CN103601897A - Preparation method and application of multiple-response nanogel - Google Patents
Preparation method and application of multiple-response nanogel Download PDFInfo
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Abstract
The invention relates to a preparation method and application of a multiple-response nanogel. The preparation method concretely comprises the steps of subjecting 2-nitrobenzyl alcohol and methacryloyl chloride to reaction to obtain 2-nitrobenzyl methacrylate; then, subjecting a monomer dimethylaminoethyl methacrylate and the 2-nitrobenzyl methacrylate to atom transfer radical polymerization to obtain an amphiphilic polymer, thereby preparing a micelle; next, adding 1, 2-bis(2-iodoethoxy)ethane as a crosslinking agent into a micelle solution, and forming a crosslinking network by using a micelle shell, thereby preparing a shell crosslinked nanogel. The nanogel has the following functions: (1) the nanogel can be used as a nanoscale carrier capable of stably carrying guest molecules; (2) the released guest molecules can be controlled through adjusting external fields such as ultraviolet irradiation, pH value, temperature and the like; (3) various external fields can be used for adjusting the dynamic release process of the guest molecules to take a synergistic effect. The multiple-response nanogel has high application values in the fields of nano-medicines, biosensors and nano-reactors.
Description
Technical field
The invention belongs to technical field of polymer materials, relate to a kind of preparation and application of multi-functional shell crosslinking nano gel.
Background technology
Nanogel is a physics for class nanoscale or the polymer beads of chemically crosslinked.The advantages such as its distinctive nanoscale effect and satisfactory stability, particle diameter adjustability, attracted nearly ten years a large amount of researchers to be applied in different fields, comprise the fields such as sensing, medical diagnosis and drug release, and obtained very large breakthrough.
But at least also there is improved space aspect two in nanogel.First is the preparation method of relevant nanogel.Most nanogels adopt letex polymerization or inversed emulsion polymerization preparation, and this method need to be carried out complicated rear purification process, has limited it in industrialized application.Second is for the nanogel with outfield stimuli responsive, and the multiple response nanogel that particularly combines light, temperature and pH is also in state to be developed at present.
Before this, applicant has applied for the patent application that publication number is 103204971A, to there is the nitrobenzene derivative group and the dimethylaminoethyl methacrylate copolymerization with pH and temperature-responsive of photoresponse, obtain having the amphipathic nature polyalcohol of multiple response, from this polymkeric substance, the aqueous solution, be self-assembled into micellelike self-assembly; But having comprised, it prepares selected material and cardinal principle processing step, and the present invention is through further further investigation and modification to invention before, to material selection and proportioning, the correction of technique, after optimization, be applied to again in present patent application, in conjunction with the method for preparing shell crosslinking nano gel of the present invention, obtain shell crosslinking nano gel of the present invention.The molar ratio of 2-nitrobenzyl alcohol and triethylamine for example, and methacrylic chloride and 2-nitrobenzyl alcohol ratio are really established a capital and have before very large difference, and the selected ratio of the present invention can more effectively be utilized 2-nitrobenzyl alcohol, thereby reduce byproduct of reaction; Brand-new research has also been carried out in preparation for polymkeric substance, and for example material proportion is selected, and processing parameter etc., make the polymkeric substance obtaining can form better nanostructure; Utilize the further nanogel arriving of preparation of micellelike self-assembly that above-mentioned preparation method obtains, make this nano-carrier can be in complex environment stable existence, further widened its use range.
Summary of the invention
In order to address the above problem, the present invention has passed through a kind of easy method, prepare a kind of novel there is light, acid and temperature the more can shell crosslinking nano gel.
The present invention will have the nitrobenzene derivative group and the dimethylaminoethyl methacrylate copolymerization with pH and temperature-responsive of photoresponse, obtain having the amphipathic nature polyalcohol of multiple response, from this polymkeric substance, the aqueous solution, be self-assembled into micellelike self-assembly, then with linking agent, the privileged site of polymer micelle (shell) is carried out to specificity crosslinked, thereby obtain having the shell crosslinking nano gel of multiple response.
