CN104072694A - Preparation method and application of quadruple-responsiveness block micelle - Google Patents
Preparation method and application of quadruple-responsiveness block micelle Download PDFInfo
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Abstract
The invention discloses a preparation method and an application of a novel quadruple-responsiveness (temperature, pH, reduction and photo-response) block polymer micelle. The preparation method of the novel quadruple-responsiveness block polymer micelle comprises the following steps: enabling an atom transfer radical polymer to react for two times so as to prepare a poly(2-nitryl benzyl methyl acrylate)-block-poly(dimethylaminoethyl methacrylate) (PNBM-SS-PDMAEMA) amphiphilic block copolymer, wherein the polymer is capable of self-assembling in water to form a nano-micelle and also capable of loading hydrophobic micromolecules (for example, nile red). The structure of the self-assembled micelle is capable of obviously changing in the presence of ultraviolet radiation, reducing agent dithiothreitol, temperature regulation and pH stimulation; and different synergetic stimulations are capable of regulating dynamic release processes of guest molecules. The polymer micelle has temperature response, pH response, reduction response and photo-response and also has a wide application prospect in the field of controlled release.
Description
Technical field
The invention belongs to technical field of polymer materials, related to a kind of preparation and application thereof of the quadruple responsiveness block micella to temperature, pH, reduction and photoresponse.
Background technology
In recent years, responsive polymer has caused the extensive concern of researcher, this mainly has benefited from intelligent polymkeric substance and can cause in the time that extraneous environment changes the variation of polymer molecule chain conformation, make this kind of material that larger physics or chemical transformation further occur, environmental stimulus gives a response to external world rapidly.The polymeric system of many substances or double response has been designed, but based on being all complicated conventionally as macromolecular bioprocesss such as protein, nucleic acid and polysaccharide, and the system that makes to design a multiple response is necessary.
At present, also do not reach desirable effect for the research of accuracy controlling polymer substance behavior.Meanwhile, for the macromolecular material with quadruple responsiveness, particularly combine temperature response, pH response, the polymer micelle system of the quadruple responsiveness of reduction response and photoresponse does not also occur.
Summary of the invention
In order to address the above problem, the invention provides a kind of preparation method of the quadruple response block micella with temperature, pH, reduction and photoresponse and potential application thereof.
The present invention is connected with the polymethyl acrylic acid dimethylaminoethyl with pH and temperature dual response the poly-2-nitrobenzyl methacrylic ester with optical Response by the disulfide linkage with reduction responsiveness, obtain having quadruple response Amphipathilic block polymer, this amphipathic nature polyalcohol can be self-assembled into nano-micelle in the aqueous solution.
Technical scheme of the present invention is: a kind of preparation method of quadruple responsiveness block polymer micelle, first prepare quadruple responsiveness segmented copolymer, and its syntheti c route is as follows:
The method specifically comprises the following steps:
Step 1: preparation 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide: by miscible to dry round-bottomed flask to 2-HEDS, excessive triethylamine and dry tetrahydrofuran (THF) (wherein the mol ratio of 2-HEDS and 2-bromine isobutyl acylbromide is 3:2), and be placed in ice-water bath.The tetrahydrofuran solution of 2-bromine isobutyl acylbromide is added drop-wise to round-bottomed flask gradually, whole reaction system nitrogen protection, stirring at room temperature 12 ~ 18 hours.After reaction finishes, remove triethylamine salt, revolve and evaporate tetrahydrofuran (THF), be dissolved in methylene dichloride, in separating funnel, wash and once make its aobvious alkalescence by aqueous sodium hydroxide washes, more extremely neutral with deionized water wash, obtain methylene dichloride organic layer.This methylene dichloride has solution to spend the night and obtain crude product through anhydrous magnesium sulfate drying, utilizes silica gel column chromatography to obtain pure 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide.
Step 2: preparation photoresponse block: under nitrogen protection, by initiator 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide, 2-nitrobenzyl methacrylic ester and cuprous bromide are dissolved in dry tetrahydrofuran (THF), use syringe holder N, N, N ', N ' ', N ' '-pentamethyl-diethylenetriamine is injected in Shu Lunke flask, after " freezing-to bleed-to thaw " five circulations, in 65 ~ 75 degree oil baths, react 2 ~ 10 hours, product is removed to catalyzer by the chromatography column that neutral alumina is housed, and by cold normal hexane precipitation 4 ~ 5 times, 50 degree vacuum-dryings 12 ~ 24 hours, obtain pure product.Wherein initiator, cuprous bromide, N, N, N ', N ' ', the mol ratio of N ' '-pentamethyl-diethylenetriamine and 2-nitrobenzyl methacrylic ester is 1:1:1:50 ~ 60.
