CN101307123A - Temperature-induced gelatinizing-in-situ triblock copolymer, preparation method and applications - Google Patents
Temperature-induced gelatinizing-in-situ triblock copolymer, preparation method and applications Download PDFInfo
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Abstract
The invention discloses a triblock copolymer by temperature induction and in-situ gelation, a method for preparing the triblock copolymer and an application of the triblock copolymer. The triblock copolymer comprises an ABA type and a BAB type, wherein, a section A is a polyN-isopropyl acrylamide; a section B is polymethacrylic acid-2-hydroxylethyl ester. The copolymer preparation process comprises the following steps that: the N-isopropyl acrylamide and the polymethacrylic acid-2-hydroxylethyl ester are used as monomers; m-2,5- dibromo adipate diethyl ester is used as a bifunctional initiator; and cuprous chloride, 1,4,8,11- tetramethyl-1,4,8,11-tetranitrogen heterocyclic ring tetradecane are used as a catalytic system; various compositions are prepared to a methanol solution and added into a mesonephric tube; oxygen in the system is removed by liquid nitrogen; and the ABA or the BAB type triblock copolymer is synthesized in the methanol solution at a temperature of 25 DEG C through feeding in sequence. The triblock copolymer, the method and the application have the advantages that: LCST(lower critical solution temperature) of the copolymer is controlled to between 26 and 34 DEG C, which is close to human temperature; the time for sol-gel transition is controlled within 60 minutes; and the copolymer has good biocompatibility and can be used as a vascular embolization material.
Description
Technical field
The present invention relates to a kind of triblock copolymer and preparation method and application of temperature-induced gelatinizing-in-situ, belong to the vascular suppository material technology in the biomedical engineering field.
Background technology
Interventional therapy is one of important measures of treatment cerebrovascular malformation (AVM) in the blood vessel.In the past, people were attempting adopting various embolism materials treatment brain AVM always, as solid particulate, silk thread, alcohol, microcoils etc., but only were used for embolism before the surgical operation because effect of embolization is unreliable, recanalization rate is high, can not be as permanent embolism.At present the liquid embolizing agent of wide clinical application is the positive butyl ester of alpha-cyanoacrylate (NBCA), it with polymerization can take place rapidly after blood contacts, thereby play the effect of permanent embolism.But, bring very big inconvenience to operation because its adhesivity is had relatively high expectations to concentration, injection speed and tube drawing opportunity.Therefore still very undesirable for bigger brain AVM embolism curative effect.In recent years, a kind of novel liquid suppository Onyx by the exploitation of U.S. MTI company is applied to clinical, and the embolism curative ratio of brain AVM is increased.Onyx is dissolved in ethylene-vinyl alcohol co-polymer (EVOH) in the dimethyl sulfoxide (DMSO) (DMSO), adds micronize tantalum powder again, makes it visual under the X line.The not sticking conduit of Onyx can slowly be injected for a long time, can reach the good disperse in deformity group, has shortened the treatment cycle for epimegetic brain AVM, has reduced medical expense.In addition, the Onyx embolism has been realized the perfusion of suppository to deformity group, has reduced the possibility of logical again and recurrence.Therefore, Onyx is considered to treat up to now the better embolism materials of brain AVM.But the recent DMSO that discovers has stronger blood vessel toxicity, can cause acute vascular spasm, damage and necrosis, and especially dosage is excessive, injection speed is too fast and excessive concentration the time.DMSO has in various degree corrosive nature to present widely used microtubular in addition, and injection is that the embolism materials of solvent needs special microtubular with DMSO, and this has also limited their clinical application.
Oppositely the macromolecule hydrogel of temperature-responsive is the bio-medical material that gets most of the attention in recent years.This temperature-sensitive macromolecular at low temperature (less than lower critical solution temperature, LCST) be injectable liquid, after being injected in the body by interposing catheter, its aqueous solution is gelatinizing-in-situ under physiological temp, do not relate to any deleterious organic solvent in the process, and curing molding is not limited by the patient part geometrical shape, is ideal drug release carrier and tissue engineering bracket material, has remarkable advantages in particular for the embolismization of brain AVM.