Technical scheme of the present invention is: the preparation method of the nanogel that a kind of shell is crosslinked, and its reaction mechanism is as follows:
The method specifically comprises the following steps:
Step 1: preparation 2-nitrobenzyl methacrylic ester: by 2-nitrobenzyl alcohol and the triethylamine ratio mixing of 1:1-1:4 in molar ratio, be dissolved in the round-bottomed flask that methylene dichloride is housed, round-bottomed flask is placed on to frozen water to be mixed in bath, the dichloromethane solution that is dissolved with methacrylic chloride is slowly dropwise added drop-wise in round-bottomed flask, wherein, methacrylic chloride and 2-nitrobenzyl alcohol ratio are 1:1 ~ 5:1; Whole reaction system nitrogen protection, the reaction times is 6-12 hour; After reaction finishes, reaction mixture is poured in separating funnel, used alkaline aqueous solution washed twice; Organic layer is taken out from separating funnel, with the dry 12-24 hour of anhydrous slufuric acid hydrogen sodium, the crude product obtaining; With silica gel column chromatography, purify, described chromatographic solution is that volume ratio is normal hexane and the ethyl acetate mixture of 6:1; The product obtaining is weak yellow liquid, standby;
Step 2: prepare polymkeric substance: by ampoule vacuum-drying and be full of nitrogen, by cuprous bromide, dimethylaminoethyl methacrylate and 2-nitrobenzyl methacrylic ester in molar ratio for the ratio of 1:50:10-1:10:10 joins ampoule, mix, use the tetrahydrofuran (THF) of 2 ~ 10 times of above-mentioned cuprous bromide, dimethylaminoethyl methacrylate and 2-nitrobenzyl methacrylic ester three quality sums to dissolve; With syringe by 1, Isosorbide-5-Nitrae, 7,10,10-hexamethyl triethylene tetramine (0.1 to 1.0 mole) joins in system; Reaction mixture is processed after three times by " freezing-to bleed-to dissolve " method, in oil bath, react 6-24 hour, temperature of reaction is 60 ℃ to 80 ℃, after reaction finishes, product, by being equipped with in the chromatography column of aluminium oxide nano particle to go out unnecessary catalyzer, is revolved to steaming by crude product, in normal hexane, precipitate, 40 ℃ of oven dry of vacuum, obtain amphipathic nature polyalcohol;
Step 3: self-assembly process: the amphipathic nature polyalcohol that step 2 is obtained and tetrahydrofuran (THF) be take mass ratio as 1 to 1 mixing; After polymkeric substance fully dissolves, the speed by 1 ml deionized water with 1-3 microlitre per second is slowly added drop-wise in mixing solutions, and to induce the formation of micella, vigorous stirring continues 2-8 hour; 8ml deionized water is joined in mixing solutions, and stop stirring; Solution is placed in deionized water to dialysis at least 24 hours, obtains thering is light, the micellar solution of temperature and the triple responsivenesss of pH;
Step 4: gelation process: get the polymer micelle solution that step 3 obtains, two (2-iodine oxyethyl group) the ethane solution of 1,2-is dropwise joined in polymer micelle solution; Add-on is 5 % ~ 20 % of polymer micelle solution; This mixing solutions is placed at 60 ~ 80 ℃ and reacts 12-~ 24 hour; The gelating soln obtaining after reaction is dialysed with dialysis membrane, obtain pure nanogel solution.
Further, in described step 1, the amount of being filled with of methylene dichloride is flask 20% ~ 80%.
Further, in described step 1, described alkaline aqueous solution is selected aqueous sodium hydroxide solution or potassium hydroxide aqueous solution.
Further, in " freezing-to bleed-dissolve " method in described step 2, freezing temp is-10 ℃ ~-20 ℃ and is refrigerated to and freezes to be as the criterion, described in the time of bleeding be 10 ~ 30min; Described dissolving can adopt in air or in warm water bath dissolve all can, take and reach that to dissolve object be standard.
