dimethyl acetal, aminoacetaldehyde diethyl acetal, 4- aminobutyl aldehydes dimethylacetal or 4- aminobutyl aldehyde diethyls
Base acetal；Alkyl gadoleic acid derivative is specially N acrylamide base dimethyl-acetal, N-2- propylacrylamide base dimethyl
Acetal, N- ethyl acrylamide base dimethyl butyrate acetals；Aminoalkyl gadoleic acid derivative or its ammonium salt are specially acrylic acid two
Methylamino ethyl ester, dimethylaminoethyl methacrylate, 3-（Methacrylamide）Hydroxypropyltrimonium chloride or N- isopropyls
Base acrylamide.
3. cation polyhydroxylated polymer embolism microball as claimed in claim 1, it is characterized in that：The function macromolecular is polyhydroxy
Based polyalcohol, is specially polyvinyl alcohol, polyethylene glycol or polysaccharide macromolecular.
4. cation polyhydroxylated polymer embolism microball as claimed in claim 3, it is characterized in that：The polysaccharide macromolecular is with straight
Chain starch, chitosan or hydroxymethyl cellulose are raw material.
5. the preparation method of one of the claim 1-3 cation polyhydroxylated polymer embolism microballs, it is characterized in that step is such as
Under：
（1）The synthesis of small molecule crosslinking agent：Sodium hydroxide is added in four-hole boiling flask and water stirs to form solution, is then slowly added
Enter the amino compound of ormal weight, the acryloyl chloride or acryloyl chloride derivative of equivalent are slowly added dropwise after stirring evenly, drip
Continue to stir half an hour after adding；Saturated nacl aqueous solution washing is added to the solution after reaction, is extracted with methyl tertiary butyl ether(MTBE)
Take, extract purifies to obtain required small molecule crosslinking agent alkyl olefin(e) acid derivative after removing water, filter, concentrate by column chromatography
Thing；
（2）The synthesis of functionalization polyhydroxylated polymer intermediate：Function macromolecular is added in the flask containing purified water, heating
Stirring and dissolving, the concentration to function macromolecular are 80-250g/L, after homogeneous solution system is formed after it, are cooled to 15-25
DEG C, then respectively step is added by the 0.5%-10% of function macromolecular quality（1）The crosslinking agent alkyl gadoleic acid derivative of synthesis and increasing
Add the amino compound of main chain positive charge density, stir 1-30min, then hydrochloric acid is added dropwise by function macromolecular quality 10%-80%,
Wherein the mass concentration of hydrochloric acid is 36%, when 10-30 DEG C of insulated and stirred 3-7 is small after completion of dropwise addition, uses 0.5- after reaction
The sodium hydroxide solution regulation system pH value of 10mol/L is finally concentrated into viscosity and reaches more than 1500cps, that is, make to 6.5-8.0
Obtain required function polyhydroxylated polymer intermediate；
（3）The synthesis of cation polyhydroxylated polymer embolism microball：Water is added to stir aminoalkyl gadoleic acid derivative or its ammonium salt,
Add 15-25 DEG C of stirring fully dissolving, then this solution is slowly added into step of persulfate（2）It is more to prepare gained functionalization
Viscosity is adjusted in hydroxy polymer intermediate, after stirring evenly to 250-400cps, it is spare to obtain polymer monomer homogeneous phase solution；
Butyl acetate is separately added in four-hole boiling flask, adjusts rotating speed 200-400rpm, adds acetylbutyrylcellulose and purified water,
Start to be passed through N2, heating systems temperature is to 40-80 DEG C, and then dropwise addition polymer monomer homogeneous phase solution, is added dropwise, 1-20min
Interior addition tetramethylethylenediamine TMEDA, forms oil mixing with water system, 50-80 DEG C of control system reaction temperature, when insulation 2-6 is small；
After reaction, solid particle is collected, is cleaned successively with butyl acetate, ethyl acetate and acetone, then it is true by 50-70 DEG C
Sky is dried to obtain cation polyhydroxylated polymer embolism microball.
6. the preparation method of cation polyhydroxylated polymer embolism microball as claimed in claim 5, it is characterized in that：In above-mentioned grease
In mixed system, polymer monomer total concentration is 50-100g/L, and wherein functionalization polyhydroxylated polymer intermediate accounts for polymer list
The 70%-95% of body gross mass, aminoalkyl gadoleic acid derivative account for the 5%-30% of polymer monomer gross mass, and persulfate concentration is
1-10g/L, the concentration of tetramethylethylenediamine is 1-10g/L, and the concentration of acetylbutyrylcellulose is 1-8g/L.
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