CN108503860A - The preparation method and application of the reversible hydrogel of temperature-responsive - Google Patents
The preparation method and application of the reversible hydrogel of temperature-responsive Download PDFInfo
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Abstract
The present invention provides a kind of preparation method and applications of the reversible hydrogel of temperature-responsive, belong to technical field of biological material, the reversible hydrogel variation with temperature of the temperature-responsive realizes reversible " collosol and gel " transformation, aerogel dressing and injection hydrogel are can be used as, while realizing the load to different pharmaceutical and controlled release.The preparation method of the reversible hydrogel of the temperature-responsive, includes the following steps：The aqueous solution for preparing the polypeptide that can be self-assembly of one-dimensional nano structure, the concentration of polypeptide is more than its self assembly critical concentration in solution, places, its is made to complete self assembly；Poly- N N-isopropylacrylamides are dissolved in Tris buffer solutions, places overnight, stirs to get poly- N N-isopropylacrylamides solution；The polypeptide solution that above-mentioned self assembly is completed is mixed with above-mentioned poly- N N-isopropylacrylamides solution at 30 DEG C, obtains final state solution, when final state solution temperature >=32 DEG C, obtains hydrogel.
Description
Technical field
The present invention relates to the preparation method of technical field of biological material more particularly to a kind of reversible hydrogel of temperature-responsive and answer
With.
Background technology
Intelligent aqueous gel has the characteristic that response is generated to extraneous environmental stimulus, in function " switch " material, medicament slow release
Material, dressing and injection aquagel etc. have important application, are the research hotspots of current biological Material Field.
Wherein, temperature sensitive type water gel refers to the hydrogel that system volume or phase behavior etc. change with temperature, and is made
There is unique advantage for Thermosensitive Material Used for Controlled Releasing of Medicine.For example, hydrogel may be at contraction state when less than human body temperature, well
It realizes the embedding to drug, and is in solvent swelling state in human body temperature, the drug molecule of embedding can be freely spread to human body
Tissue, realizes effective controlled release.Polymer molecule is assembled when most of temperature sensitive type water gels are based on temperature change
The variation of gel volume or intensity is realized in the variation of state, and is generally difficult to realize the reversible transition of " sol-gel ".
Responsive to temperature type polymer " poly-N-isopropyl acrylamide " (PNIPAM) is thermal shrinkage type temperature sensitive polymer, intramolecular
Not only contain hydrophobic grouping but also have hydrophilic radical.When temperature is lower than minimum critical transition temperature (LCST), what is mainly worked is
Active force between amide group and hydrone keeps high molecular solvent swelling state.With temperature when being increased beyond LCST, high score
Hydrophobic effect enhancing between sub internal and macromolecule, this makes the combination of hydrone and macromolecular chain be destroyed, hydrone quilt
Discharge is to generate phase transformation.But PNIPAM solution itself can not form hydrogel with temperature raising, it is even more impossible to realize " colloidal sol-
The reversible transition of gel ".Polypeptide one-dimensional nano structure is then formed due to its amino acid, has good biocompatibility and relatively low
Toxicity, this structure can provide surface group or hydrophobic interior cavity is combined and loads to drug molecule, be drug
The ideal material of controlled release application, but it does not have temperature-responsive.
Invention content
The purpose of the present invention is to provide a kind of preparation method and applications of the reversible hydrogel of temperature-responsive.It is different by N-
Propylacrylamide solution is mixed to get intercrossed network type binary complex system with self assembly polypeptide solution, by the former temperature
The drug loading and release performance of response and the latter effectively combine, and successfully preparing variation with temperature has reversible " colloidal sol-
Gel " changes the material of performance, can be used as aerogel dressing and injection aquagel, realizes the load to drug and controlled release.