Preferably, in described step 2 by cuprous bromide, dimethylaminoethyl methacrylate and 2-nitrobenzyl methacrylic ester in molar ratio for the ratio of 1:50:10 ~ 1:10:10 joins ampoule.
Further, the nanogel that described step 4 obtains is for having nucleocapsid structure; Its shell is the cross-linked layer with three-dimensional net structure, and moiety is the dimethylaminoethyl methacrylate with the quaternary ammonium salinization of hydrophilic portion, and its stratum nucleare is for having hydrophobic poly-2-nitrobenzyl methacrylic ester.
Further, the nanogel that described method prepares can be used as the loading bin of nanoscale, good at normal temperature, neutrallty condition stability inferior, but can under pH, temperature and UV-irradiation, the guest molecule of loading be discharged.
Further, the nanogel that described method prepares has synergistic effect, can under different outfield incentive condition combinations, regulate the kinetics dispose procedure of guest molecule.
A kind of nanogel preparing according to the method described in the present invention.Be applied to external stimulus controllable release field, specific as follows:
2 milligrams of amphipathic nature polyalcohols based on nitrobenzene derivative that above-mentioned steps is obtained are dissolved in 1 milliliter of tetrahydrofuran (THF), add 0.3 milligram of Nile red molecule simultaneously, with magnetic stirring apparatus, fully stir 30 molecules, make polymkeric substance and Nile red be dissolved in tetrahydrofuran (THF) completely, form uniform solution, then the speed with 1 microlitre per second slowly drips 1 ml deionized water in solution, vigorous stirring 3 hours, the formation of induction micella.Then in solution, add 8 ml deionized water, with the fixing micella of formation.And then by 1 milliliter micellar solution 1, two (2-iodine oxyethyl group) the ethane solution (12 mg/mL, are dissolved in tetrahydrofuran (THF)) of 2-dropwise joins in polymer micelle solution.This mixing solutions is placed at 60 ℃ and is reacted 24 hours.The gelating soln obtaining after reaction is dialysed at least 24 hours with the dialysis membrane of 10,000 g/mol, with tetrahydrofuran (THF) and the small particle of going out in solution, can obtain loading the nanogel solution of guest molecule.
The macromolecular material that this institute uses is a kind of crosslinked amphipathic nature polyalcohol.Amphipathic nature polyalcohol refers to that same polymer has the phase structure that the phase structure of two kinds of different in kinds (as water and oil phase, two kinds of oil phases, two kinds of solid phases of not allowing etc.) has affinity simultaneously.Amphipathic nature polyalcohol selective solvent (to wherein one section be good solvent, and to another section be poor solvent) in, can assemble formation micella.Wherein spherical macromolecule micelle self-assembly is modal Polymer Systems, the core of the poor formation micella of solvability wherein, and the segment that solvability is good forms the shell of micella.Due to the existence of solvation shell, the micella that amphipathic nature polyalcohol forms stable existence for a long time within the scope of finite concentration, but when low concentration is as following in micelle-forming concentration, self-assembled structures disintegration, micella can break.Therefore, self-assembled micelle is cross-linked to form to nanogel, can greatly improves its stability.
The nanogel that amphipathic nature polyalcohol self-assembled micelle forms can be used as pharmaceutical carrier, and there are many advantages, as there is very strong stability, there is good biocompatibility, the medicine very little for solubleness has solublization, and can obtain targeting drug administration carrier in gel surface chemically modified.The hydrophobic kernel of polymer nanocomposite gel can load hydrophobic drug and as medicine storage storehouse, and hydrophilic shell can reduce cytophagous interaction in micella and body, is conducive to dispersed in water of nanogel.
Stimulating responsive polymer nanogel has good application prospect in control release field.Wherein temperature-responsive and pH responsiveness are studied at most by people, because much the temperature of lesions position cells is than Normocellular temperature drift, and enchylema is acid.When polymer nanocomposite gel runs to lesions position in human body, can be subject to the stimulation of temperature or pH, polymkeric substance pattern changes, thereby by the drug release of loading out.And seldom, it can realize the controllability in any place any time and discharge the current report of polymer nanocomposite gel of photoresponse, thereby realizes the release more accurately to medicine.
