CN103205081A - Preparation method for temperature-sensitive chitosan-based polyelectrolyte composite micelle - Google Patents
Preparation method for temperature-sensitive chitosan-based polyelectrolyte composite micelle Download PDFInfo
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- CN103205081A CN103205081A CN2013100089720A CN201310008972A CN103205081A CN 103205081 A CN103205081 A CN 103205081A CN 2013100089720 A CN2013100089720 A CN 2013100089720A CN 201310008972 A CN201310008972 A CN 201310008972A CN 103205081 A CN103205081 A CN 103205081A
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Abstract
The invention discloses a preparation method for a temperature-sensitive chitosan-based polyelectrolyte composite micelle. The preparation method comprises the following concrete steps: dissolving chitosan in an acetic acid solution, adding a temperature-sensitive monomer N-isopropylacrylamide under stirring, adding a water-soluble initiator under the protection of nitrogen, carrying out a reaction for 4 to 12 h at a certain temperature, subjecting a reaction solution to acetone precipitation and pumping filtration and carrying out drying so as to obtain chitosan-grafted poly(N-isopropylacrylamide); and dissolving the synthesized graft copolymer in distilled water with a certain pH value, adding a certain proportion of an anionic polyelectrolyte solution under stirring and carrying out a reaction for 12 to 48 h. The temperature-sensitive chitosan-based polyelectrolyte composite micelle prepared in the invention has good biocompatibility, temperature sensitivity and stability performance and uniform particle size distribution; the preparation method is simple, and reaction conditions are mild; and the temperature-sensitive chitosan-based polyelectrolyte composite micelle has a potential application value in fields like drug delivery, micro-reactors and biosensors and is especially applicable to controllable loading and releasing of drugs.
Description
Technical field
The present invention relates to a kind of temperature sensitive polymer material, specifically introduced the preparation method of the chitosan-based polyelectrolyte composite micelle of a kind of temperature sensitivity, belong to functional high polymer material field.
Background technology
Polyelectrolyte compound (PEC) micella is the family macromolecule micella that the hydrophilic copolymers by two kinds of oppositely chargeds forms by electrostatic interaction.Wherein, the polyelectrolyte segment of oppositely charged is by the nuclear of electrostatic interaction formation composite micelle, and uncharged hydrophilic segment extends in the shell that the outside forms micella.Polyelectrolyte composite micelle by self-assembling method preparation is the novel high polymer matrix material that development in recent years is got up, and its preparation method is simple, no chemical pollution, raw material sources enrich and have potential use in fields such as biomedicine, environmental protection, adsorption of metal ions, new membrane material, Preparation of Catalyst.The polyelectrolyte composite micelle except the characteristics with traditional polymer micella, also has its special advantages as pharmaceutical carrier.On the one hand, polyelectrolyte composite micelle medicine carrying is in extensive range, both can pass through hydrophobic interaction load hydrophobic drug, can pass through static or hydrogen bond action load hydrophilic medicament again; On the other hand, the medicine carrying process is carried out in the aqueous solution substantially, has avoided the use of organic solvent, can eliminate the toxic side effect that dissolvent residual causes.
Chitosan (CS) is the alkaline polysaccharide of the unique existence of occurring in nature, has excellent biological compatibility, biodegradability, characteristic such as nontoxic.Contain abundant amino and hydroxyl on the chitosan molecule chain, can obtain containing the chitosan derivatives of different hydrophilic, hydrophobic property segments by certain chemical modification, increased its application in biomedical sector greatly.Amino on chitosan and the derivative molecular chain thereof is positively charged when low pH value, and it can form compound polyelectrolyte with electronegative polyelectrolyte and cause people's great interest as the research of drug-loading microcapsule in the aqueous solution.Yet relevant chitosan-based polyelectrolyte composite micelle is reported less as the research of pharmaceutical carrier so far.Chitosan-based polyelectrolyte composite micelle is except the advantage with two kinds of polyelectrolyte, nano material is because the superiority on the size in addition, the drug-carrying molecule passes through epithelium, conduct drugs to target site, heighten the effect of a treatment, reduce side effect, so this nano-micelle has great application potential at biomedicine field.
Existing polyelectrolyte composite micelle is as the report of pharmaceutical carrier in the document; (analogy continues bravely as the pharmaceutical carrier of N,O-Diacetylmuramidase to have reported composite micelle that casein grafting dextran and N,O-Diacetylmuramidase form as Jiang Ming etc.; Gao Gao; Yao Ping; Jiang Ming, SCI, 2008; 5,1027-1032.).Hsiue etc. have reported the di-block copolymer of polyoxyethylene glycol and polylysine and polyion complex compound carrier micelle (Wang, the C-H. that rhodamine B forms; Wang, W-T.; Hsiue, Gg-H. Biomaterials, 2009,30,3352-3358).This class polyelectrolyte composite micelle can't be realized the controllable release of medicine carrying as pharmaceutical carrier.Introduce temperature sensitive property group by the method for grafting and then can prepare the polyelectrolyte composite micelle with temperature sensitivity and biocompatibility in the chitosan polyelectrolyte, this composite micelle can realize that as pharmaceutical carrier controlled delivery of pharmaceutical agents discharges by the change of envrionment temperature.