Step 3: the activity of clearing end position bromine: product obtained above and sodiumazide are dissolved in dimethyl formamide, stirs 24 ~ 36 hours cold normal hexane precipitation, 50 degree vacuum-dryings 12 ~ 48 hours in 55 ~ 65 degree oil baths.Wherein, the mol ratio of above-mentioned products therefrom and sodiumazide is 1:30 ~ 100.
Step 4: preparation photoresponse macromole evocating agent: product that end position bromine is terminated, triethylamine and dry tetrahydrofuran (THF) are miscible to dry round-bottomed flask, and are placed in ice-water bath.The tetrahydrofuran solution of 2-bromine isobutyl acylbromide is added drop-wise to round-bottomed flask gradually, whole reaction system nitrogen protection, stirring at room temperature 48 ~ 72 hours.Remove not dissolved salt, concentrated by rotary evaporation, cold normal hexane precipitation, obtains macromole evocating agent.Wherein, the product that end position bromine is terminated and the mol ratio of 2-bromine isobutyl acylbromide are 1:100.
Step 5: above-mentioned macromole evocating agent, dimethylaminoethyl methacrylate and cuprous bromide are dissolved in dry tetrahydrofuran (THF), use syringe holder N, N, N ', N ' ', N ' '-pentamethyl-diethylenetriamine is injected in Shu Lunke flask, after " freezing-to bleed-to thaw " five circulations, in 68 ~ 75 degree oil baths, react 48 ~ 36 hours, product is removed to catalyzer by the chromatography column that neutral alumina is housed, and by cold normal hexane precipitation 3 times, 50 degree vacuum-dryings 12 ~ 24 hours, obtain pure product.Wherein, macromole evocating agent, cuprous bromide, N, N, N ', N ' ', the mol ratio of N ' '-pentamethyl-diethylenetriamine and dimethylaminoethyl methacrylate is 1:1:1:200.
Step 6: Micellization process: the Amphipathilic block polymer that step 5 is obtained and tetrahydrofuran (THF) are taking mass ratio as 1:1 mix and blend 5 hours, after this polymkeric substance dissolves completely, 1 ml deionized water is approximately added drop-wise in above-mentioned tetrahydrofuran solution with the speed of 2 microlitres per second, induces micelle formation.Gentle stirring is after 3 ~ 5 hours again, the disposable mixing solutions that is added to fast of 8 ml deionized water.Finally this solution is positioned in air to one week, tetrahydrofuran (THF) is volatilized completely, obtain the micellar solution with temperature, pH, reduction and light quadruple responsiveness of unloaded guest molecule.
Further, the block polymer obtaining in described step 5 is amphipathic, and hydrophilic section is polymethyl acrylic acid dimethylaminoethyl, and hydrophobic section is nitrobenzyl methacrylic ester, and centre connects by disulfide linkage.
One prepares block micella self-assembly in accordance with the method for claim 1.Be applied to the extraneous collaborative controllable release field that stimulates, specific as follows:
Amphipathilic block polymer prepared by 2 milligrams of above-mentioned steps and 0.25 milligram of Nile red are dissolved in 1 milliliter of tetrahydrofuran (THF) completely, then 1 ml deionized water are approximately added drop-wise in above-mentioned tetrahydrofuran solution with the speed of 2 microlitres per second, induce micelle formation.Continue gentle stirring after 5 hours, the disposable mixing solutions that is added to fast of 8 ml deionized water, makes micella sizing.In gained solution left standstill air one week, volatilization tetrahydrofuran (THF), removed the Nile red that is deposited in bottom unloaded, the micellar solution that obtains loading guest molecule Nile red.
The macromolecular material that this institute uses is a kind of Amphipathilic block polymer.Amphipathic nature polyalcohol refers to and in same polymer, has the phase structure to two kinds of different in kinds simultaneously the affinity polymkeric substance of (as water and oil phase, two kinds of oil phases, two kinds of inconsistent solid phases etc.).Amphipathic nature polyalcohol, in selective solvent (wherein a segment is good solvent, and another segment is poor solvent), can be self-assembled into micella.In macromolecular self-assembly system, spherical micelle is modal, and the segment that wherein solvability is good forms the shell of micella, and poorly soluble segment forms the core of micella.Due to the existence of solvation shell, the micella that amphipathic nature polyalcohol forms is (being greater than its critical micell solubility) stable existence for a long time within the scope of certain solubility.