Usefulness of the present invention is: the polymer nanocomposite gel with photoresponse, temperature response and pH response that the present invention is prepared can load guest molecule by series of process, and the guest molecule meeting controllable release of loading under above-mentioned outer field action out.This polymer nanocomposite gel is under UV-irradiation, and the polymer molecule generation photodegradation in nanogel core is reacted, thereby the guest molecule of loading is discharged.The in the situation that of rising temperature, be originally that hydrophilic polymer segment changes hydrophobicity into, thereby nanogel is shunk, a part of guest molecule is extruded to carrier.Under acidic conditions, due to the protonation of polymer molecule, hydrophilic segment wetting ability is strengthened, induced nano gel expands, and the guest molecule loading is dropped out.By characterization methods such as transmission electron microscope and fluorescence spectrums, proved the respondent behavior of above-mentioned polymer nanocomposite gel under outer field action.The present invention controls the fields such as release and has broad application prospects at medicine.
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accompanying drawing explanation
Fig. 1 is the transmission electron microscope schematic diagram of the nanogel of the unloaded guest molecule of preparation;
Fig. 2 is that blank nanogel is subject to the transmission electrical schematic after UV-irradiation 20 minutes;
Fig. 3 is the transmission electron microscope schematic diagram of blank nanogel in the environment of pH 3;
Fig. 4 is blank nanogel is the transmission electron microscope schematic diagram in the environment of 60 ℃ in temperature;
Fig. 5 is the nanogel of the loading Nile red of preparation, the variation schematic diagram of the fluorescent absorption intensity UV-irradiation asynchronism(-nization) of Nile red;
Fig. 6 is the nanogel of the loading Nile red of preparation, the fluorescent absorption intensity variation with temperature schematic diagram of Nile red;
Fig. 7 is the nanogel of the loading Nile red of preparation, the variation schematic diagram of the fluorescent absorption intensity pH of Nile red;
Fig. 8 is the nanogel of the loading Nile red of preparation, the variation schematic diagram of the burst size of Nile red under the collaborative stimulation of pH, illumination and temperature.
Embodiment
According to concrete enforcement, technical scheme of the present invention is described further below.
Embodiment 1
Preparation 2-nitrobenzyl methacrylic ester: 4.21 grams of 2-nitrobenzyl alcohol and 7.68 milliliters of triethylamines are dissolved in 100 milliliters of round-bottomed flasks that methylene dichloride is housed, and the frozen water that round-bottomed flask is placed on to 0 ℃ mixes in bath.The dichloromethane solution that is dissolved with methacrylic chloride is dropwise added drop-wise in round-bottomed flask.Whole reaction system nitrogen protection, the reaction times is 12 hours.After reaction finishes, reaction mixture is poured in separating funnel, by aqueous sodium hydroxide washes, washed twice.Organic layer is taken out from separating funnel, with anhydrous slufuric acid hydrogen sodium, be dried 12 hours.The crude product obtaining, with silica gel column chromatography purification (chromatographic solution is that volume ratio is normal hexane and the ethyl acetate mixture of 6:1).The product obtaining is weak yellow liquid.
Prepare polymkeric substance.By the ampoule vacuum-drying of 5 milliliters and be full of nitrogen.Add inside 0.15 gram of cuprous bromide, 4.71 grams of dimethylaminoethyl methacrylates and 2.21 grams of 2-nitrobenzyl methacrylic esters to join ampoule, with 3 milliliters of tetrahydrofuran (THF)s, dissolve.With syringe by 35 milligram 1, Isosorbide-5-Nitrae, 7,10,10-hexamethyl triethylene tetramine joins in system.Reaction mixture is processed after three times by " freezing-to bleed-to dissolve " method, reacted 18 hours in oil bath, temperature of reaction is 68 ℃.After reaction finishes, by product by being equipped with in the chromatography column of aluminium oxide nano particle to go out unnecessary catalyzer.Crude product is revolved to steaming, in normal hexane, precipitate, 40 ℃ of oven dry of vacuum, obtain amphipathic nature polyalcohol solid.