From Literature Consult,, up to the present only there is the research of minority to report real temperature sensitive suppository although the researchist makes great efforts to explore the feasibility [1,2] that poly-(N-N-isopropylacrylamide) based high molecular of temperature sensitive property is used for embolism.[3] such as Matsumaru of Japan attempt the random copolymers of N-isopropylacrylamide and n-propyl acrylamide is used for the blood vessel embolism of rabbit kidney artery the earliest.Recently, our study group [4,5] prepared a kind of terpolymer vascular suppository material based on N-isopropylacrylamide, successfully realized embolism (Chinese invention patent ZL200510013133.3) to tame pig cerebral arteries deformity net, but above-mentioned two kinds of materials are random radical copolymerizations owing to what adopt, make that the molecular structure of this copolymer material can't be designed in advance, and molecular weight of copolymer and dispersion index are uncontrollable.In addition, the polymer segment dehydration was subsided when temperature sensitive random copolymers surpassed LCST in temperature, easily was precipitated out.Utilize atom transfer radical polymerization (ATRP) technology to prepare and have the controlled block polymer of ad hoc structure, molecular weight and distribution.Prepare the multipolymer that contains temperature sensitive segment and hydrophobic segment with the ATRP technology, this polymer segment (surpasses more than the micelle-forming concentration) in the aqueous solution to be self-assembled into micella, when temperature surpasses LCST, by intermicellar running through assembling the formation gelation.Satisfy embolism needs in the body by changing close and distant water segmental adjustable ratio control phase transition temperature and response speed, but and the micella load medicine that is assembled into of close and distant water segment, having expanded the scope of application of temperature sensitive injectable liquids embolism materials, is the upgrading products of the ternary atactic copolymer vascular suppository material of N-isopropylacrylamide.
The reference that relates to this background technology is as follows:
[1]Robb?SA，Lee?BH，McLemore?R，Vernon?BL.Simultaneously?physically?and?chemicallygelling?polymer?system?utilizing?a?poly(NIPAAm-co-cysteamine)-based?copolymer.Biomacromolecules?2007，8(7)：2294-2300.
[2]Vernon?B，Martinez?A.Gel?strength?and?solution?viscosity?of?temperature-sensitive，in-situ-gelling?polymers?for?endovascular?embolization.1：J?Biomater?Sci?Polym?Ed.2005，16(9)：1153-1166.
[3]Matsumaru，et?al.Application?of?thermosensitive?polymers?as?a?new?embolic?material?forintravascular?neurosurgery.J.Biomater.Sci.Polymer.Edn.1996，7：795-804.
[4]Li?XW，Liu?WG?et?al.Thermosensitive?N-isopropylacrylamide-N-propylacrylamide-vinylpyrrolidone?terpolymers：Synthesis，characterization?and?preliminary?application?as?embolicagents.Biomaterials，2005，26(34)：7002-7011.
[5] Liu Wenguang, Li Xiaowei, Ye Gui a, famous physician of the Qing Dynasty perfume (or spice), Yao Kangde, thrombus material preparation of injectable isopropyl acrylamide terpolymer and application, ZL200510013133.3
Summary of the invention
The object of the present invention is to provide a kind of triblock copolymer and preparation method and application of temperature-induced gelatinizing-in-situ, the LCST of this aqueous copolymers solution has excellent biological compatibility near human body temperature, and its preparation method is simple.
The present invention is realized by the following technical programs, a kind of triblock copolymer of temperature-induced gelatinizing-in-situ, it is characterized in that, this triblock copolymer is ABA type or BAB type, ABA type structural formula is shown in 1 formula, BAB type structural formula is shown in 2 formulas, wherein, A section polymkeric substance is for gathering (N-N-isopropylacrylamide) (PNIPAAm), segment polymerization degree scope is 40-960 in segmented copolymer, B section polymkeric substance is polymethacrylate-2-hydroxy-ethyl ester (PHEMA), and segment polymerization degree scope is 10-300 in segmented copolymer.