The micella being self-assembled into by amphipathic nature polyalcohol can be used as pharmaceutical carrier, and there are many advantages, as all more stable in vivo and in vitro, have good biocompatibility, the medicine very little to solubleness has solublization, can serve as targeting drug administration carrier in addition at the micella of the specific modified in surface.The hydrophobic inner core of micella can be used as the storage of medicine, and hydrophilic outer shell can reduce cytophagous effect in micella and body, is conducive to the dispersiveness of micella in water.
Stimulating responsive polymer micella has great application prospect in the control release field of medicine.People's most study is temperature and pH response, because the temperature of the normal cell of temperature correction of a lot of lesions positions is generally higher, and enchylema is acid.Be mounted with the micella of medicine in running to lesions position, be subject to the stimulation of temperature or pH, the pattern of micella changes or directly breaks, and drug molecule is discharged and act on focus.Disulfide linkage is a covalent linkage that Protein requirement three-dimensional net structure is important, and under existing, reductive agent (gsh or dithiothreitol (DTT)) can degrade, general cancer cells be reductibility, so disulfide linkage polymkeric substance is also studied much as the carrier of macromolecular drug.Comparatively speaking, it is fewer that photoresponse micella is reported, but because it has extraordinary space-time, thereby can realize more accurately drug release.
Usefulness of the present invention is: polymkeric substance used in the present invention is the Amphipathilic block polymer with temperature, pH, reduction and photoresponse, and the micella preparing by series of process can load hydrophobic molecule.Under acidic conditions, under UV-irradiation, there is photodegradation reaction in this polymer micelle, destroyed the close and distant water balance of micella, causes micella to break, thereby the guest molecule loading is discharged.Under same acidity, in micellar solution, add a certain amount of dithiothreitol (DTT), because disulfide linkage is cleaved, the close and distant water balance of micella changes, and micella is broken, and causes the guest molecule loading to discharge.Prove the behavior of above-mentioned micella under various stimulations by means such as dynamic light scattering, transmission electron microscope, Fluorescence spectrophotometer and uv-spectrophotometric instrument.The present invention has broad application prospects in fields such as medicine control releases.
Brief description of the drawings
The nuclear magnetic spectrogram of Fig. 1 gained block polymer.
Fig. 2 is the transmission electron microscope photo of the polymer micelle of preparation.
Fig. 3 is the transmission electron microscope photo of polymer micelle at 60 degree.
Fig. 4 is the transmission electron microscope photo of polymer micelle at pH 5.
Fig. 5 is the transmission electron microscope photo of polymer micelle at pH 9.
Fig. 6 is the polymer micelle UV-irradiation transmission electron microscope photo of 2 hours.
Fig. 7 is the transmission electron microscope photo that blank micella reductive agent is processed 48 hours.
Fig. 8 is loaded in Nile red in the polymer micelle release graphics along with the different ultraviolet lighting time.
Fig. 9 is loaded in Nile red in the polymer micelle release graphics along with different concns reductive agent.
Figure 10 is loaded in the release graphics that the Nile red in polymer micelle (is followed successively by pH, light, reductive agent) under different stimulated.
Figure 11 is loaded in Nile red in the polymer micelle release graphics of (pH, light, reductive agent) under triple collaborative stimulations.
Embodiment
According to concrete enforcement, the technical scheme of invention is described further below.
Example 1
Step 1: preparation 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide: by miscible to dry round-bottomed flask to 4.62 grams of 2-HEDSs, 4 milliliters of triethylamines and 100 milliliters of dry tetrahydrofuran (THF)s, and be placed in ice-water bath.40 milliliters of tetrahydrofuran solutions of 4.598 grams of 2-bromine isobutyl acylbromides are added drop-wise to round-bottomed flask gradually, whole reaction system nitrogen protection, stirring at room temperature 16 hours.After reaction finishes, remove triethylamine hydrochloride, revolve and evaporate tetrahydrofuran (THF), be dissolved in methylene dichloride, in separating funnel, wash and once make its aobvious alkalescence by aqueous sodium hydroxide washes, more extremely neutral with deionized water wash, obtain organic layer.This organic solution is spent the night and is obtained crude product with anhydrous magnesium sulfate drying, utilizes silica gel column chromatography to obtain pure 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide.