Self-assembly process: the amphipathic nature polyalcohol preparing and tetrahydrofuran (THF) be take to mass ratio as 1 to 1 mixing.After polymkeric substance fully dissolves, the speed by 1 ml deionized water with 1-3 microlitre per second is slowly added drop-wise in mixing solutions, and to induce the formation of micella, vigorous stirring continues 4 hours.8 ml deionized water are joined in mixing solutions, and stop stirring.Solution is placed in deionized water and is dialysed at least 24 hours, obtain not loading the micellar solution with light, temperature and the triple responsivenesss of pH of guest molecule.
Gelation process: get the polymer micelle solution preparing, two (2-iodine oxyethyl group) the ethane solution of 1,2-is dropwise joined in polymer micelle solution; Add-on is 5 % (volume ratio) of polymer micelle solution; This mixing solutions is placed at 60 ℃ and is reacted 12 hours; The gelating soln obtaining after reaction is dialysed with dialysis membrane, obtain pure nanogel solution.Fig. 1 is the transmission electron microscope picture of nanogel, therefrom can see, it has perfect nanoscale globosity, and it is good to distribute.
The sign of multiple response: our transmission electron microscope is watched the morphology change of nanogel at light, pH and temperature.Fig. 2 is the pattern of nanogel after illumination 20 minutes, can find out that nanogel has slight change large, and innerly occurs a small amount of hollow.Fig. 3 is the pattern of nanogel in the situation that pH is 3, can find out that nanogel has obvious change large, and this is because the inner hydrophilic and hydrophobic changes in balance of gel causes.Fig. 4 is nanogel is the transmission electron microscope schematic diagram in the environment of 60 ℃ in temperature, can find out that nanogel size obviously becomes very little, probably in 70 nanometers left and right.
Embodiment 2
Preparation 2-nitrobenzyl methacrylic ester: 8.42 grams of 2-nitrobenzyl alcohol and 23.04 milliliters of triethylamines are dissolved in 100 milliliters of round-bottomed flasks that methylene dichloride is housed, and the frozen water that round-bottomed flask is placed on to 0 ℃ mixes in bath.The dichloromethane solution that is dissolved with methacrylic chloride is dropwise added drop-wise in round-bottomed flask.Whole reaction system nitrogen protection, the reaction times is 12 hours.After reaction finishes, reaction mixture is poured in separating funnel, by aqueous sodium hydroxide washes, washed twice.Organic layer is taken out from separating funnel, with anhydrous slufuric acid hydrogen sodium, be dried 12 hours.The crude product obtaining, with silica gel column chromatography purification (chromatographic solution is that volume ratio is normal hexane and the ethyl acetate mixture of 6:1).The product obtaining is weak yellow liquid.
Prepare polymkeric substance.By the ampoule vacuum-drying of 5 milliliters and be full of nitrogen.Add inside 0.3 gram of cuprous bromide, 9.42 grams of dimethylaminoethyl methacrylates and 4.42 grams of 2-nitrobenzyl methacrylic esters to join ampoule, with 6 milliliters of tetrahydrofuran (THF)s, dissolve.With syringe by 70 milligram 1, Isosorbide-5-Nitrae, 7,10,10-hexamethyl triethylene tetramine joins in system.Reaction mixture is processed after three times by " freezing-to bleed-to dissolve " method, reacted 20 hours in oil bath, temperature of reaction is 75 ℃.After reaction finishes, by product by being equipped with in the chromatography column of aluminium oxide nano particle to go out unnecessary catalyzer.Crude product is revolved to steaming, in normal hexane, precipitate, 40 ℃ of oven dry of vacuum, obtain amphipathic nature polyalcohol solid.