Summary of the invention
The object of the present invention is to provide the preparation method of the chitosan-based polyelectrolyte composite micelle of a kind of temperature sensitivity.Be that main raw material prepares the temperature sensitivity chitose graft copolymer by radical polymerization with chitosan, temperature sensitive monomer at first, utilize the electrostatic interaction between the yin, yang ion to form the polyelectrolyte composite micelle then under certain condition, this method is simple in technological operation.
The concrete steps that realize the object of the invention employing are as follows:
(1) chitosan is dissolved in the acetum, is made into quality solubility and is 1 ~ 10% solution, stir 1 ~ 5 hour fully the dissolving back add the N-N-isopropylacrylamide, fully stir it mixed, vacuumize, logical nitrogen.Be that 0.5 ~ 5% water soluble starter joins in the above-mentioned solution with mass concentration, be warming up to 30～60 ℃ of reactions 4～12 hours.After reaction finished, (wherein the volume ratio of reaction solution and acetone was that 1:2～1:5), suction filtration obtains crude product, uses the methyl alcohol extracting again 12～48 hours, and drying obtains product in vacuum drying oven with acetone precipitation with reaction solution.
(2) under 25 ℃, it is in 4.0～6.5 the distilled water that the chitosan graft poly N-isopropyl acrylamide is dissolved in the pH value, be made into the solution that mass concentration is 0.1～2.0mg/mL, add natural anionic polyelectrolyte solution, the continuation stirring that mass concentration is 0.1～2.0mg/mL under the agitation condition and obtained the chitosan-based polyelectrolyte composite micelle of temperature sensitivity in 12～48 hours, wherein the mass ratio of graft copolymer and anionic polyelectrolyte is 1:0.1～1:9 in the composite micelle.
The mass percent concentration of acetum is 5 ~ 20% described in the step (1), and the mass ratio of chitosan and N-N-isopropylacrylamide is 1:0.5～1:5.
Water soluble starter described in the step (2) is a kind of in Potassium Persulphate, ammonium persulphate, Tetramethyl Ethylene Diamine, the ceric ammonium nitrate.
Used natural anionic polyelectrolyte is a kind of in Xylo-Mucine, sodium alginate, the pectin in the step (2).
Compared with prior art, temperature sensitivity polyelectrolyte composite micelle preparation method provided by the invention is simple, and the preparation condition gentleness is not used any organic solvent in the preparation process, has energy-conservation and characteristics environmental protection.
Temperature sensitivity polyelectrolyte composite micelle preparation method provided by the invention, raw material sources such as the natural polyelectrolyte of selecting for use and temperature sensitive monomer are abundant, low price, nontoxic, have excellent biological compatibility, biodegradability, the polymkeric substance that synthesize can satisfy the requirement of biomedical sector application.
The chitosan-based polyelectrolyte composite micelle of temperature sensitivity of the present invention's preparation has satisfactory stability, can preserve more than two months under 4 ℃ of temperature, and the particle diameter of nano-micelle is 100 ~ 450nm, even size distribution.
The chitosan-based polyelectrolyte composite micelle of temperature sensitivity of the present invention's preparation has temperature sensitivity, phase transition temperature is at 31 ~ 38 ℃, in fields such as drug conveying, microreactor and biosensors potential purposes is arranged, especially be fit to come drug loading by the control temperature, variation by envrionment conditions controllably discharges medicine then, thereby realizes controllable load and release to medicine.
Description of drawings
Fig. 1 is the transmission electron microscope photo of the chitosan-based polyelectrolyte composite micelle of temperature sensitivity.
Embodiment
Embodiment 1
The 0.6g chitosan is dissolved in the acetum of 40mL 5%, after treating fully to dissolve, adds 0.5g N-N-isopropylacrylamide, fully mix; Vacuumize, logical nitrogen adds initiator (the 0.1g ceric ammonium nitrate is dissolved in 10mL distilled water) under nitrogen protection, be warming up to 40 ℃, at the uniform velocity stirs reaction down 4 hours.Reaction solution poured in the acetone precipitate, suction filtration gets crude product, removes homopolymer in 24 hours with the methyl alcohol extracting again, and drying obtains chitosan graft poly N-isopropyl acrylamide multipolymer in vacuum drying oven.It is in 5.0 the distilled water that Xylo-Mucine, chitosan graft poly N-isopropyl acrylamide are dissolved in the pH value respectively, mass concentration such as being made into is the solution of 0.5mg/mL, under agitation condition, by mass ratio 5:5 graft copolymer solution is slowly joined in the carboxymethylcellulose sodium solution, continue stirring and obtained chitosan graft poly N-isopropyl acrylamide/sodium carboxymethyl cellulose polyelectrolyte composite micelle in 24 hours.
