CN111978463B - Preparation method of hydrogel drug carrier with light control characteristic - Google Patents

Preparation method of hydrogel drug carrier with light control characteristic Download PDF

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CN111978463B
CN111978463B CN202010903193.7A CN202010903193A CN111978463B CN 111978463 B CN111978463 B CN 111978463B CN 202010903193 A CN202010903193 A CN 202010903193A CN 111978463 B CN111978463 B CN 111978463B
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azobenzene
solution
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CN111978463A (en
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胡小红
庞娟
王昕�
陈频
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Jinling Institute of Technology
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Abstract

The invention provides a preparation method of a hydrogel drug carrier with light-operated characteristics, which comprises the steps of dissolving diaminoazobenzene in dimethylformamide, adding triethylamine and acryloyl chloride, and reacting to generate an azobenzene cross-linking agent; and mixing the prepared azobenzene cross-linking agent with hydroxyethyl methacrylate monomer and N-vinyl pyrrolidone, adding an initiator to form a composite hydrogel drug carrier, and finally loading the drug into the hydrogel drug carrier in an adsorption mode or copolymerization mode. According to the invention, the azobenzene cross-linking agent is introduced into the hydrogel, so that the control on the mesh structure of the hydrogel is realized, the loading and controlled release capacity of the hydrogel on the medicament is improved, the obtained hydrogel has the characteristic of reversible response under the action of light and can be repeatedly used, the performance of the obtained product meets the basic requirement of a hydrogel medicament carrier, the release of the medicament can be controlled, and the hydrogel medicament carrier has great social benefit and economic benefit.

Description

Preparation method of hydrogel drug carrier with light control characteristic
Technical Field
The invention belongs to the technical field of new materials, and particularly relates to a preparation method of a hydrogel drug carrier with light control characteristics.
Background
Treatment of many diseases is accomplished by drugs. In this process, too low a drug concentration may not be therapeutic; too high a drug concentration may cause side effects and even damage to normal tissues and organs. In addition, the therapeutic effect depends on whether the drug can be maintained at the affected site for a sufficient time. In order to improve the therapeutic effect of the drug, the concentration and the frequency of administration of the drug are often increased, but excessive amounts of the drug may damage normal tissues and organs.
The hydrogel is a macromolecular network structure which swells in water, has better biocompatibility, is soft and elastic after absorbing water, and is not easy to cause tissue damage. In addition, the hydrogel has a water-soluble environment similar to that of extracellular matrix, so that the hydrogel has certain bionic characteristics, and the characteristics cause wide attention in the field of drug delivery. Conventional hydrogels are formed by free radical polymerization or copolymerization of some hydrophilic monomers to form a hydrogel network. However, as a drug carrier, the hydrogel must have drug loading and controlled release capabilities. Because conventional hydrogels lack ligands for drug interaction, they have limited drug loading and controlled release capabilities.
The hydrogel is added with a control unit which is helpful for the control capability of the hydrogel on the drug, the common control unit comprises cyclodextrin, the drug is wrapped in the cavity of the hydrogel through hydrophobic effect, and the sustained release and controlled release of the drug are realized through ion exchange effect. The carrier obtained by the method has better slow release effect, but the controlled release effect is still to be improved. The hydrogel is introduced with experimental drugs such as nano particles, polymer micelles and the like with response characteristics to release under the triggering of specific conditions, but the composite drug carrier has the characteristic of disposable use, and functional units in the hydrogel disappear after the composite drug carrier completes corresponding functions. The reversible characteristic is not provided.
Based on this, the present invention provides a method for preparing hydrogel drug carriers with photocontrol characteristics to solve the above problems.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of a hydrogel drug carrier with light control characteristics, an azobenzene cross-linking agent is introduced on the basis of the traditional hydrogel to increase a light control unit, and the obtained hydrogel has the characteristic of reversible response under the action of light and can be repeatedly used.
