CN108503860B - Preparation method and application of temperature-responsive reversible hydrogel - Google Patents

Preparation method and application of temperature-responsive reversible hydrogel Download PDF

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CN108503860B
CN108503860B CN201810373751.6A CN201810373751A CN108503860B CN 108503860 B CN108503860 B CN 108503860B CN 201810373751 A CN201810373751 A CN 201810373751A CN 108503860 B CN108503860 B CN 108503860B
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曹美文
王瑜
沈阳
王生杰
夏永清
吕建仁
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China University of Petroleum East China
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Abstract

The invention provides a preparation method and application of a temperature-responsive reversible hydrogel, belonging to the field of biological materials. The preparation method of the temperature-responsive reversible hydrogel comprises the following steps: preparing an aqueous solution of polypeptide capable of forming a one-dimensional nanostructure through self-assembly, wherein the concentration of the polypeptide in the aqueous solution is greater than the self-assembly critical concentration of the polypeptide, and placing the aqueous solution to complete self-assembly; dissolving poly N-isopropyl acrylamide in Tris buffer solution, standing overnight, and stirring to obtain poly N-isopropyl acrylamide solution; and (3) mixing the polypeptide solution after the self-assembly with the poly-N-isopropylacrylamide solution at the temperature of 30 ℃ to obtain a final solution, wherein the hydrogel is obtained when the temperature of the final solution is more than or equal to 32 ℃.