Step 2: preparation photoresponse block: under nitrogen protection, by 0.0302 gram of initiator 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide, 1.1050 grams of 2-nitrobenzyl methacrylic esters and 0.0143 gram of cuprous bromide are dissolved in 2 milliliters of dry tetrahydrofuran (THF)s, with syringe holder 20 microlitre N, N, N ', N ' ', N ' '-pentamethyl-diethylenetriamine is injected in Shu Lunke flask, after " freezing-to bleed-to thaw " five circulations, in 70 degree oil baths, react 2 hours, product is removed to catalyzer by the chromatography column that neutral alumina is housed, and by cold normal hexane precipitation 3 times, 50 degree vacuum-dryings 12 hours, obtain pure product.
Step 3: the activity of clearing end position bromine: 0.23 gram of product obtained above and 0.14 gram of sodiumazide are dissolved in dimethyl formamide, stirs 24 hours in 60 degree oil baths, cold normal hexane precipitation, 50 degree vacuum-dryings 12 hours.
Step 4: preparation photoresponse macromole evocating agent: product, 0.1 mmole triethylamine and 20 milliliters of dry tetrahydrofuran (THF)s that 0.05 mmole end position bromine is terminated are miscible to dry round-bottomed flask, and are placed in ice-water bath.The tetrahydrofuran solution of 2.5 mmole 2-bromine isobutyl acylbromides is added drop-wise to round-bottomed flask gradually, whole reaction system nitrogen protection, stirring at room temperature 48 hours.Remove not dissolved salt, concentrated by rotary evaporation, cold normal hexane precipitation, obtains macromole evocating agent.
Step 5:0.2 gram of above-mentioned macromole evocating agent, 2 milliliters of dimethylaminoethyl methacrylates and 0.0087 gram of cuprous bromide are dissolved in 1 milliliter of dry tetrahydrofuran (THF), with syringe holder 13 microlitre N, N, N ', N ' ', N ' '-pentamethyl-diethylenetriamine is injected in Shu Lunke flask, after " freezing-to bleed-to thaw " five circulations, in 70 degree oil baths, react 48 hours, product is removed to catalyzer by the chromatography column that neutral alumina is housed, and by cold normal hexane precipitation 3 times, 50 degree vacuum-dryings 12 hours, obtain pure product.
Step 6: Micellization process: the Amphipathilic block polymer that step 5 is obtained and tetrahydrofuran (THF) are taking mass ratio as 1:1 mix and blend 5 hours, after this polymkeric substance dissolves completely, 1 ml deionized water is approximately added drop-wise in above-mentioned tetrahydrofuran solution with the speed of 2 microlitres per second, induces micelle formation.Gentle stirring is after 4 hours again, the disposable mixing solutions that is added to fast of 9 ml deionized water.Finally this solution is positioned in air to one week, tetrahydrofuran (THF) is volatilized completely, obtain thering is temperature, the micellar solution of pH, reduction and light quadruple responsiveness.
Example 2
Step 1: preparation 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide: by miscible to dry round-bottomed flask to 2-HEDS, triethylamine and dry tetrahydrofuran (THF), and be placed in ice-water bath.The tetrahydrofuran solution of 2-bromine isobutyl acylbromide is added drop-wise to round-bottomed flask gradually, whole reaction system nitrogen protection, stirring at room temperature 24 hours.After reaction finishes, remove triethylamine hydrochloride, revolve and evaporate tetrahydrofuran (THF), be dissolved in methylene dichloride, in separating funnel, wash and once make its aobvious alkalescence by aqueous sodium hydroxide washes, more extremely neutral with deionized water wash, obtain organic layer.This organic solution is spent the night and is obtained crude product with anhydrous magnesium sulfate drying, carries out silica gel column chromatography obtain pure 2-hydroxyl-2'-(bromine isobutyryl with the eluent of ether and normal hexane (3/7 V/V)) ethyl disulphide.Wherein the mol ratio of 2-HEDS and 2-bromine isobutyl acylbromide is 3:2.