The invention adopts the following technical scheme:
a preparation method of hydrogel drug carrier with light control characteristics comprises the steps of dissolving diaminoazobenzene in dimethylformamide, and adding triethylamine and acryloyl chloride to react to generate azobenzene cross-linking agent; and mixing the prepared azobenzene cross-linking agent with hydroxyethyl methacrylate (HEMA) monomer and vinyl pyrrolidone (NVP), adding an initiator to form a composite hydrogel drug carrier, and finally loading the drug into the hydrogel drug carrier in an adsorption mode or copolymerization mode.
Further, the invention specifically comprises the following steps:
s1, preparation of an azobenzene crosslinking agent:
dissolving p-diaminoazobenzene in dimethylformamide, adding triethylamine, dropwise adding acryloyl chloride by using a pipette, and stirring the reaction at room temperature overnight; adding water to the reacted solution, dropwise adding concentrated HCl aqueous solution to adjust the pH of the mixed solution to 4, collecting precipitated orange solid by suction filtration, and using saturated NaHCO3Washing with distilled water once respectively, and then freeze-drying to obtain orange azobenzene cross-linking agent powder;
s2, preparation of a composite hydrogel drug carrier:
adding hydroxyethyl methacrylate (HEMA) and N-vinyl pyrrolidone (NVP) into a centrifuge tube, mixing and shaking up, then adding the azobenzene cross-linking agent prepared in S1 into the mixture, shaking until solid powder particles completely disappear, adding an initiator into the solution, finally adding a medicinal aqueous solution or water into the solution, and stirring uniformly; and (3) injecting the mixture into a mold, then placing the mold into a constant-temperature drying oven for drying to form a film, and finally taking out the formed hydrogel for later use.
Further, in S1, the concentration of dimethylformamide is in the range of 0.1 to 5mol/L, preferably 0.5 to 2 mol/L.
Furthermore, in S1, triethylamine and p-diaminoazobenzene are added in a molar ratio of 5: 1-1: 1, preferably 2: 1-3.5: 1; the molar ratio of the acryloyl chloride to the p-diaminoazobenzene is 5:1 to 1:1, preferably 2:1 to 3: 1.
Further, in S1, the volume ratio of the water added into the reacted solution to the dimethylformamide is 1:100 to 1:10, preferably 1:50 to 1: 20.
Further, in S1, saturated NaHCO is passed3And distilled water washed orangeAnd (3) freeze-drying the colored solid by a freeze dryer at the temperature of-50 ℃ and under the pressure of 7-8 Pa.
Further, in S2, the molar ratio of hydroxyethyl methacrylate (HEMA) to N-vinyl pyrrolidone (NVP) added is 10: 0-3: 1, preferably 10: 1-7: 2; most preferably 7.4: 2.
Further, in S2, the added azobenzene crosslinking agent accounts for 0.01 to 1% of the mole fraction of the mixture of hydroxyethyl methacrylate (HEMA) and N-vinyl pyrrolidone (NVP), further 0.05 to 0.5%, and optimally 0.1 to 0.5%.
Further, in S2, the initiator is one of ammonium persulfate/tetramethylethylenediamine, potassium persulfate/tetramethylethylenediamine, and vitamin C/hydrogen peroxide, preferably vitamin C/hydrogen peroxide, wherein the oxidant and the reducing agent are in equimolar numbers; the concentration of the initiator is 2 mM-10 mM, preferably 3 mM-7 mM, and most preferably 5 mM.
Further, in S2, when the initiator is vitamin C/hydrogen peroxide, the set temperature of the constant-temperature drying oven is 60 ℃; when the initiator is ammonium persulfate/tetramethylethylenediamine or potassium persulfate/tetramethylethylenediamine, the set temperature of the constant-temperature drying oven is 20-60 ℃.
Furthermore, in S2, the time in the constant-temperature drying oven is 0.5-5 h, preferably 1-3 h.
Further, the p-diaminoazobenzene may be replaced with an azobenzene derivative having amino, carboxyl, or hydroxyl substituents on the p-dihydroxyazobenzene or m-diaminoazobenzene or other azobenzenes (provided that one substituent of active H is on each benzene ring).
Further, in S2, the molecular weight of the drug is less than ten thousand, and the drug includes but is not limited to norfloxacin, ofloxacin, puerarin and cyclosporine.