Self-assembly process.2 milligrams of amphipathic nature polyalcohols based on nitrobenzene derivative are dissolved in 1 milliliter of tetrahydrofuran (THF), add 0.2 milligram of Nile red simultaneously, with magnetic stirring apparatus, fully stir 3 minutes, Nile red and polymkeric substance are dissolved in completely and in tetrahydrofuran (THF), form uniform solution.Then by 1 ml deionized water, the speed with 1 microlitre per second is added drop-wise in solution in solution.After being added dropwise to complete, continue to stir the formation of 4 hours induction micellas.Finally add 8 ml deionized water, with the fixing micella of formation.Micellar solution is at least dialysed 24 hours in dialysis tubing, Nile red and the tetrahydrofuran (THF) of going out in solution, the micellar solution that can obtain loading Nile red.
Gelation process: get the polymer micelle solution preparing, two (2-iodine oxyethyl group) the ethane solution of 1,2-is dropwise joined in polymer micelle solution; Add-on is 10 % (volume ratio) of polymer micelle solution; This mixing solutions is placed at 70 ℃ and is reacted 36 hours; The gelating soln obtaining after reaction is dialysed with dialysis membrane, obtain pure nanogel solution.
The sign of release performance: in order to show that nanogel has the ability that responsiveness discharges, we select Nile red as guest molecule, thereby observe its release conditions.Fig. 5 is for loading the nanogel of Nile red, the variation schematic diagram of the fluorescent absorption intensity UV-irradiation asynchronism(-nization) of Nile red.Therefrom can find out, along with the growth of light application time, the fluorescence intensity of Nile red declines gradually, has showed its good release performance.Fig. 6 is the nanogel of the loading Nile red of preparation, the fluorescent absorption intensity variation with temperature schematic diagram of Nile red.Can find out the rising along with temperature, Nile red fluorescence intensity declines.Fig. 7 is the nanogel of the loading Nile red of preparation, and the variation schematic diagram of the fluorescent absorption intensity pH of Nile red, along with the decline of pH, causes the expansion of nanogel, thereby the Nile red loading is wherein discharged.
Embodiment 3
Preparation 2-nitrobenzyl methacrylic ester: 6.315 grams of 2-nitrobenzyl alcohol and 5.76 milliliters of triethylamines are dissolved in 100 milliliters of round-bottomed flasks that methylene dichloride is housed, and the frozen water that round-bottomed flask is placed on to 0 ℃ mixes in bath.The dichloromethane solution that is dissolved with methacrylic chloride is dropwise added drop-wise in round-bottomed flask.Whole reaction system nitrogen protection, the reaction times is 12 hours.After reaction finishes, reaction mixture is poured in separating funnel, by aqueous sodium hydroxide washes, washed twice.Organic layer is taken out from separating funnel, with anhydrous slufuric acid hydrogen sodium, be dried 12 hours.The crude product obtaining, with silica gel column chromatography purification (chromatographic solution is that volume ratio is normal hexane and the ethyl acetate mixture of 6:1).The product obtaining is weak yellow liquid.
Prepare polymkeric substance.By the ampoule vacuum-drying of 5 milliliters and be full of nitrogen.Add inside 0.225 gram of cuprous bromide, 7.065 grams of dimethylaminoethyl methacrylates and 3.315 grams of 2-nitrobenzyl methacrylic esters to join ampoule, with 4.5 milliliters of tetrahydrofuran (THF)s, dissolve.With syringe by 52.5 milligram 1, Isosorbide-5-Nitrae, 7,10,10-hexamethyl triethylene tetramine joins in system.Reaction mixture is processed after three times by " freezing-to bleed-to dissolve " method, reacted 24 hours in oil bath, temperature of reaction is 80 ℃.After reaction finishes, by product by being equipped with in the chromatography column of aluminium oxide nano particle to go out unnecessary catalyzer.Crude product is revolved to steaming, in normal hexane, precipitate, vacuum 40-80 ℃ of oven dry, obtains amphipathic nature polyalcohol solid.