Step 2: preparation photoresponse block: under nitrogen protection, by initiator 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide, 2-nitrobenzyl methacrylic ester and cuprous bromide are dissolved in dry tetrahydrofuran (THF), use syringe holder N, N, N ', N ' ', N ' '-pentamethyl-diethylenetriamine is injected in Shu Lunke flask, after " freezing-to bleed-to thaw " five circulations, in 75 degree oil baths, react 6 hours, product is removed to catalyzer by the chromatography column that neutral alumina is housed, and by cold normal hexane precipitation 3 times, 45 degree vacuum-dryings 24 hours, obtain pure product.Wherein initiator, cuprous bromide, N, N, N ', N ' ', the mol ratio of N ' '-pentamethyl-diethylenetriamine and 2-nitrobenzyl methacrylic ester is 1:1:1:50.
Step 3: the activity of clearing end position bromine: product obtained above and sodiumazide are dissolved in dimethyl formamide, 60 degree stir 24 hours in oil baths, and dimethyl formamide is first dialysed, then by cold normal hexane precipitation, 50 spend vacuum-dryings 24 hours.Wherein, the mol ratio of above-mentioned products therefrom and sodiumazide is 1:50.
Step 4: preparation photoresponse macromole evocating agent: product that end position bromine is terminated, triethylamine and dry tetrahydrofuran (THF) are miscible to 50 milliliters of dry round-bottomed flasks, and are placed in ice-water bath.The tetrahydrofuran solution of 2-bromine isobutyl acylbromide is added drop-wise to round-bottomed flask gradually, whole reaction system nitrogen protection, stirring at room temperature 72 hours.Remove not dissolved salt, concentrated by rotary evaporation, cold normal hexane precipitation three times, obtains macromole evocating agent.Wherein, the product that end position bromine is terminated and the mol ratio of 2-bromine isobutyl acylbromide are 1:100.
Step 5: above-mentioned macromole evocating agent, dimethylaminoethyl methacrylate and cuprous bromide are dissolved in dry tetrahydrofuran (THF), use syringe holder N, N, N ', N ' ', N ' '-pentamethyl-diethylenetriamine is injected in the Shu Lunke flask of 25 milliliters, after " freezing-to bleed-to thaw " five circulations, in 65 degree oil baths, react 60 hours, use liquid nitrogen termination reaction, 20 milliliters of tetrahydrofuran (THF) dilutions, product is removed to catalyzer by the chromatography column that neutral alumina is housed, and by cold normal hexane precipitation 2 times, 50 degree vacuum-dryings 12 hours, obtain pure product.Hydrophilic section molecule number and hydrophobic section number are 9:1.Molecular weight is 25000g/mol.
Step 6: Micellization process: the Amphipathilic block polymer that step 5 is obtained and tetrahydrofuran (THF) are taking mass ratio as 1:1 mix and blend 5 hours, after this polymkeric substance dissolves completely, 1 ml deionized water is approximately added drop-wise in above-mentioned tetrahydrofuran solution with the speed of 2 microlitres per second, induces micelle formation.Gentle stirring is after 5 hours again, the disposable mixing solutions that is added to fast of 8 ml deionized water.Finally, by this solution dialysis three days, remove tetrahydrofuran (THF), obtain thering is temperature, the micellar solution of pH, reduction and light quadruple responsiveness.
Embodiment 3:
Step 1: preparation 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide: by miscible to dry round-bottomed flask to 2-HEDS, triethylamine and dry tetrahydrofuran (THF), and be placed in ice-water bath.The tetrahydrofuran solution of 2-bromine isobutyl acylbromide is added drop-wise to round-bottomed flask gradually, whole reaction system nitrogen protection, stirring at room temperature 24 hours.After reaction finishes, remove triethylamine hydrochloride, revolve and evaporate tetrahydrofuran (THF), be dissolved in methylene dichloride, in separating funnel, wash and once make its aobvious alkalescence by aqueous sodium hydroxide washes, more extremely neutral with deionized water wash, obtain organic layer.This organic solution is spent the night and is obtained crude product with anhydrous magnesium sulfate drying, carries out silica gel column chromatography obtain pure 2-hydroxyl-2'-(bromine isobutyryl with the eluent of ether and normal hexane (3/7 V/V)) ethyl disulphide.Wherein the mol ratio of 2-HEDS and 2-bromine isobutyl acylbromide is 3:2.