Further, in S2, the drug is loaded in a manner that the hydrogel is soaked in a 1.5-3 mg/ml drug solution to allow the drug to permeate into the hydrogel network; or the drug is copolymerized with hydroxyethyl methacrylate, N-vinyl pyrrolidone and azobenzene cross-linking agent monomer, wherein the dosage of the drug is 1-5 mg/g monomer.
The invention has the beneficial effects that:
according to the novel hydrogel with good drug controlled release capability, the azobenzene cross-linking agent is introduced into the hydrogel, the control of the mesh structure of the hydrogel is realized, the loading and controlled release capability of the hydrogel on drugs is improved, the obtained hydrogel has the characteristic of reversible response under the action of light and can be repeatedly used, the performance of the obtained product meets the basic requirements of a hydrogel drug carrier, the release of the drugs can be controlled, and the novel hydrogel has great social benefit and economic benefit.
Description of the drawings:
FIG. 1 is a nuclear magnetic H spectrum and structure of an azobenzene crosslinking agent of example 1 of the present invention;
FIG. 2 is an SEM photograph of a lyophilized hydrogel of the present invention, wherein a is an SEM photograph of the lyophilized hydrogel of comparative example 1, b is an SEM photograph of the lyophilized hydrogel of example 1, and c is an SEM photograph of the lyophilized hydrogel of comparative example 2;
FIG. 3 is a graph of the UV spectrum of a hydrogel according to example 1 of the present invention as a function of response time;
FIG. 4 is a graph of UV spectrum versus recovery time for a hydrogel in example 1 of the present invention;
FIG. 5 is the variation of the absorbance with the illumination period of 373 nm hydrogel with the peak value in example 1 of the present invention;
FIG. 6 shows the response time and recovery time of example 1 as a function of the illumination cycle, with a test condition of 1000Lux white light intensity and room temperature;
FIG. 7 is a graph showing the change of the recovery time with the illumination intensity and the change of the ambient temperature in example 1 of the present invention, wherein a is a graph showing the change of the recovery time with the illumination intensity; b is a change curve of the recovery time along with the ambient temperature;
FIG. 8 is a graph of the in vitro release behavior study of example 1 of the present invention, wherein a is the release profile of the carrier liquid gel in PBS of example 1; b is the release profile of the carrier gel in PBS in example 1 in the dark after irradiation under UV conditions.
The specific implementation mode is as follows:
in order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
The invention provides a preparation method of a hydrogel drug carrier with light control characteristics, which comprises the steps of dissolving diaminoazobenzene in dimethylformamide, and adding triethylamine and acryloyl chloride to react to generate an azobenzene cross-linking agent; and mixing the prepared azobenzene cross-linking agent with hydroxyethyl methacrylate (HEMA) monomer and vinyl pyrrolidone (NVP), adding an initiator to form a composite hydrogel drug carrier, and finally loading the drug into the hydrogel drug carrier in an adsorption mode or copolymerization mode.
Further, the invention specifically comprises the following steps:
s1, preparation of an azobenzene crosslinking agent:
dissolving p-diaminoazobenzene (p-dihydroxyazobenzene, m-diaminoazobenzene or azobenzene derivatives with amino, carboxyl and hydroxyl substituted groups on other azobenzenes) in dimethylformamide, adding triethylamine, dropwise adding acryloyl chloride by using a pipette, and stirring the reaction at room temperature overnight; adding water to the reacted solution, dropwise adding concentrated HCl aqueous solution to adjust the pH of the mixed solution to 4, collecting precipitated orange solid by suction filtration, and using saturated NaHCO3And washing with distilled water once respectively, and then freeze-drying by a freeze-drying machine at the temperature of-50 ℃ and the pressure of 7-8 Pa to obtain orange azobenzene cross-linking agent powder. Wherein the concentration of the dimethylformamide ranges from 0.1 to 5mol/L, and preferably ranges from 0.5 to 2 mol/L; adding triethylamine and p-diaminoazobenzene at a molar ratio of 5: 1-1: 1, preferably 2: 1-3.5: 1; adding acryloyl chloride and p-diaminoazobenzene at a molar ratio of 5: 1-1: 1, preferably 2: 1-3: 1; the volume ratio of water to dimethylformamide added to the solution after the reactionIs 1:100 to 1:10, preferably 1:50 to 1: 20.