One aspect of the present invention provides a kind of preparation method of the reversible hydrogel of temperature-responsive, includes the following steps：
The aqueous solution for preparing the polypeptide that can be self-assembly of one-dimensional nano structure, in solution the concentration of polypeptide be more than its from
Critical concentration is assembled, is placed, it is made to complete self assembly；
Poly-N-isopropyl acrylamide is dissolved in Tris buffer solutions, places overnight, stirs to get poly-N-isopropyl propylene
Amide solution, a concentration of 5-40mg/mL；
Polypeptide solution that above-mentioned self assembly is completed and above-mentioned poly-N-isopropyl acrylamide solution at 20-30 DEG C according to
Following compounding condition is mixed, and obtains final state solution, compounding condition is：The a concentration of of polypeptide is more than its self assembly in final state solution
Critical concentration and evenly dispersed concentration is kept simultaneously, a concentration of 1.0- of poly-N-isopropyl acrylamide in final state solution
40mg/mL；
Final state solution temperature is adjusted, when final state solution temperature >=32 DEG C, obtains hydrogel；32 DEG C of final state solution temperature ＜
When, obtain colloidal sol.
Preferably, the polypeptide that can be self-assembly of one-dimensional nano structure is selected from I3K、A6K、I3CGK、Nap-
FFGPLGLARKRK、V3G3I3A3K3、K3G3A3V3I3In one kind.
Another aspect of the present invention provides the reversible hydrogel of temperature-responsive that the above method is prepared, and the temperature is rung
The reversible hydrogel of answering property varies with temperature the reversible transition that hydrogel and colloidal sol may be implemented.
Further aspect of the present invention provides application of the reversible hydrogel of above-mentioned temperature-responsive in drug loading and controlled release,
Include the following steps：
Drug molecule is added in self assembly polypeptide solution or the final state solution for completing self assembly, stirring places and is more than 2
Hour, the mixed solution of carrying medicament is obtained, the temperature-responsive that mixed solution is warming up to 32-80 DEG C of formation carrying medicament is reversible
The reversible hydrogel of the temperature-responsive of above-mentioned carrying medicament is put into 32-80 DEG C of pure water or buffer solution by hydrogel, is carried out
Medicine controlled releasing.
Further aspect of the present invention provides the reversible hydrogel of above-mentioned temperature-responsive in preparing intelligent aqueous gel dressing
Using.
Further aspect of the present invention provides the reversible hydrogel of above-mentioned temperature-responsive answering in preparing injection aquagel
With.
The positive and advantageous effect of the present invention is：
(1) method of the invention obtains one-dimensional nano structure and poly-N-isopropyl acryloyl by self assembly self-assembling polypeptide
Realize that the preparation of the reversible hydrogel of temperature-responsive, method are simple easily real between amine (PNIPAM) by the method for physical crosslinking
It applies；
(2) available self assembly peptide molecule type is more in preparation method of the invention, derives from a wealth of sources, as long as being capable of group
Dress is long one-dimentional structure such as nanofiber, nanotube, nanobelt；
(3) the reversible hydrogel of temperature-responsive of the invention is capable of providing hydrophobic environment or surface group for drug
Interaction, to realize the high-efficient carrier of drug, has temperature sensitivity, can carry out the controlled release of drug；
(4) phase transition temperature of the reversible hydrogel of temperature-responsive of the invention can pass through human body skin near body temperature
Skin or tissue temperature realize that heating forms the process of hydrogel, can also be by the Physical temperature-lowerings such as ice compress mode simply and easily
Realize that cooling restores the process of solution state, so as to be used for intelligent aqueous gel dressing or injection aquagel.
Description of the drawings
The I that Fig. 1 is provided by the embodiment of the present invention3Atomic force microscope (AFM) shape appearance figure of K fibers；
The I that Fig. 2 is provided by the embodiment of the present invention3The photograph of K/PNIPAM mixed solutions different conditions in 30 DEG C and 37 DEG C
Piece；
The I for the reversible hydrogel load adriamycin (DOX) of temperature-responsive that Fig. 3 is provided by the embodiment of the present invention3K fibers
Atomic force microscope (AFM) shape appearance figure；
Fig. 4 DOX burst size versus time curves at 37 DEG C for the reversible hydrogel of temperature-responsive of the invention.