Step 2: preparation photoresponse block: under nitrogen protection, by initiator 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide, 2-nitrobenzyl methacrylic ester and cuprous bromide are dissolved in dry tetrahydrofuran (THF), use syringe holder N, N, N ', N ' ', N ' '-pentamethyl-diethylenetriamine is injected in Shu Lunke flask, after " freezing-to bleed-to thaw " five circulations, in 75 degree oil baths, react 6 hours, product is removed to catalyzer by the chromatography column that neutral alumina is housed, and by cold normal hexane precipitation 3 times, 45 degree vacuum-dryings 24 hours, obtain pure product.Wherein initiator, cuprous bromide, N, N, N ', N ' ', the mol ratio of N ' '-pentamethyl-diethylenetriamine and 2-nitrobenzyl methacrylic ester is 1:1:1:60.
Step 3: the activity of clearing end position bromine: product obtained above and sodiumazide are dissolved in dimethyl formamide, 60 degree stir 24 hours in oil baths, and dimethyl formamide is first dialysed, then by cold normal hexane precipitation, 50 spend vacuum-dryings 24 hours.Wherein, the mol ratio of above-mentioned products therefrom and sodiumazide is 1:100.
Step 4: preparation photoresponse macromole evocating agent: product that end position bromine is terminated, triethylamine and dry tetrahydrofuran (THF) are miscible to 50 milliliters of dry round-bottomed flasks, and are placed in ice-water bath.The tetrahydrofuran solution of 2-bromine isobutyl acylbromide is added drop-wise to round-bottomed flask gradually, whole reaction system nitrogen protection, stirring at room temperature 72 hours.Remove not dissolved salt, concentrated by rotary evaporation, cold normal hexane precipitation three times, obtains macromole evocating agent.Wherein, the product that end position bromine is terminated and the mol ratio of 2-bromine isobutyl acylbromide are 1:100.
Step 5: above-mentioned macromole evocating agent, dimethylaminoethyl methacrylate and cuprous bromide are dissolved in dry tetrahydrofuran (THF), use syringe holder N, N, N ', N ' ', N ' '-pentamethyl-diethylenetriamine is injected in the Shu Lunke flask of 25 milliliters, after " freezing-to bleed-to thaw " five circulations, in 65 degree oil baths, react 60 hours, use liquid nitrogen termination reaction, 20 milliliters of tetrahydrofuran (THF) dilutions, product is removed to catalyzer by the chromatography column that neutral alumina is housed, and by cold normal hexane precipitation 2 times, 50 degree vacuum-dryings 12 hours, obtain pure product.
Step 6: Micellization process: the Amphipathilic block polymer that step 5 is obtained and tetrahydrofuran (THF) are taking mass ratio as 1:1 mix and blend 5 hours, after this polymkeric substance dissolves completely, 1 ml deionized water is approximately added drop-wise in above-mentioned tetrahydrofuran solution with the speed of 2 microlitres per second, induces micelle formation.Gentle stirring is after 5 hours again, the disposable mixing solutions that is added to fast of 8 ml deionized water.Finally, by this solution dialysis three days, remove tetrahydrofuran (THF), obtain thering is temperature, the micellar solution of pH, reduction and light quadruple responsiveness.
Claims (3)
1. a preparation method for quadruple responsiveness block polymer micelle, is characterized in that, the steps include:
Step 1: preparation 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide: by miscible to dry round-bottomed flask to 2-HEDS, triethylamine and dry tetrahydrofuran (THF), and be placed in ice-water bath; The tetrahydrofuran solution of 2-bromine isobutyl acylbromide is added drop-wise to described round-bottomed flask gradually; whole reaction system nitrogen protection; stirring at room temperature 12 ~ 24 hours; after reaction finishes, remove triethylamine hydrochloride, revolve and evaporate tetrahydrofuran (THF); be dissolved in methylene dichloride; in separating funnel, wash and once make its aobvious alkalescence by aqueous sodium hydroxide washes, more extremely neutral with deionized water wash, obtain
methylene dichlorideorganic layer, will
methylene dichloridehave solution to spend the night and obtain crude product through anhydrous magnesium sulfate drying, utilize silica gel column chromatography to obtain pure 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide, wherein, the mol ratio of described 2-HEDS and 2-bromine isobutyl acylbromide is 3:2;