Fig. 1 is the projection electromicroscopic photograph of the chitosan-based polyelectrolyte composite micelle of this temperature sensitivity, and the median size that dynamic light scattering records composite micelle is 245nm, and the size distribution index is 1.12, and the critical phase transition temperature of this composite micelle is 31.8 ℃.
Embodiment 2
The 0.6g chitosan is dissolved in the acetum of 40mL 4%, after treating fully to dissolve, adds 1.0g N-N-isopropylacrylamide, fully mix; Vacuumize, logical nitrogen adds initiator (the 0.1g Potassium Persulphate is dissolved in 10mL distilled water) under nitrogen protection, be warming up to 60 ℃, at the uniform velocity stirs reaction down 8 hours.Reaction solution poured in the acetone precipitate, suction filtration gets crude product, removes homopolymer in 36 hours with the methyl alcohol extracting again, the dry multipolymer that obtains the chitosan graft poly N-isopropyl acrylamide in vacuum drying oven.It is in 6.0 the distilled water that sodium alginate, chitosan graft poly N-isopropyl acrylamide are dissolved in the pH value respectively, be made into the solution that mass concentration is 1mg/mL, under agitation condition, by mass ratio 3:7 graft copolymer solution is slowly joined in the sodium alginate soln, continue stirring and obtained chitosan graft poly N-isopropyl acrylamide/sodium alginate polyelectrolyte composite micelle in 24 hours.
The median size that dynamic light scattering records composite micelle is 278nm, and the size distribution index is 1.18, and the critical phase transition temperature of this composite micelle is 37.5 ℃.
Embodiment 3
The 0.6g chitosan is dissolved in the acetum of 40mL 10%, after treating fully to dissolve, adds 2.0g N-N-isopropylacrylamide, fully mix; Vacuumize, logical nitrogen adds initiator (the 0.1g Potassium Persulphate is dissolved in 10mL distilled water) under nitrogen protection, be warming up to 65 ℃, at the uniform velocity reacts 8 hours under the magnetic agitation.Reaction solution poured in the acetone precipitate, suction filtration gets crude product, removes homopolymer in 48 hours with the methyl alcohol extracting again, the dry multipolymer that obtains the chitosan graft poly N-isopropyl acrylamide in vacuum drying oven.It is in 6.0 distilled water that sodium alginate, synthetic graft copolymer are dissolved in the pH value respectively, be made into the solution that mass concentration is 1mg/mL, under agitation condition, by mass ratio 4:6 graft copolymer solution is slowly joined in the sodium alginate soln, continue stirring and obtained chitosan graft poly N-isopropyl acrylamide/sodium alginate polyelectrolyte composite micelle in 24 hours.
The median size that dynamic light scattering records composite micelle is 232nm, and the size distribution index is 1.13, and the critical phase transition temperature of this composite micelle is 36.8 ℃.
Claims (6)
1. according to the preparation method of the chitosan-based polyelectrolyte composite micelle of the described a kind of temperature sensitivity of claim 1, it is characterized in that comprising the steps:
(1) chitosan is dissolved in the acetum, be made into quality solubility and be 1 ~ 10% solution, stir and add temperature sensitivity monomer N-N-isopropylacrylamide after 1 ~ 5 hour, fully mix, vacuumize, logical nitrogen, be that 0.5 ~ 5% water soluble starter joins in the above-mentioned solution with mass concentration, be warming up to 30～60 ℃ of reactions 4～12 hours, (volume ratio of reaction solution and acetone is 1:2～1:5) with acetone precipitation with reaction solution, suction filtration obtains crude product, uses the methyl alcohol extracting again 12～48 hours, and drying obtains the chitosan graft poly N-isopropyl acrylamide in vacuum drying oven.
2.(2) under 25 ℃, it is in 4.0～6.5 the distilled water that the chitosan graft poly N-isopropyl acrylamide is dissolved in the pH value, be made into the solution that mass concentration is 0.1～2.0mg/mL, adding mass concentration under the agitation condition is the anionic polyelectrolyte solution of 0.1～2.0mg/mL, continue stirring and obtained the chitosan-based polyelectrolyte composite micelle of temperature sensitivity in 12～48 hours, wherein the mass ratio of graft copolymer and anionic polyelectrolyte is 1:0.1～1:9 in the composite micelle.