Specific implementation mode
The technical scheme in the embodiments of the invention will be clearly and completely described below, it is clear that described implementation
Example is only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, this field is common
The every other embodiment that technical staff is obtained without making creative work belongs to the model that the present invention protects
It encloses.
An embodiment of the present invention provides a kind of preparation methods of the reversible hydrogel of temperature-responsive, including：
S1：The aqueous solution for preparing the polypeptide that can be self-assembly of one-dimensional nano structure, the concentration of polypeptide is big in aqueous solution
It in its self assembly critical concentration, places, it is made to complete self assembly.
Self assembly self-assembling polypeptide is at one-dimensional nano structure in this step, since its amino acid forms, has raw well
Object compatibility and low toxicity, this structure can provide surface group again or hydrophobic interior cavity ties drug molecule
It closes and load, this step passes through with relatively the polypeptide of assembling ability is self-assembly of long Nanowire on a certain concentration by force
The assemblies structure such as dimension, nanotube, it is to be understood that the peptide molecule of one-dimensional nano structure can be formed in optional model
It encloses, it is preferred that such as I3K、A6K、I3CGK、Nap-FFGPLGLARKRK、V3G3I3A3K3、K3G3A3V3I3Deng.
S2：Poly-N-isopropyl acrylamide is dissolved in Tris buffer solutions, places overnight, stirs to obtain poly-N-isopropyl propylene
Amide solution, a concentration of 5-40mg/mL.
Poly-N-isopropyl acrylamide (PNIPAM) has temperature sensitivity phase behavior, when low temperature molten in water in this step
Swollen, 32 DEG C or more cohesions are precipitated.
S3：The polypeptide solution that above-mentioned self assembly is completed is with above-mentioned poly-N-isopropyl acrylamide solution at 20-30 DEG C
It is mixed according to following compounding condition, obtains final state solution, compounding condition is：The a concentration of of polypeptide is more than it certainly in final state solution
It assembles critical concentration and keeps evenly dispersed concentration simultaneously, a concentration of 1.0- of poly-N-isopropyl acrylamide in final state solution
40mg/mL。
In in this step, pass through the method for physical crosslinking between one-dimensional nano structure and PNIPAM that self-assembling polypeptide is formed
Realize the preparation of the reversible hydrogel of temperature-responsive.
S4:Final state solution temperature is adjusted, when final state solution temperature >=32 DEG C, obtains hydrogel；Final state solution temperature ＜ 32
DEG C when, obtain colloidal sol.
In this step, final state solution is warming up to 32 DEG C or more, and solution loses flowability, and can form hydrogel, be less than
Mobility is replied at 32 DEG C.And still mobility is good after self assembly polypeptide solution single under this concentration or the heating of PNIPAM solution
It is good, hydrogel cannot be formed.
Another embodiment of the present invention provides the reversible hydrogel of temperature-responsive that the above method is prepared.
Yet another embodiment of the invention provides the reversible hydrogel of above-mentioned temperature-responsive answering in drug loading and controlled release
With including the following steps：
Drug molecule is added in self assembly polypeptide solution or the final state solution for completing self assembly, stirring places and is more than 2
Hour, the mixed solution of carrying medicament is obtained, the temperature-responsive that mixed solution is warming up to 32-80 DEG C of formation carrying medicament is reversible
The reversible hydrogel of the temperature-responsive of above-mentioned carrying medicament is put into 32-80 DEG C of pure water or buffer solution by hydrogel, is carried out
Medicine controlled releasing.In the present embodiment, due to the presence of self-assembling polypeptide nanostructure, a large amount of drug binding site is provided, it can
To conveniently realize load and the control release to different pharmaceutical.Above-mentioned hydrogel can form water-setting in >=32 DEG C of range
Glue, the drug effect based on drug, preferred temperature range is at 32-40 DEG C.