S2, preparation of a composite hydrogel drug carrier:
adding hydroxyethyl methacrylate (HEMA) and N-vinyl pyrrolidone (NVP) into a centrifuge tube, mixing and shaking up, then adding an azobenzene cross-linking agent prepared in S1 into the mixture, shaking until solid powder particles completely disappear, and the solution is clear and transparent, then adding an initiator, finally adding a drug (the molecular weight of the drug is less than ten thousand, and the drug comprises but is not limited to norfloxacin, ofloxacin, puerarin and cyclosporine) aqueous solution or water into the solution, and stirring uniformly; and injecting the mixture into a mold, then putting the mold into a constant-temperature drying oven for 0.5-5 h for drying to form a film, and finally taking out the formed hydrogel for later use. Wherein the molar ratio of the added hydroxyethyl methacrylate (HEMA) to the N-vinyl pyrrolidone (NVP) is 10: 0-3: 1, preferably 10: 1-7: 2; optimally 7.4: 2; the added azobenzene cross-linking agent accounts for 0.01-1% of the mole fraction of the mixture of hydroxyethyl methacrylate (HEMA) and N-vinyl pyrrolidone (NVP), further 0.05-0.5%, and optimally 0.1-0.5%; the initiator is one of ammonium persulfate/tetramethylethylenediamine, potassium persulfate/tetramethylethylenediamine and vitamin C/hydrogen peroxide, preferably vitamin C/hydrogen peroxide, wherein the mole number of the oxidant and the reducing agent is equal; the concentration of the initiator is 2 mM-10 mM, preferably 3 mM-7 mM, and most preferably 5 mM; when the initiator is vitamin C/hydrogen peroxide, the set temperature of the constant-temperature drying oven is 60 ℃; when the initiator is ammonium persulfate/tetramethylethylenediamine or potassium persulfate/tetramethylethylenediamine, the set temperature of the constant-temperature drying oven is 20-60 ℃; the loading mode of the medicine is that the hydrogel is soaked in 1.5-3 mg/ml medicine solution, and the medicine is made to permeate into the hydrogel network; or the dosage of the drug is 1-5 mg/g of monomer by a mode of copolymerizing the drug and the monomer.
Example 1
S1, preparation of an azobenzene crosslinking agent:
paradiaminoazobenzene (265 mg, 1.25mmo 1) was dissolved in 20mL Dimethylformamide (DMF) and triethylamine (540. mu.L, 3.875 mmol) was added, followed byAcryloyl chloride (305 μ L, 3.75 mmol) was then added dropwise with a pipette and the reaction stirred at room temperature overnight; pouring the reacted solution into 600mL of water, and adjusting the pH of the mixed solution to 4 by dropwise adding a concentrated HCl aqueous solution; the precipitated orange solid was collected by suction filtration and washed with saturated NaHCO3Washing with distilled water once respectively, and freeze-drying with a freeze dryer (-50 deg.C, 7-8 Pa) to obtain orange powder product, i.e. azobenzene cross-linking agent;
s2, preparation of a composite hydrogel drug carrier:
hydroxyethyl methacrylate (HEMA, 2 mL) and N-vinyl pyrrolidone (NVP, 465 μ L) are added into a 10mL centrifuge tube to be mixed and shaken evenly, and then azobenzene cross-linking agent (2.54 mg) is added into the mixture to be shaken until solid powder particles completely disappear, and the solution is clear and transparent; then adding initiator ammonium persulfate (APS, 14 mg) and N, N, N ', N' -tetramethyl ethylenediamine (10 mu L) in an equimolar ratio, and finally adding 2mL of aqueous solution of the drug levofloxacin (1 mg/mL) into the solution and uniformly stirring; injecting the mixture into a round model (0.3 mm thick), and then putting the round model into a constant-temperature drying oven at 60 ℃ for drying to form a film; after one hour, the shaped hydrogel was removed for use.