The polymethacrylate-2-hydroxy-ethyl ester of above-mentioned thermoinducible gelatinizing-in-situ and poly-(N-N-isopropylacrylamide) preparation method with three blocks (BAB) multipolymer of polymethacrylate-2-hydroxy-ethyl ester is characterized in that comprising following process:
Press the monomer N-isopropylacrylamide, the monomer 2-hydroxyethyl methacrylate, between bifunctional initiator-2,5-dibromo diethylene adipate, catalyzer cuprous chloride and ligand 1,4,8,11-tetramethyl--1,4,8, the mol ratio of the 11-four heterocyclic tetradecanes is (40-960): (10-300): 1: 2: 2 proportioning, at first will between-2,5-dibromo diethylene adipate, cuprous chloride and solvent methanol add in the Xi Laike pipe, through liquid nitrogen freezing, the degassing, and then feeding nitrogen, so carry out the oxygen that freeze thawing removes in the reaction system for 2～3 times repeatedly, then with N-isopropylacrylamide, 1,4,8,11-tetramethyl--1,4,8,11-four heterocyclic tetradecane dissolve with methanol join under nitrogen protection in the Xi Laike pipe through liquid nitrogen freezing, the degassing, feed nitrogen, so carry out the oxygen that freeze thawing removes in the reaction system for 2～3 times repeatedly, 25 ℃ of following vacuum-sealings, magnetic agitation reaction 1-12 hour, under nitrogen protection, the methanol solution that adds 2-hydroxyethyl methacrylate again in reaction system is through three freeze thawing, vacuum seal reactor, use the liquid nitrogen freezing termination reaction behind 25 ℃ of reaction 2-24h, the product of evaporation behind the methanol solvate is dissolved in the deionized water again, dialyses in deionized water with the dialysis tubing of molecular weight cut-off 3500 and removes unreacted monomer, changes one time water in 12 hours, the freeze-drying after 7 days of dialysing obtains the polymethacrylate-2-hydroxy-ethyl ester and poly-(N-N-isopropylacrylamide) triblock copolymer with polymethacrylate-2-hydroxy-ethyl ester of white; Be BAB type polymer powder.
Poly-(the N-N-isopropylacrylamide) of above-mentioned thermoinducible gelatinizing-in-situ and polymethacrylate-2-hydroxy-ethyl ester and poly-(N-N-isopropylacrylamide) three blocks (ABA) copolymer method is characterized in that comprising following process:
Press the monomer 2-hydroxyethyl methacrylate; the monomer N-isopropylacrylamide; between bifunctional initiator-2; 5-dibromo diethylene adipate; catalyzer cuprous chloride and ligand 1; 4; 8; 11-tetramethyl--1; 4; 8; the mol ratio of the 11-four heterocyclic tetradecanes is (10-300): (40-960): 1: 2: 2; at first will between-2; 5-dibromo diethylene adipate; cuprous chloride; in the molten adding of the methyl alcohol Xi Laike pipe; through liquid nitrogen freezing; the degassing; and then feeding nitrogen; so carry out the oxygen that freeze thawing removes in the reaction system for 2～3 times repeatedly; then with 2-hydroxyethyl methacrylate; 1; 4,8,11-tetramethyl--1; 4; 8,11-four heterocyclic tetradecane dissolve with methanol join under nitrogen protection in the Xi Laike pipe; through liquid nitrogen freezing; the degassing feeds nitrogen, so carries out the oxygen that freeze thawing removes in the reaction system for 2～3 times repeatedly; vacuum-sealing under the room temperature; magnetic agitation reaction 1-12 hour under nitrogen protection, adds the methanol solution of N-isopropylacrylamide in the tube reaction system of above-mentioned uncommon Rec; through three freeze thawing; the vacuum seal reactor is used the liquid nitrogen freezing termination reaction behind 25 ℃ of reaction 2-24h, and the product behind the evaporation methanol solvate is dissolved in the deionized water again; dialyse in deionized water with the dialysis tubing of molecular weight cut-off 3500 and to remove unreacted monomer in the product; changed water in 8 hours one time, the freeze-drying after 7 days of dialysing obtains white poly-(N-N-isopropylacrylamide) and polymethacrylate-2-hydroxy-ethyl ester and poly-(N-N-isopropylacrylamide) three blocks (ABA) multipolymer.
Polymethacrylate-2-hydroxy-ethyl ester that aforesaid method makes and poly-(N-N-isopropylacrylamide) three blocks (BAB) multipolymer with polymethacrylate-2-hydroxy-ethyl ester, perhaps poly-(N-N-isopropylacrylamide) is mixed with the photographic developer that mass content is 3-10% copolymer solution and 0.769g Iopromide/ml with polymethacrylate-2-hydroxy-ethyl ester and poly-(N-N-isopropylacrylamide) three blocks (ABA) multipolymer, by volume 1: (1-0.3) mix the solution that obtains, behind 120 ℃ of high-temperature sterilizations, this mixed solution is as vascular suppository material.