Self-assembly process.2 milligrams of amphipathic nature polyalcohols based on nitrobenzene derivative are dissolved in 1 milliliter of tetrahydrofuran (THF), add 0.2 milligram of Nile red simultaneously, with magnetic stirring apparatus, fully stir 5-30 minute, Nile red and polymkeric substance are dissolved in completely and in tetrahydrofuran (THF), form uniform solution.Then 1 ml deionized water is slowly added drop-wise in solution in solution.After being added dropwise to complete, continue to stir the formation of 4-8 hour induction micella.Finally add 8 ml deionized water, with the fixing micella of formation.By micellar solution at least dialysis in dialysis tubing
12-24 hour, Nile red and the tetrahydrofuran (THF) of going out in solution, the micellar solution that can obtain loading Nile red.
Gelation process: get the polymer micelle solution preparing, two (2-iodine oxyethyl group) the ethane solution of 1,2-is dropwise joined in polymer micelle solution; Add-on is 20% (volume ratio) of polymer micelle solution; This mixing solutions is placed at 80 ℃ and is reacted 48 hours; The gelating soln obtaining after reaction is dialysed with dialysis membrane, obtain pure nanogel solution.
The sign of collaborative release effects: for the collaborative release effects of multiple incentive condition that further this nano gel system of checking has, we adopt the mode of multiple incentive condition combination that its effect is described.Fig. 8 is the nanogel of the loading Nile red of preparation, the variation schematic diagram of the burst size of Nile red under the collaborative stimulation of pH, illumination and temperature.From figure, can significantly find out that under two kinds or three kinds of stimulations, the releasability of nanogel has obtained very large improvement, effect is more obvious compared with single stimulation, thereby makes this nanogel have more wide using value controlling release field.
Claims (8)
1. a preparation method for multiple response nanogel, is characterized in that: its step comprises:
Step 1: preparation 2-nitrobenzyl methacrylic ester: by 2-nitrobenzyl alcohol and the triethylamine ratio mixing of 1:1-1:4 in molar ratio, be dissolved in the round-bottomed flask that methylene dichloride is housed, round-bottomed flask is placed on to frozen water to be mixed in bath, the dichloromethane solution that is dissolved with methacrylic chloride is slowly dropwise added drop-wise in round-bottomed flask, wherein, methacrylic chloride and 2-nitrobenzyl alcohol ratio are 1:1 ~ 5:1; Whole reaction system nitrogen protection, the reaction times is 6-12 hour; After reaction finishes, reaction mixture is poured in separating funnel, used alkaline aqueous solution washed twice; Organic layer is taken out from separating funnel, with the dry 12-24 hour of anhydrous slufuric acid hydrogen sodium, the crude product obtaining; With silica gel column chromatography, purify, described chromatographic solution is that volume ratio is normal hexane and the ethyl acetate mixture of 6:1; The product obtaining is weak yellow liquid, standby;
Step 2: prepare polymkeric substance: by ampoule vacuum-drying and be full of nitrogen, by cuprous bromide, dimethylaminoethyl methacrylate and 2-nitrobenzyl methacrylic ester in molar ratio for the ratio of 1:50:10-1:10:10 joins ampoule, mix, use the tetrahydrofuran (THF) of 2 ~ 10 times of above-mentioned cuprous bromide, dimethylaminoethyl methacrylate and 2-nitrobenzyl methacrylic ester three quality sums to dissolve; With syringe by 1, Isosorbide-5-Nitrae, 7,10,10-hexamethyl triethylene tetramine (0.1 to 1.0 mole) joins in system; Reaction mixture is processed after three times by " freezing-to bleed-to dissolve " method, in oil bath, react 6-24 hour, temperature of reaction is 60 ℃ to 80 ℃, after reaction finishes, product, by being equipped with in the chromatography column of aluminium oxide nano particle to go out unnecessary catalyzer, is revolved to steaming by crude product, in normal hexane, precipitate, 40 ℃ of oven dry of vacuum, obtain amphipathic nature polyalcohol;
Step 3: self-assembly process: the amphipathic nature polyalcohol that step 2 is obtained and tetrahydrofuran (THF) be take mass ratio as 1 to 1 mixing; After polymkeric substance fully dissolves, the speed by 1 ml deionized water with 1-3 microlitre per second is slowly added drop-wise in mixing solutions, and to induce the formation of micella, vigorous stirring continues 2-8 hour; 8ml deionized water is joined in mixing solutions, and stop stirring; Solution is placed in deionized water to dialysis at least 24 hours, obtains thering is light, the micellar solution of temperature and the triple responsivenesss of pH;
Step 4: gelation process: get the polymer micelle solution that step 3 obtains, two (2-iodine oxyethyl group) the ethane solution of 1,2-is dropwise joined in polymer micelle solution; Add-on is 5 % ~ 20 % of polymer micelle solution; This mixing solutions is placed at 60 ℃ and reacts 12-~ 24 hour; The gelating soln obtaining after reaction is dialysed with dialysis membrane, obtain pure nanogel solution.