Step 2: preparation photoresponse block: under nitrogen protection, by initiator 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide, 2-nitrobenzyl methacrylic ester and cuprous bromide are dissolved in dry tetrahydrofuran (THF), be placed in Shu Lunke flask, use syringe holder N, N, N ', N ' ', N ' '-pentamethyl-diethylenetriamine is injected in described Shu Lunke flask, after " freezing-to bleed-to thaw " five circulations, in 65 ~ 80 degree oil baths, react 2 ~ 10 hours, product is removed to catalyzer by the chromatography column that neutral alumina is housed, and by cold normal hexane precipitation 2 ~ 4 times, be 40 ~ 50 degree in temperature, vacuum-drying 12 ~ 48 hours, obtain pure product A, wherein, described 2-hydroxyl-2'-(bromine isobutyryl) ethyl disulphide, cuprous bromide, N, N, N ', N ' ', the mol ratio of N ' '-pentamethyl-diethylenetriamine and 2-nitrobenzyl methacrylic ester is 1:1:1:50 ~ 60,
Step 3: the activity of clearing end position bromine: step 2 prepares product A and sodiumazide is dissolved in dimethyl formamide by taking respectively, in the oil bath of 50-65 degree, stir 20 ~ 36 hours, cold normal hexane precipitation, be under 40 ~ 50 degree in temperature, vacuum-drying 12 ~ 48 hours, the product B that obtains end position bromine and be terminated, wherein, the mol ratio of the product A that described end position bromine is terminated and 2-bromine isobutyl acylbromide is 1:30 ~ 100;
Step 4: preparation photoresponse macromole evocating agent: take respectively that end position bromine and the product B being terminated, triethylamine and dry tetrahydrofuran (THF) are miscible joins dry round-bottomed flask, and be placed in ice-water bath, again the tetrahydrofuran solution of 2-bromine isobutyl acylbromide is added drop-wise in described round-bottomed flask gradually, whole reaction system nitrogen protection, stirring at room temperature 36 ~ 72 hours, remove not dissolved salt, concentrated by rotary evaporation, cold normal hexane precipitation, obtain photoresponse macromole evocating agent, wherein, the product B that end position bromine is terminated and the mol ratio of 2-bromine isobutyl acylbromide are 1:100;
Step 5: the photoresponse macromole evocating agent that step 4 prepares, dimethylaminoethyl methacrylate and cuprous bromide are dissolved in dry tetrahydrofuran (THF), be placed in Shu Lunke flask, use syringe holder N, N, N ', N ' ', N ' '-pentamethyl-diethylenetriamine is injected in described Shu Lunke flask, after " freezing-to bleed-to thaw " four to eight circulations, be to react 36 ~ 72 hours in the oil bath of 65-80 degree in temperature, product is removed to catalyzer by the chromatography column that neutral alumina is housed, and by cold normal hexane precipitation 2 ~ 4 times, be 45 ~ 55 degree in temperature, vacuum-drying 12 ~ 48 hours, obtain pure product C, product C is Amphipathilic block polymer, wherein, described photoresponse macromole evocating agent, cuprous bromide, N, N, N ', N ' ', the mol ratio of N ' '-pentamethyl-diethylenetriamine and dimethylaminoethyl methacrylate is 1:1:1:200,
Step 6: the Amphipathilic block polymer that step 5 is prepared and tetrahydrofuran (THF) are taking mass ratio as 1:1 mix and blend 4 ~ 6 hours, after this polymkeric substance dissolves completely, 1 ml deionized water is added drop-wise in above-mentioned tetrahydrofuran solution with the speed of 2 microlitres per second, induce micelle formation, gentle stirring is after 3 ~ 6 hours again, by the disposable 8 ml deionized water mixing solutions that is added to fast, finally this solution is positioned in air to three days or seven days, tetrahydrofuran (THF) is volatilized completely, what obtain has a temperature, pH, the quadruple responsiveness block polymer micelle of reduction and light.
2. in accordance with the method for claim 1, it is characterized in that: the block polymer that described step 5 obtains is amphiphilic, its hydrophilic segment is polymethyl acrylic acid dimethylaminoethyl, and hydrophobic segment is poly-2-nitrobenzyl methacrylic ester.
3. the block polymer micelle preparing is in accordance with the method for claim 1 applied in multiple, long-range controllable release field.