Description

Preparation method and application of temperature-responsive reversible hydrogel
Technical Field
The invention relates to the field of biological materials, in particular to a preparation method and application of a temperature-responsive reversible hydrogel.
Background
The intelligent hydrogel has the characteristic of response to external environment stimulation, has important application in the aspects of functional 'switch' materials, drug slow-release materials, dressings, injectable hydrogel and the like, and is a research hotspot in the field of current biomaterials.
The temperature-sensitive hydrogel is hydrogel with system volume or phase behavior changing with temperature, and has unique advantages as drug sustained-release material. For example, the hydrogel can be in a contracted state at a temperature lower than the temperature of a human body, so that the drug can be well embedded, and can be in a swollen state at the temperature of the human body, so that the embedded drug molecules can be freely diffused to the tissues of the human body, and effective controllable release can be realized. Most temperature-sensitive hydrogels achieve a change in gel volume or strength based on a change in the aggregation state of polymer molecules upon a change in temperature, and it is generally difficult to achieve a reversible "sol-gel" transition.
The temperature sensitive polymer 'poly-N-isopropylacrylamide' (PNIPAM) is a thermal shrinkage type temperature sensitive polymer, and a molecule contains a hydrophobic group and a hydrophilic group, when the temperature is lower than the lowest critical transition temperature (L CST), the temperature sensitive polymer mainly plays a role in acting force between an amide group and water molecules, the swelling state of the high molecules is kept, when the temperature rises to exceed L CST, the hydrophobic effect between the interior of the high molecules and the swelling state of the high molecules is enhanced, so that the combination of the water molecules and the high molecular chains is destroyed, and the water molecules are discharged to generate phase change.
Disclosure of Invention
The invention aims to provide a preparation method and application of a temperature-responsive reversible hydrogel. An interpenetrating network type binary composite system is obtained by mixing an N-isopropyl acrylamide solution and a self-assembly polypeptide solution, the temperature responsiveness of the N-isopropyl acrylamide solution and the drug loading and releasing performance of the self-assembly polypeptide solution are effectively combined, and the material with reversible sol-gel conversion performance along with the change of temperature is successfully prepared, can be used as a hydrogel dressing and an injectable hydrogel, and realizes the loading and controlled release of drugs.
The invention provides a preparation method of a temperature-responsive reversible hydrogel, which comprises the following steps:
preparing an aqueous solution of polypeptide capable of forming a one-dimensional nanostructure through self-assembly, wherein the concentration of the polypeptide in the aqueous solution is greater than the self-assembly critical concentration of the polypeptide, and placing the aqueous solution to complete self-assembly;
dissolving poly N-isopropyl acrylamide in a Tris buffer solution, standing overnight, and stirring to obtain a poly N-isopropyl acrylamide solution with the concentration of 5-40mg/m L;
mixing the polypeptide solution after the self-assembly and the poly-N-isopropylacrylamide solution at the temperature of between 20 and 30 ℃ according to the following compounding conditions to obtain a final solution, wherein the concentration of the polypeptide in the final solution is greater than the self-assembly critical concentration of the polypeptide and the concentration of the polypeptide in the final solution is kept to be uniformly dispersed, and the concentration of the poly-N-isopropylacrylamide in the final solution is between 1.0 and 40mg/m L;
adjusting the temperature of the final solution to obtain hydrogel when the temperature of the final solution is more than or equal to 32 ℃; when the temperature of the final state solution is less than 32 ℃, the sol is obtained.
Preferably, the polypeptide capable of self-assembling to form a one-dimensional nanostructure is selected from I3K、A6K、I3CGK、Nap-FFGPLGLARKRK、V3G3I3A3K3、K3G3A3V3I3One kind of (1).
The invention also provides the temperature-responsive reversible hydrogel prepared by the method, and the temperature-responsive reversible hydrogel can realize reversible transformation between the hydrogel and the sol along with temperature change.
In another aspect, the present invention provides an application of the reversible temperature-responsive hydrogel in drug loading and controlled release, comprising the following steps:
adding drug molecules into the self-assembled polypeptide solution or the final solution which is subjected to self-assembly, stirring, standing for more than 2 hours to obtain a drug-loaded mixed solution, heating the mixed solution to 32-80 ℃ to form drug-loaded temperature-responsive reversible hydrogel, and placing the drug-loaded temperature-responsive reversible hydrogel into pure water or buffer solution at 32-80 ℃ to perform drug controlled release.
In another aspect, the invention provides an application of the temperature-responsive reversible hydrogel in preparation of an intelligent hydrogel dressing.
In a further aspect, the present invention provides the use of the above temperature-responsive reversible hydrogel in the preparation of an injectable hydrogel.
The invention has the positive and beneficial effects that:
(1) according to the method, the preparation of the reversible hydrogel with temperature responsiveness is realized by a physical crosslinking method between the one-dimensional nanostructure obtained by self-assembly of the self-assembly polypeptide and the poly N-isopropylacrylamide (PNIPAM), and the method is simple and easy to implement;
(2) the self-assembly polypeptide molecules which can be selected in the preparation method have various types and wide sources, and can be assembled into long one-dimensional structures such as nano fibers, nano tubes, nano belts and the like;
(3) the temperature-responsive reversible hydrogel can provide a hydrophobic environment or surface groups for interaction of drugs, so that efficient loading of the drugs is realized, the temperature sensitivity is realized, and controlled release of the drugs can be realized;
(4) the phase transition temperature of the temperature-responsive reversible hydrogel is near body temperature, the process of heating to form the hydrogel can be realized through the temperature of human skin or tissues, and the process of cooling to recover the solution state can be simply and conveniently realized through physical cooling modes such as ice compress and the like, so that the temperature-responsive reversible hydrogel can be used for intelligent hydrogel dressings or injectable hydrogels.
Drawings
FIG. 1 shows a schematic diagram of a circuit diagram I3Atomic Force Microscopy (AFM) topography for K fibers;
FIG. 2 shows a schematic diagram of a circuit diagram I3Photographs of the K/PNIPAM mixed solution at different states at 30 ℃ and 37 ℃;
FIG. 3 shows temperature-responsive reversible hydrogel Doxorubicin (DOX) -loaded I provided by an embodiment of the present invention3Atomic Force Microscopy (AFM) topography for K fibers;
FIG. 4 is a graph showing the change in DOX release amount at 37 ℃ over time for the temperature-responsive reversible hydrogel of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The embodiment of the invention provides a preparation method of a temperature-responsive reversible hydrogel, which comprises the following steps:
s1: preparing aqueous solution of polypeptide capable of self-assembling to form a one-dimensional nano structure, wherein the concentration of the polypeptide in the aqueous solution is greater than the self-assembling critical concentration, and placing the aqueous solution to complete self-assembly.
The polypeptide self-assembled in the step is self-assembled into a one-dimensional nano structure, the structure has good biocompatibility and lower toxicity due to the amino acid composition, the structure can provide surface groups or hydrophobic internal cavities to combine and load drug molecules, the polypeptide with strong assembly capacity is self-assembled above a certain concentration to form long assembly structures such as nano fibers, nano tubes and the like, and the polypeptide molecules capable of forming the one-dimensional nano structure can be understood to be in an optional range, preferably, such as I3K、A6K、I3CGK、Nap-FFGPLGLARKRK、V3G3I3A3K3、K3G3A3V3I3And the like.
S2, dissolving the poly-N-isopropylacrylamide in a Tris buffer solution, standing overnight, and stirring to obtain a poly-N-isopropylacrylamide solution with the concentration of 5-40mg/m L.
In the step, the poly-N-isopropyl acrylamide (PNIPAM) has temperature sensitive phase behavior, swells in water at low temperature and is coagulated and separated out at the temperature of more than 32 ℃.
And S3, mixing the polypeptide solution after the self-assembly and the poly-N-isopropylacrylamide solution at the temperature of between 20 and 30 ℃ according to the following compounding conditions to obtain a final solution, wherein the compounding conditions are that the concentration of the polypeptide in the final solution is greater than the self-assembly critical concentration of the polypeptide and the polypeptide concentration is uniformly dispersed, and the concentration of the poly-N-isopropylacrylamide in the final solution is 1.0 to 40mg/m L.
In the step, the preparation of the temperature-responsive reversible hydrogel is realized by a physical crosslinking method between the one-dimensional nanostructure formed by polypeptide self-assembly and the PNIPAM.
S4, adjusting the temperature of the final solution to obtain hydrogel when the temperature of the final solution is more than or equal to 32 ℃; when the temperature of the final state solution is less than 32 ℃, the sol is obtained.
In the step, the final solution is heated to above 32 ℃, the solution loses fluidity and can form hydrogel, and the fluidity is recovered when the temperature is lower than 32 ℃. And the single self-assembly polypeptide solution or PNIPAM solution at the concentration still has good fluidity after being heated, and can not form hydrogel.
Another embodiment of the present invention provides a temperature-responsive reversible hydrogel prepared by the above method.
The invention further provides an application of the temperature-responsive reversible hydrogel in drug loading and controlled release, which comprises the following steps:
adding drug molecules into the self-assembled polypeptide solution or the final solution which is subjected to self-assembly, stirring, standing for more than 2 hours to obtain a drug-loaded mixed solution, heating the mixed solution to 32-80 ℃ to form drug-loaded temperature-responsive reversible hydrogel, and placing the drug-loaded temperature-responsive reversible hydrogel into pure water or buffer solution at 32-80 ℃ to perform drug controlled release. In the embodiment, due to the existence of the polypeptide self-assembly nano structure, a large number of drug binding sites are provided, and loading and controlled release of different drugs can be conveniently realized. The hydrogel can form hydrogel at a temperature of 32 ℃ or higher, and the preferred temperature range is 32-40 ℃ based on the drug effect of the drug.
The invention further provides application of the temperature-responsive reversible hydrogel in preparation of an intelligent hydrogel dressing. In the embodiment, as the hydrogel dressing, the temperature-responsive hydrogel disclosed by the invention has the advantages of being rich in water, capable of promoting autolysis debridement, absorbing wound exudate, keeping the wound moist, improving regeneration capacity of wound granulation tissues and the like of a common hydrogel dressing, and can be used for converting gel into flowable sol to spontaneously run off through temperature change when the dressing is removed, so that the wound is not adhered, secondary damage to the wound is avoided, and pain is reduced.
In a further embodiment of the present invention, there is provided a use of the above-described reversible temperature-responsive hydrogel for the preparation of an injectable hydrogel. In this embodiment, as an injectable hydrogel, a defect of any shape can be filled using its initial sol state, and the temperature of the body tissue itself can be used to heat the system to form a hydrogel during implantation without the need for surgical operations.
In order to more clearly and specifically describe the preparation method and the application of the temperature-responsive reversible hydrogel provided by the embodiments of the present invention, the following description will be made with reference to specific embodiments.
Examples
The preparation concentration is 10.0mM (more than I)3K critical self-assembly critical concentration) of3K aqueous solution, the pH of which is 4.5 +/-0.5, is placed for more than 1 day to complete the self-assembly, and the self-assembled nano fibrous structure is shown in figure 1;
dissolving poly N-isopropyl acrylamide (PNIPAM) in Tris buffer solution with the concentration of 20mg/m L, standing overnight, and stirring to obtain poly N-isopropyl acrylamide solution.
The self-assembly of the above I3And mixing the solution K and the poly-N-isopropylacrylamide solution at the temperature of 30 ℃ for equal volume, stirring for 10min, and uniformly mixing to obtain a final solution, wherein the concentration of the polypeptide in the final solution is greater than the self-assembly critical concentration of the polypeptide, and the concentration of the poly-N-isopropylacrylamide in the final solution is greater than 1.0mg/m L while the uniformly dispersed concentration is kept.
Adjusting the temperature of the final solution to be more than or equal to 32 ℃ to obtain the temperature-responsive reversible hydrogel; when the temperature of the final solution is less than 32 ℃, the sol of the temperature-responsive reversible hydrogel is obtained, as shown in fig. 2, and the single polypeptide solution and the single PNIPAM solution both keep good fluidity before and after heating, and can not form the hydrogel.
Loading medicine, using adriamycin DOX as model medicine, adding 0.05-2.0mg/m L DOX into the final solution, stirring for fully dissolving, standing for more than 2 hr to make medicine molecule and I react3K fiber is fully acted and loaded on the fiber to obtain mixed solution loaded with the drug, I loaded with the drug3The K fiber is shown in fig. 3.
And (2) releasing the drug, namely heating the mixed solution loaded with the drug to 37 ℃ to form the reversible hydrogel loaded with the drug and having temperature response, putting the reversible hydrogel loaded with the drug into pure water or buffer solution at 37 ℃, taking out 200 mu L supernatant after standing for a certain time, measuring the concentration of DOX in the reversible hydrogel loaded with the drug, calculating the release amount, adding 200 mu L pure water into the mixed solution again, repeating the process, wherein the change curve of the released DOX amount along with the time is shown in figure 4, and as can be seen from figure 4, the drug molecules loaded by the reversible sol-gel system can be efficiently and controllably released in a gel state.