3. according to the preparation method of the chitosan-based polyelectrolyte composite micelle of the described a kind of temperature sensitivity of claim 1, the mass percent concentration that it is characterized in that acetum described in the step (1) is 5 ~ 20%, and the mass ratio of chitosan and N-N-isopropylacrylamide is 1:0.5～1:5.
4. according to the preparation method of the chitosan-based polyelectrolyte composite micelle of the described a kind of temperature sensitivity of claim 2, it is characterized in that water soluble starter in the step (2) is a kind of in Potassium Persulphate, ammonium persulphate, Tetramethyl Ethylene Diamine, the ceric ammonium nitrate.
5. according to the preparation method of the chitosan-based polyelectrolyte composite micelle of the described a kind of temperature sensitivity of claim 2, it is characterized in that anionic polyelectrolyte in the step (2) is a kind of in Xylo-Mucine, sodium alginate, the pectin.
6. according to the preparation method of the chitosan-based polyelectrolyte composite micelle of the described temperature sensitivity of claim 2, it is characterized in that the composite micelle of this method preparation has excellent biological compatibility and temperature sensitivity, stability is good, and size distribution is even.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103665393A (en) * | 2013-12-03 | 2014-03-26 | 江南大学 | Electrostatic interaction induced micelle preparation method |
| CN109731133A (en) * | 2019-02-01 | 2019-05-10 | 浙江大学 | A kind of antibacterial, anti-adhesive, the temperature sensitive chitosan gel rubber dressing of injection type and preparation method thereof |
| CN109851716A (en) * | 2019-01-30 | 2019-06-07 | 浙江大学 | A kind of water soluble chitosan and preparation method thereof with temperature sensitive properties |
| CN109964927A (en) * | 2019-04-04 | 2019-07-05 | 江南大学 | A kind of preparation method for the nano-antibacterial system that temperature/pH double-bang firecracker is answered |
| CN110055208A (en) * | 2019-02-27 | 2019-07-26 | 杭州妥爱沐医疗器械有限公司 | A kind of non-pancreatin digestion harvest cell culture processes based on temperature-sensitive hydrogel material |
| CN110098000A (en) * | 2019-05-13 | 2019-08-06 | 安徽升隆电气有限公司 | A kind of fire detector early warning composite material and preparation method |
| CN112023042A (en) * | 2020-09-09 | 2020-12-04 | 大连民族大学 | Photo-thermal and photodynamic cooperative treatment reagent and preparation method and application thereof |
| CN112442759A (en) * | 2020-12-03 | 2021-03-05 | 大连工业大学 | Pectin/quaternized chitosan composite fiber and preparation method and application thereof |
-
2013
- 2013-01-11 CN CN2013100089720A patent/CN103205081A/en active Pending
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| TING ZHANG,ET AL.: "Synthesis of thermo-sensitive CS-g-PNIPAM/CMC complex nanoparticles for controlled release of 5-FU", 《INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES》 * |
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103665393A (en) * | 2013-12-03 | 2014-03-26 | 江南大学 | Electrostatic interaction induced micelle preparation method |
| CN109851716A (en) * | 2019-01-30 | 2019-06-07 | 浙江大学 | A kind of water soluble chitosan and preparation method thereof with temperature sensitive properties |
| CN109851716B (en) * | 2019-01-30 | 2020-09-15 | 浙江大学 | Water-soluble chitosan with temperature sensitivity and preparation method thereof |
| CN109731133A (en) * | 2019-02-01 | 2019-05-10 | 浙江大学 | A kind of antibacterial, anti-adhesive, the temperature sensitive chitosan gel rubber dressing of injection type and preparation method thereof |
| CN110055208A (en) * | 2019-02-27 | 2019-07-26 | 杭州妥爱沐医疗器械有限公司 | A kind of non-pancreatin digestion harvest cell culture processes based on temperature-sensitive hydrogel material |
| CN109964927A (en) * | 2019-04-04 | 2019-07-05 | 江南大学 | A kind of preparation method for the nano-antibacterial system that temperature/pH double-bang firecracker is answered |
| CN109964927B (en) * | 2019-04-04 | 2021-12-03 | 江南大学 | Preparation method of temperature/pH dual-response nano antibacterial system |
| CN110098000A (en) * | 2019-05-13 | 2019-08-06 | 安徽升隆电气有限公司 | A kind of fire detector early warning composite material and preparation method |
| CN110098000B (en) * | 2019-05-13 | 2020-12-01 | 宝应县金运开发有限公司 | Early warning composite material for fire detector and preparation method thereof |
| CN112023042A (en) * | 2020-09-09 | 2020-12-04 | 大连民族大学 | Photo-thermal and photodynamic cooperative treatment reagent and preparation method and application thereof |
| CN112442759A (en) * | 2020-12-03 | 2021-03-05 | 大连工业大学 | Pectin/quaternized chitosan composite fiber and preparation method and application thereof |
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Application publication date: 20130717 |