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Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104725581A (en) * | 2015-02-02 | 2015-06-24 | 北京科技大学 | Method for preparing and applying light/temperature sensitive amphiphilic block polymer micelle |
| CN104910338A (en) * | 2015-06-18 | 2015-09-16 | 辽宁大学 | Preparation method of temperature/pH dual-response flexible polymer Janus hollow sphere |
| CN105440190A (en) * | 2015-12-23 | 2016-03-30 | 北京科技大学 | Preparation method of multi-responsiveazobenzene functionalized polymer |
| CN106496571A (en) * | 2016-10-17 | 2017-03-15 | 江苏师范大学 | Reduction response Amphipathilic block polymer and nano-micelle and application |
| CN106916266A (en) * | 2017-02-21 | 2017-07-04 | 北京科技大学 | A kind of preparation and its application of quadruple responsive nano compound |
| CN108815536A (en) * | 2018-08-08 | 2018-11-16 | 陕西师范大学 | A kind of drug delivery materials and its preparation method and application with pH and dual redox responsiveness |
| CN109232899A (en) * | 2018-09-14 | 2019-01-18 | 陕西师范大学 | A kind of application of pH and optical Response polymer carrier materials and its preparation and immobilization pectase |
| CN111471185A (en) * | 2020-05-12 | 2020-07-31 | 陕西师范大学 | Triple-stimulus-responsive block polymer micelle and preparation method and application thereof |
| CN113519513A (en) * | 2021-07-06 | 2021-10-22 | 合肥工业大学 | Ultraviolet-light-responsive pesticide sustained-release preparation, preparation method and application thereof |
| WO2023210671A1 (en) * | 2022-04-26 | 2023-11-02 | 京セラ株式会社 | Copolymer, polymer film, measuring device, and support for measurement |
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| CN103204971A (en) * | 2013-01-16 | 2013-07-17 | 北京科技大学 | Preparation method and application of triple response polymer self assembly based on nitrobenzene |
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| CN103204971A (en) * | 2013-01-16 | 2013-07-17 | 北京科技大学 | Preparation method and application of triple response polymer self assembly based on nitrobenzene |
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| HAO WU ET AL.: "Multi-responsive nitrobenzene-based amphiphilic random copolymer assemblies", 《CHEM.COMMUN.》 * |
| WANG X ET AL.: "Synthesis of multi-responsive polymeric nanocarriers for controlled release of bioactive agents", 《POLYM. CHEM.》 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104725581B (en) * | 2015-02-02 | 2017-08-11 | 北京科技大学 | The preparation of light/temperature responsive type Amphipathilic block polymer micelle and application process |
| CN104725581A (en) * | 2015-02-02 | 2015-06-24 | 北京科技大学 | Method for preparing and applying light/temperature sensitive amphiphilic block polymer micelle |
| CN104910338A (en) * | 2015-06-18 | 2015-09-16 | 辽宁大学 | Preparation method of temperature/pH dual-response flexible polymer Janus hollow sphere |
| CN105440190A (en) * | 2015-12-23 | 2016-03-30 | 北京科技大学 | Preparation method of multi-responsiveazobenzene functionalized polymer |
| CN106496571B (en) * | 2016-10-17 | 2019-10-11 | 江苏师范大学 | Restore responsiveness Amphipathilic block polymer and nano-micelle and application |
| CN106496571A (en) * | 2016-10-17 | 2017-03-15 | 江苏师范大学 | Reduction response Amphipathilic block polymer and nano-micelle and application |
| CN106916266A (en) * | 2017-02-21 | 2017-07-04 | 北京科技大学 | A kind of preparation and its application of quadruple responsive nano compound |
| CN108815536A (en) * | 2018-08-08 | 2018-11-16 | 陕西师范大学 | A kind of drug delivery materials and its preparation method and application with pH and dual redox responsiveness |
| CN108815536B (en) * | 2018-08-08 | 2021-04-09 | 陕西师范大学 | Drug delivery material with pH and dual redox responsiveness and preparation method and application thereof |
| CN109232899A (en) * | 2018-09-14 | 2019-01-18 | 陕西师范大学 | A kind of application of pH and optical Response polymer carrier materials and its preparation and immobilization pectase |
| CN109232899B (en) * | 2018-09-14 | 2021-09-14 | 陕西师范大学 | PH and photoresponse polymer carrier material, preparation thereof and application of immobilized pectinase |
| CN111471185A (en) * | 2020-05-12 | 2020-07-31 | 陕西师范大学 | Triple-stimulus-responsive block polymer micelle and preparation method and application thereof |
| CN113519513A (en) * | 2021-07-06 | 2021-10-22 | 合肥工业大学 | Ultraviolet-light-responsive pesticide sustained-release preparation, preparation method and application thereof |
| WO2023210671A1 (en) * | 2022-04-26 | 2023-11-02 | 京セラ株式会社 | Copolymer, polymer film, measuring device, and support for measurement |
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