The advantage of invention is that the multipolymer segment can form micella, reaches gelation by intermicellar gathering, and the LCST of this multipolymer is controlled at 26～34 ℃, and near human body temperature, the sol-gel transition time is controlled at less than 60s, and velocity of transformation is very fast; Not only change the multipolymer of segmented copolymer, and change the adjustable micellization of block sequence and the gelation behavior of multipolymer under the copolymerization ratio same case, this multipolymer has excellent biological compatibility.
Description of drawings
Fig. 1 is embodiment one, and embodiment two, the nucleus magnetic hydrogen spectrum of embodiment three prepared multipolymers.
Among the figure: BAB1-6 is embodiment one a gained multipolymer spectral line, and BAB1-8 is embodiment two gained multipolymer spectral lines, and ABA1-8 is embodiment three gained multipolymer spectral lines.
Fig. 2 is the modulus-temperature curve figure of 10% solution of embodiment two prepared BAB1-8 multipolymers.
Fig. 3 is the modulus-temperature curve figure of 10% solution of embodiment three prepared ABA1-8 multipolymers.
Fig. 4 is the angiogram of the abnormal net of pig brain before the embolism.Square is denoted as the basis cranii capillary network and develops because of hyperemia among the figure.
Fig. 5 is for embodiment two gained copolymer quality concentration being 10% polymers soln and the angiogram of 1: 1 by volume blended material of the photographic developer embolism abnormal net of pig brain after one month that contains 0.769g Iopromide/ml.Show among the figure that ascending pharyngeal artery stops up, do not see again and lead to that the basis cranii capillary network is not seen again logical, shows that this material has good effect of embolization.
Embodiment
Embodiment one:
With between bifunctional initiator-2,5-dibromo diethylene adipate (9.1mg, 0.025mmol), catalyzer cuprous chloride (4.9mg, 0.05mmol) and 2mL methyl alcohol add in the Xi Laike pipe, with liquid nitrogen freezing (198 ℃), the degassing, 25 ℃ make this system lead to nitrogen while melting then, so multigelation is three times, to remove the oxygen in the reaction system.With monomer N-isopropylacrylamide (NIPAAm) (1.3578g; 11.998mmol; the theoretical polymerization degree: 480) and ligand 1,4,8; 11-tetramethyl--1; 4,8, the 11-four heterocyclic tetradecane (12.8mg; 0.050mmol) be dissolved in the 6mL methyl alcohol, under nitrogen protection, transfer in the reaction vessel with syringe.Behind the reaction mixture process multigelation three times, return to room temperature (25 ℃), the vacuum-sealing reaction vessel reacted after 6 hours, and logical purity is 99.99% nitrogen in reaction system.With the theoretical polymerization degree of segmental 40 2-hydroxyethyl methacrylate (HEMA) (0.2603g, 2.0mmol) be dissolved in the 2ml methanol solution, again this solution is added in the tube reaction system of above-mentioned uncommon Rec with syringe, with liquid nitrogen freezing (198 ℃), the degassing, 25 ℃ make this system lead to nitrogen while melting then, through three freeze thawing, the vacuum seal reactor, 25 ℃ of reaction 24h.After finishing, reaction uses the freezing termination reaction of liquid nitrogen (198 ℃).To be dissolved in the deionized water behind 25 ℃ of placements of product taking-up evaporation in 6 hours methanol solvate, product is dialysed in deionized water with molecular weight cut-off 3500 dialysis tubings and is removed unreacted monomer, changed water in 8 hours one time, the freeze-drying after 7 days of dialysing obtains the polymethacrylate-2-hydroxy-ethyl ester and poly-(N-N-isopropylacrylamide) triblock copolymer powder HEMA with polymethacrylate-2-hydroxy-ethyl ester of white
40-NIPAAm
480-HEMA
40(numbering BAB1-6).
Nucleus magnetic hydrogen spectrum detects: take by weighing HEMA
40-NIPAAm
480-HEMA
40Sample 20mg is dissolved in deuterated dimethyl sulfoxide (DMSO-d
6) in, record on nuclear magnetic resonance spectrometer Varian UNITY plus 400
1The H-NMR spectrogram, as shown in Figure 1.