Claims (5)

1. The preparation method of the temperature-responsive reversible hydrogel is characterized by comprising the following steps of:
preparation of I capable of self-assembling to form one-dimensional nanostructures3K polypeptide water solution, the concentration of polypeptide in the solution is larger than the self-assembly critical concentration, and the solution is placed to complete the self-assembly;
dissolving poly N-isopropyl acrylamide in a Tris buffer solution, standing overnight, and stirring to obtain a poly N-isopropyl acrylamide solution with the concentration of 5-40mg/m L;
mixing the polypeptide solution after the self-assembly and the poly-N-isopropylacrylamide solution at the temperature of between 20 and 30 ℃ according to the following compounding conditions to obtain a final solution, wherein the concentration of the polypeptide in the final solution is greater than the self-assembly critical concentration of the polypeptide and the concentration of the polypeptide in the final solution is kept to be uniformly dispersed, and the concentration of the poly-N-isopropylacrylamide in the final solution is between 1.0 and 40mg/m L;
adjusting the temperature of the final solution to obtain hydrogel when the temperature of the final solution is more than or equal to 32 ℃; when the temperature of the final state solution is less than 32 ℃, the sol is obtained.
2. The reversible temperature-responsive hydrogel produced by the production method according to claim 1, wherein the reversible temperature-responsive hydrogel undergoes reversible transition between hydrogel and sol with a change in temperature.
3. The use of the reversible temperature-responsive hydrogel of claim 2 for drug loading and controlled release, comprising the steps of:
adding drug molecules into the self-assembled polypeptide solution or the final solution which is subjected to self-assembly, stirring, standing for more than 2 hours to obtain a drug-loaded mixed solution, heating the mixed solution to 32-80 ℃ to form drug-loaded temperature-responsive reversible hydrogel, and placing the drug-loaded temperature-responsive reversible hydrogel into pure water or buffer solution at 32-80 ℃ to perform drug controlled release.
4. Use of the temperature-responsive reversible hydrogel of claim 2 in the preparation of a smart hydrogel dressing.
5. Use of the temperature-responsive reversible hydrogel of claim 2 for the preparation of an injectable hydrogel.
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TWI730586B (en) 2020-01-10 2021-06-11 國立陽明交通大學 Thermoresponsive peptide hydrogel
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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