Yet another embodiment of the invention provides the reversible hydrogel of above-mentioned temperature-responsive in preparing intelligent aqueous gel dressing
Application.In the present embodiment, as aerogel dressing, temperature-responsive hydrogel of the invention not only have rich in moisture, can
Promote autolyzed debridement, absorbs wound fluid, keep surface of a wound moistening, improve the general water such as wound granulation regeneration life ability
The advantages of gel dressing, and removing can make gel conversion be the spontaneous stream of colloidal sol of flowability by temperature change when dressing
It loses, the adhesion surface of a wound, avoid the secondary damage of the surface of a wound and reduces pain.
Yet another embodiment of the invention provides the reversible hydrogel of above-mentioned temperature-responsive in preparing injection aquagel
Using.In the present embodiment, the defect of arbitrary shape can be filled using its initial collosol state as injection aquagel,
The temperature realization of tissue itself can be utilized to form hydrogel to the heating of system when implantation, be not required to surgical operation.
In order to become apparent from the preparation side for introducing the reversible hydrogel of temperature-responsive that the embodiment of the present invention is provided in detail
Method and application, illustrate below with reference to specific embodiment.
Embodiment
Compound concentration is that 10.0mM (is more than I3The critical self assembly critical concentrations of K) I3K aqueous solutions, aqueous solution pH be 4.5 ±
0.5, place 1 day or more, so that it is completed self assembly, the nanofibre-like structure of self assembly is as shown in Figure 1；
Poly-N-isopropyl acrylamide (PNIPAM) is dissolved in Tris buffer solutions, a concentration of 20mg/mL is placed overnight,
Stir to obtain poly-N-isopropyl acrylamide solution.
The I that above-mentioned self assembly is completed3K solution is mixed in 30 DEG C of volumetrics with above-mentioned poly-N-isopropyl acrylamide solution
Close, stir 10min, be uniformly mixed, obtain final state solution, in final state solution polypeptide it is a concentration of be more than its self assembly critical concentration and
While evenly dispersed concentration is kept, the concentration of poly-N-isopropyl acrylamide is more than 1.0mg/mL in final state solution.
Final state solution temperature is adjusted, final state solution temperature >=32 DEG C or more obtain the reversible hydrogel of temperature-responsive；Final state is molten
When 32 DEG C of liquid temperature ＜, the colloidal sol of the reversible hydrogel of temperature-responsive is obtained, as shown in Fig. 2, and single polypeptide solution and single
Good fluidity is all kept before and after the heating of PNIPAM solution, hydrogel cannot be formed.
Carry medicine：Using adriamycin DOX as model drug, final state solution is added in 0.05-2.0mg/mLDOX, stirring makes fully
Dissolving is placed and is more than 2 hours, makes drug molecule and I3K fibers fully act on, and load on fiber, obtain the mixed of carrying medicament
Close solution, the I of carrying medicament3K fibers are as shown in Figure 3.
Drug release：The temperature-responsive that the mixed solution of carrying medicament is warming up to 37 DEG C of formation carrying medicaments can be against the current
The reversible hydrogel of the temperature-responsive of above-mentioned carrying medicament is put into 37 DEG C of pure water or buffer solution by gel, is placed certain
200 μ L supernatant liquors are taken out after time, measure DOX concentration therein, calculate burst size, while rejoining into mixed solution
200 μ L pure water；This process is repeated, the DOX amount versus time curves of release are as shown in Figure 4.It can be seen that by Fig. 4, this hair
Efficiently controllable release may be implemented in the drug molecule of bright reversible " sol-gel " system load under gel state.