Measure the gelation rate of BAB1-6 polymkeric substance with appearance method: at first polymer formulation being become mass concentration is 5% and 10% HEMA
40-NIPAAm
480-HEMA
40The aqueous solution, at first constant temperature 30min in 20 ℃ of Water Tanks with Temp.-controlled is transferred to 37 ℃ of Water Tanks with Temp.-controlled then rapidly, writes down its sol-gel transition time; Be mass concentration that 5% and 10% sample is warming up to 37 ℃ again, treat that sample is inverted that moment is transferred in 20 ℃ of constant temperature water baths when not flowing, write down its gel-sol fringe time.Data see the following form:
Embodiment two:
With between bifunctional initiator-2,5-dibromo diethylene adipate (9.1mg, 0.025mmol), catalyzer cuprous chloride (4.9mg, 0.05mmol) and 2mL methyl alcohol add in the Xi Laike pipe, with liquid nitrogen freezing (198 ℃), the degassing, the logical nitrogen of dissolving then, so multigelation is three times, to remove the oxygen in the reaction system.With monomer N-isopropylacrylamide (NIPAAm) (1.8103g; 16mmol; the theoretical polymerization degree: 640) and ligand 1,4,8; 11-tetramethyl--1; 4,8, the 11-four heterocyclic tetradecane (12.8mg; 0.050mmol) be dissolved in the 6mL methyl alcohol, under nitrogen protection, transfer in the reaction vessel with syringe.Behind the reaction mixture process multigelation three times, return to room temperature, vacuum-sealing, the magnetic agitation reaction is after 6 hours, logical 99.99% nitrogen in reaction system, the methanol solution that adds 2ml 2-hydroxyethyl methacrylate (HEMA) (the theoretical polymerization degree of each segmental is 40 for 0.2603g, 2.0mmol) with syringe.Through three freeze thawing, vacuum seal reactor, 25 ℃ of reaction 24h.After finishing, reaction uses the liquid nitrogen freezing termination reaction.25 ℃ of placements were dissolved in the deionized water behind the evaporating solvent in 6 hours, dialysed in deionized water with Cellu SepH1 dialysis tubing (molecular weight cut-off 3500) and removed unreacted monomer, changed water one time in 8 hours, and the freeze-drying after 7 days of dialysing obtains white HEMA
40-NIPAAm
640-HEMA
40(numbering BAB1-8) polymer powder.
Nucleus magnetic hydrogen spectrum detects: take by weighing HEMA
40-NIPAAm
640-HEMA
40Sample 20mg is dissolved in deuterated dimethyl sulfoxide (DMSO-d
6) in, record on nuclear magnetic resonance spectrometer Varian UNITY plus 400
1The H-NMR spectrogram, as shown in Figure 1.
Rheology testing: by RELOGICA INSTRUMRENTS AB rheometer measurement HEMA
40-NIPAAm
640-HEMA
40The copolymer solution rheological property.Mould is Bob-Cup 25, and temperature rise rate is controlled at 0.5 ℃ of min by computer program
-1, precision is ± 0.05 ℃.Setpoint frequency is 0.2rads
-1, strain is 0.2, (G ") is with variation of temperature, as shown in Figure 2 for the storage modulus (G ') of detection copolymer solution and out-of-phase modulus.
The multipolymer and the photographic developer that contains 0.769g Iopromide/ml that with mass concentration are 10% present embodiment are applied to the abnormal net of embolism pig brain by 1: 1 equal-volume mixed solution, radiography such as Fig. 4 before the embolism, the abnormal net angiography of pig brain after one month such as Fig. 5, show the ascending pharyngeal artery obturation, do not see again logical, the basis cranii capillary network is not seen again logical, shows that this material has good effect of embolization.