2. the preparation method of multi-functional shell crosslinking nano gel according to claim 1, is characterized in that: in described step 1, the amount of being filled with of methylene dichloride is flask 20% ~ 80%.
3. the preparation method of multiple response nanogel according to claim 1, is characterized in that: in described step 1, described alkaline aqueous solution is selected aqueous sodium hydroxide solution or potassium hydroxide aqueous solution.
4. the preparation method of multiple response nanogel according to claim 1, is characterized in that: in " freezing-to bleed-to dissolve " method in described step 2, freezing temp is-10 ℃ ~-20 ℃ and is refrigerated to and freezes to be as the criterion, described in the time of bleeding be 10 ~ 30min.
5. the preparation method of multiple response nanogel according to claim 1, is characterized in that: the nanogel that described step 4 obtains is for having nucleocapsid structure; Its shell is the cross-linked layer with three-dimensional net structure, and moiety is the dimethylaminoethyl methacrylate with the quaternary ammonium salinization of hydrophilic portion, and its stratum nucleare is for having hydrophobic poly-2-nitrobenzyl methacrylic ester.
6. the preparation method of multiple response nanogel according to claim 1, is characterized in that: the temperature of reaction in oil bath in described step 2 is 75 ℃ to 80 ℃, reaction 20-24 hour.
7. the preparation method of multiple response nanogel according to claim 1, it is characterized in that: the nanogel that described method prepares is as the loading bin of nanoscale, good at normal temperature, neutrallty condition stability inferior, and can under pH, temperature and UV-irradiation, the guest molecule of loading be discharged.
8. the application of multiple response nanogel according to claim 1, is characterized in that: the nanogel that described method prepares has synergistic effect, can under different outfield incentive condition combinations, regulate the kinetics dispose procedure of guest molecule.
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| CN106589422A (en) * | 2016-12-09 | 2017-04-26 | 江苏苏博特新材料股份有限公司 | Dispersing agent and preparation method and application thereof in dispersion of nano titanium dioxide |
| CN106719617A (en) * | 2016-11-16 | 2017-05-31 | 武汉理工大学 | A kind of optical Response pesticide nano micella and preparation method thereof and purposes |
| CN110105508A (en) * | 2019-05-22 | 2019-08-09 | 北京化工大学 | A kind of preparation method, nanogel obtained and its application of aqueous photoresponse nanogel |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105601962A (en) * | 2016-01-20 | 2016-05-25 | 四川大学 | Metal nano-particle with stable internal cross-linked micelles, method for preparing metal nano-particle and application of metal nano-particle to catalysis |
| CN106719617A (en) * | 2016-11-16 | 2017-05-31 | 武汉理工大学 | A kind of optical Response pesticide nano micella and preparation method thereof and purposes |
| CN106589422A (en) * | 2016-12-09 | 2017-04-26 | 江苏苏博特新材料股份有限公司 | Dispersing agent and preparation method and application thereof in dispersion of nano titanium dioxide |
| CN110105508A (en) * | 2019-05-22 | 2019-08-09 | 北京化工大学 | A kind of preparation method, nanogel obtained and its application of aqueous photoresponse nanogel |
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