Claims (6)
1. the preparation method of the reversible hydrogel of temperature-responsive, which is characterized in that include the following steps：
The aqueous solution for preparing the polypeptide that can be self-assembly of one-dimensional nano structure, the concentration of polypeptide is more than its self assembly in solution
Critical concentration is placed, it is made to complete self assembly；
Poly-N-isopropyl acrylamide is dissolved in Tris buffer solutions, places overnight, stirs to get poly-N-isopropyl acrylamide
Solution, a concentration of 5-40mg/mL；
The polypeptide solution that above-mentioned self assembly is completed is with above-mentioned poly-N-isopropyl acrylamide solution according to as follows at 20-30 DEG C
Compounding condition is mixed, and final state solution is obtained, and compounding condition is：Polypeptide is a concentration of critical more than its self assembly in final state solution
Concentration and evenly dispersed concentration is kept simultaneously, a concentration of 1.0-40mg/mL of poly-N-isopropyl acrylamide in final state solution；
Final state solution temperature is adjusted, when final state solution temperature >=32 DEG C, obtains hydrogel；When 32 DEG C of final state solution temperature ＜, obtain
To colloidal sol.
2. the preparation method of the reversible hydrogel of temperature-responsive according to claim 1, which is characterized in that described to can oneself
The polypeptide that assembling forms one-dimensional nano structure is selected from I3K、A6K、I3CGK、Nap-FFGPLGLARKRK、V3G3I3A3K3、
K3G3A3V3I3In one kind.
3. the reversible hydrogel of temperature-responsive that preparation method as claimed in claim 1 or 2 is prepared, which is characterized in that institute
It states the reversible hydrogel of temperature-responsive and varies with temperature the reversible transition for carrying out hydrogel and colloidal sol.
4. application of the reversible hydrogel of temperature-responsive in drug loading and controlled release described in claim 3, which is characterized in that
Include the following steps：
Drug molecule is added in self assembly polypeptide solution or the final state solution for completing self assembly, stirring, is placed small more than 2
When, the mixed solution of carrying medicament is obtained, the temperature-responsive that mixed solution is warming up to 32-80 DEG C of formation carrying medicament can be against the current
The reversible hydrogel of the temperature-responsive of above-mentioned carrying medicament is put into 32-80 DEG C of pure water or buffer solution by gel, carries out medicine
Object controlled release.
5. application of the reversible hydrogel of temperature-responsive in preparing intelligent aqueous gel dressing described in claim 3.
6. application of the reversible hydrogel of temperature-responsive in preparing injection aquagel described in claim 3.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111995769A (en) * | 2020-07-30 | 2020-11-27 | 东南大学 | Controllable dual-temperature-sensitive hydrogel and preparation method thereof |
| CN112773930A (en) * | 2021-02-02 | 2021-05-11 | 福州大学 | Injectable temperature-controllable antibacterial hydrogel |
| CN113384743A (en) * | 2021-07-09 | 2021-09-14 | 吉林省国大生物工程有限公司 | Preparation method of temperature-sensitive dressing with tissue repair promoting and antibacterial functions |
| US11690935B2 (en) | 2020-01-10 | 2023-07-04 | National Chiao Tung University | Thermosensitive peptide hydrogel |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US11690935B2 (en) | 2020-01-10 | 2023-07-04 | National Chiao Tung University | Thermosensitive peptide hydrogel |
| CN111995769A (en) * | 2020-07-30 | 2020-11-27 | 东南大学 | Controllable dual-temperature-sensitive hydrogel and preparation method thereof |
| CN111995769B (en) * | 2020-07-30 | 2022-06-10 | 东南大学 | Controllable dual-temperature-sensitive hydrogel and preparation method thereof |
| CN112773930A (en) * | 2021-02-02 | 2021-05-11 | 福州大学 | Injectable temperature-controllable antibacterial hydrogel |
| CN113384743A (en) * | 2021-07-09 | 2021-09-14 | 吉林省国大生物工程有限公司 | Preparation method of temperature-sensitive dressing with tissue repair promoting and antibacterial functions |
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