Embodiment three:
Adopt between bifunctional initiator-2,5-dibromo diethylene adipate (9.1mg, 0.025mmol), cuprous chloride (12.8mg, 0.050mmol) add in the Xi Laike pipe, with liquid nitrogen freezing (198 ℃), the degassing, the logical nitrogen of dissolving then, so multigelation is three times, to remove the oxygen in the reaction system.With monomer 2-hydroxyethyl methacrylate (HEMA) (0.2603g; 2.000mmol; the theoretical polymerization degree: 80) and ligand 1,4,8; 11-tetramethyl--1; 4,8, the 11-four heterocyclic tetradecane (12.8mg; 0.050mmol) be dissolved in the 6mL methyl alcohol in 25 ℃ the methyl alcohol, under nitrogen protection, transfer in the reaction vessel with syringe.Behind the reaction mixture process multigelation three times, return to room temperature, the vacuum-sealing reaction vessel, the magnetic agitation reaction is after 6 hours, and logical 99.99% nitrogen adds 6ml N-isopropylacrylamide (NIPAAm) (1.810g with syringe in reaction system, 16mmol, the theoretical polymerization degree that each chain is forged is 320) methanol solution, after three freeze thawing, 25 ℃ of reaction 24h under vacuum.After finishing, reaction uses the liquid nitrogen freezing termination reaction.25 ℃ of placements were dissolved in the deionized water behind the evaporating solvent in 6 hours, dialysed in deionized water with Cellu SepH1 dialysis tubing (molecular weight cut-off 3500) and removed unreacted monomer, changed water one time in 8 hours, and the freeze-drying after 7 days of dialysing obtains white NIPAAm
320-HEMA
80-NIPAAm
320(numbering ABA1-8) polymer powder.
Nucleus magnetic hydrogen spectrum detects: take by weighing NIPAAm
320-HEMA
80-NIPAAm
320Sample 20mg is dissolved in deuterated dimethyl sulfoxide (DMSO-d
6) in, record on nuclear magnetic resonance spectrometer Varian UNITY plus 400
1The H-NMR spectrogram, as shown in Figure 1.
Rheology testing: by RELOGICA INSTRUMRENTS AB rheometer measurement NIPAAm
320-HEMA
80-NIPAAm
320The copolymer solution rheological property.Mould is Bob-Cup 25, and temperature rise rate is controlled at 0.5 ℃ of min by computer program
-1, precision is ± 0.05 ℃.Setpoint frequency is 0.2rads
-1, strain is 0.2, (G ") is with variation of temperature, as shown in Figure 3 for the storage modulus (G ') of detection copolymer solution and out-of-phase modulus.
Embodiment four:
With between bifunctional initiator-2,5-dibromo diethylene adipate (9.1mg, 0.025mmol), catalyzer cuprous chloride (4.9mg, 0.05mmol) and 2mL methyl alcohol add in the Xi Laike pipe, use liquid nitrogen freezing, the degassing, the logical nitrogen of dissolving then, so multigelation is three times, to remove the oxygen in the reaction system.With monomer N-isopropylacrylamide (NIPAAm) (0.113g, 1mmol, the theoretical polymerization degree: 40) and ligand 1,4; 8,11-tetramethyl--1,4,8; (12.8mg 0.050mmol) is dissolved in the 6mL methyl alcohol 11-four heterocyclic tetradecanes, transfers in the reaction vessel with syringe under nitrogen protection.Behind the reaction mixture process multigelation three times, return to room temperature, vacuum-sealing, the magnetic agitation reaction is after 6 hours, logical 99.99% nitrogen in reaction system, the methanol solution that adds 2ml 2-hydroxyethyl methacrylate (HEMA) (the theoretical polymerization degree of each segmental is 5 for 0.0325g, 0.25mmol) with syringe.Through three freeze thawing, vacuum seal reactor, 25 ℃ of reaction 24h.After finishing, reaction uses the liquid nitrogen freezing termination reaction.Place for 25 ℃ and be dissolved in the deionized water behind the evaporating solvent in 6 hours, dialyse in deionized water with CelluSepH1 dialysis tubing (molecular weight cut-off 3500) and remove unreacted monomer, changed water one time in 8 hours, dialyse freeze after 7 days in, obtain white HEMA
5-NIPAAm
40-HEMA
5Polymer powder.
Embodiment five:
With between bifunctional initiator-2,5-dibromo diethylene adipate (9.1mg, 0.025mmol), catalyzer cuprous chloride (4.9mg, 0.05mmol) and 2mL methyl alcohol add in the Xi Laike pipe, use liquid nitrogen freezing, the degassing, the logical nitrogen of dissolving then, so multigelation is three times, to remove the oxygen in the reaction system.With monomer N-isopropylacrylamide (NIPAAm) (2.712g; 24mmol; the theoretical polymerization degree: 960) and ligand 1,4,8; 11-tetramethyl--1; 4,8, the 11-four heterocyclic tetradecane (12.8mg; 0.050mmol) be dissolved in the 12mL methyl alcohol, under nitrogen protection, transfer in the reaction vessel with syringe.Behind the reaction mixture process multigelation three times, return to room temperature, vacuum-sealing, the magnetic agitation reaction is after 6 hours, logical 99.99% nitrogen in reaction system, the methanol solution that adds 2ml 2-hydroxyethyl methacrylate (HEMA) (the theoretical polymerization degree of each segmental is 150 for 0.975g, 7.5mmol) with syringe.Through three freeze thawing, vacuum seal reactor, 25 ℃ of reaction 24h.After finishing, reaction uses the liquid nitrogen freezing termination reaction.25 ℃ of placements were dissolved in the deionized water behind the evaporating solvent in 6 hours, dialysed in deionized water with CelluSepH1 dialysis tubing (molecular weight cut-off 3500) and removed unreacted monomer, changed water one time in 8 hours, and the freeze-drying after 7 days of dialysing obtains white HEMA
150-NIPAAm
960-HEMA
150Polymer powder.
Claims (5)
1, a kind of triblock copolymer of temperature-induced gelatinizing-in-situ, it is characterized in that, this triblock copolymer is that BAB type structural formula is shown in the formula 1, this copolymer A section is a poly N-isopropyl acrylamide, the B section is a polymethacrylate-2-hydroxy-ethyl ester, the chain length scope of polymethacrylate-2-hydroxy-ethyl ester section is 10-300, and the chain length scope of poly N-isopropyl acrylamide section is 40-960.
2, a kind of method for preparing the triblock copolymer of the described temperature-induced gelatinizing-in-situ of claim 1 is characterized in that comprising following process:
Press the monomer N-isopropylacrylamide, the monomer 2-hydroxyethyl methacrylate, between bifunctional initiator-2,5-dibromo diethylene adipate, catalyzer cuprous chloride and ligand 1,4,8,11-tetramethyl--1,4,8, the mol ratio of the 11-four heterocyclic tetradecanes is (40-960): (10-300): 1: 2: 2 proportioning, at first will between-2,5-dibromo diethylene adipate, cuprous chloride and solvent methanol add in the Xi Laike pipe, through liquid nitrogen freezing, the degassing, and then feeding nitrogen, so carry out the oxygen that freeze thawing removes in the reaction system for 2～3 times repeatedly, then with N-isopropylacrylamide, 1,4,8,11-tetramethyl--1,4,8,11-four heterocyclic tetradecane dissolve with methanol join under nitrogen protection in the Xi Laike pipe through liquid nitrogen freezing, the degassing, feed nitrogen, so carry out the oxygen that freeze thawing removes in the reaction system for 2～3 times repeatedly, 25 ℃ of following vacuum-sealings, magnetic agitation reaction 1-12 hour, under nitrogen protection, the methanol solution that adds 2-hydroxyethyl methacrylate again in reaction system is through three freeze thawing, vacuum seal reactor, use the liquid nitrogen freezing termination reaction behind 25 ℃ of reaction 2-24h, the product of evaporation behind the methanol solvate is dissolved in the deionized water again, dialyses in deionized water with the dialysis tubing of molecular weight cut-off 3500 and removes unreacted monomer, changes one time water in 12 hours, the freeze-drying after 7 days of dialysing obtains the polymethacrylate-2-hydroxy-ethyl ester of white and the triblock copolymer of poly N-isopropyl acrylamide and polymethacrylate-2-hydroxy-ethyl ester; Be BAB type polymer powder.
The triblock copolymer of 3 one kinds of temperature-induced gelatinizing-in-situs, it is characterized in that, this triblock copolymer is that ABA type structural formula is shown in the formula 2, this copolymer A section is a poly N-isopropyl acrylamide, the B section is a polymethacrylate-2-hydroxy-ethyl ester, the chain length scope of polymethacrylate-2-hydroxy-ethyl ester section is 10-300, and the chain length scope of poly N-isopropyl acrylamide section is 40-960.
4; a kind of triblock copolymer for preparing temperature-induced gelatinizing-in-situ as claimed in claim 3 method; it is characterized in that comprising following process: press the monomer 2-hydroxyethyl methacrylate; the monomer N-isopropylacrylamide; between bifunctional initiator-2; 5-dibromo diethylene adipate; catalyzer cuprous chloride and ligand 1; 4; 8; 11-tetramethyl--1; 4; 8; the mol ratio of the 11-four heterocyclic tetradecanes is (10-300): (40-960): 1: 2: 2; at first will between-2; 5-dibromo diethylene adipate; cuprous chloride; in the molten adding of the methyl alcohol Xi Laike pipe; through liquid nitrogen freezing; the degassing; and then feeding nitrogen; so carry out the oxygen that freeze thawing removes in the reaction system for 2～3 times repeatedly; then with 2-hydroxyethyl methacrylate; 1; 4; 8; 11-tetramethyl--1; 4; 8; 11-four heterocyclic tetradecane dissolve with methanol; under nitrogen protection, join in the Xi Laike pipe, through liquid nitrogen freezing, the degassing; feed nitrogen; so carry out the oxygen that freeze thawing removes in the reaction system for 2～3 times repeatedly, vacuum-sealing under the room temperature, magnetic agitation reaction 1-12 hour; under nitrogen protection; the methanol solution that adds N-isopropylacrylamide in the tube reaction system of above-mentioned uncommon Rec is through three freeze thawing, vacuum seal reactor; use the liquid nitrogen freezing termination reaction behind 25 ℃ of reaction 2-24h; the product of evaporation behind the methanol solvate is dissolved in the deionized water again, dialyses in deionized water with the dialysis tubing of molecular weight cut-off 3500 and removes unreacted monomer in the product, changes one time water in 8 hours; the freeze-drying after 7 days of dialysing obtains poly N-isopropyl acrylamide and the polymethacrylate-2-hydroxy-ethyl ester and the poly N-isopropyl acrylamide three block ABA multipolymers of white.
5, a kind of application of the triblock copolymer as claim 1 or 3 described temperature-induced gelatinizing-in-situs, this multipolymer is mixed with the photographic developer that mass concentration is 3-10% copolymer solution and 0.769g Iopromide/ml, by volume 1: (1-0.3) mix the solution that obtains, behind 120 ℃ of high-temperature sterilizations, this mixed solution is as the application of vascular suppository material.
Priority Applications (1)
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106620826A (en) * | 2016-11-04 | 2017-05-10 | 华中科技大学 | Temperature-sensitive vascular thrombosis material capable of performing long-term self-development and preparation method thereof |
| CN108426903A (en) * | 2018-03-14 | 2018-08-21 | 长春黄金研究院有限公司 | A method of observation is higher than block copolymer micelle pattern under room temperature state |
| CN110099996A (en) * | 2016-12-22 | 2019-08-06 | Dic株式会社 | Cell culture substrate |
| CN111748065A (en) * | 2019-03-26 | 2020-10-09 | 南开大学 | Thermo-sensitive triblock copolymer hydrogel fire extinguishing agent |
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2008
- 2008-07-02 CN CNA2008100537270A patent/CN101307123A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106620826A (en) * | 2016-11-04 | 2017-05-10 | 华中科技大学 | Temperature-sensitive vascular thrombosis material capable of performing long-term self-development and preparation method thereof |
| CN106620826B (en) * | 2016-11-04 | 2019-11-01 | 华中科技大学 | It is a kind of can long-term autography temperature sensitive vascular suppository material and preparation method thereof |
| CN110099996A (en) * | 2016-12-22 | 2019-08-06 | Dic株式会社 | Cell culture substrate |
| US11427803B2 (en) | 2016-12-22 | 2022-08-30 | Fujifilm Corporation | Cell culture substrate |
| CN108426903A (en) * | 2018-03-14 | 2018-08-21 | 长春黄金研究院有限公司 | A method of observation is higher than block copolymer micelle pattern under room temperature state |
| CN111748065A (en) * | 2019-03-26 | 2020-10-09 | 南开大学 | Thermo-sensitive triblock copolymer hydrogel fire extinguishing agent |
| CN111748065B (en) * | 2019-03-26 | 2023-01-17 | 南开大学 | Thermo-sensitive triblock copolymer hydrogel fire extinguishing agent |
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