Example 2
S1, preparation of an azobenzene crosslinking agent:
p-diaminoazobenzene (265 mg, 1.25mmo 1) was dissolved in dimethylformamide (DMF, 20 mL) and triethylamine (2.5 mmol) was added, followed by dropwise addition of acryloyl chloride (2.5 mmol) with a pipette, and the reaction was stirred at room temperature overnight; pouring the reacted solution into 600mL of water, and adjusting the pH of the mixed solution to 4 by dropwise adding a concentrated HCl aqueous solution; the precipitated orange solid was collected by suction filtration and washed with saturated NaHCO3And distilled water, and then freeze-dried with a freeze-dryer (-50 ℃, 7-8 Pa) to obtain the desired orange powder product, i.e., azobenzene cross-linker.
S2, preparation of a composite hydrogel drug carrier:
hydroxyethyl methacrylate (HEMA, 2.5 mL) is added into a 10mL centrifuge tube for mixing and shaking up, then azobenzene cross-linking agent (2.54 mg) is added into the mixture for shaking until solid powder particles completely disappear, and the solution is clear and transparent; adding initiator ammonium persulfate (APS, 14 mg) and N, N, N ', N' -tetramethylethylenediamine (10 mu L) with the same molar ratio, finally adding 2mL of aqueous solution of the drug levofloxacin (2 mg/mL), and uniformly stirring; the mixture was poured into a round mold (0.3 mm thick), and then dried in a constant temperature oven at 60 ℃ to form a film. After one hour, the shaped hydrogel was removed for use.
Example 3
S1, preparation of an azobenzene crosslinking agent:
p-diaminoazobenzene (265 mg, 1.25mmo 1) was dissolved in dimethylformamide (DMF, 20 mL) and triethylamine (3 mmol) was added, followed by dropwise addition of acryloyl chloride (3 mmol) with a pipette, and the reaction was stirred at room temperature overnight; pouring the reacted solution into 600mL of water, and adjusting the pH of the mixed solution to 4 by dropwise adding a concentrated HCl aqueous solution; the precipitated orange solid was collected by suction filtration and washed with saturated NaHCO3And distilled water, and then freeze-dried with a freeze-dryer (-50 ℃, 7-8 Pa) to obtain the desired orange powder product, i.e., azobenzene cross-linker.
S2, preparation of a composite hydrogel drug carrier:
hydroxyethyl methacrylate (HEMA, 2.1 mL) and N-vinyl pyrrolidone (NVP, 365 μ L) were added to a 10mL centrifuge tube and mixed and shaken, and then azobenzene cross-linking agent (2.54 mg) was added to the mixture and shaken until the solid powder particles completely disappeared and the solution was clear and transparent; adding initiator ammonium persulfate (APS, 14 mg) and N, N, N ', N' -tetramethylethylenediamine (10 μ L) with equal molar ratio, finally adding 2mL of puerarin (1 mg/mL) aqueous solution, and stirring uniformly; injecting the mixture into a round model (0.3 mm thick), and then putting the round model into a constant-temperature drying oven at 60 ℃ for drying to form a film; after one hour, the shaped hydrogel was removed for use.
Example 4
S1, preparation of azobenzene cross-linking agent:
p-dihydroxyazobenzene (265 mg, 1.25mmo 1) was dissolved in dimethylformamide (DMF, 20 mL) and triethylamine (540. mu.L, 3.875 mmol) was added, followed by dropwise addition of acryloyl chloride (305. mu.L, 3.75 mmol) with a pipette and the reaction stirred at room temperature overnight; pouring the reacted solution into 600mL of water, and adjusting the pH of the mixed solution to 4 by dropwise adding a concentrated HCl aqueous solution; the precipitated orange solid was collected by suction filtration and washed with saturated NaHCO3Washing with distilled water once respectively, and freeze-drying with freeze dryer (-50 deg.C, 7-8 Pa) to obtain desired product, i.e. azobenzene cross-linking agent;
s2, preparation of the composite hydrogel drug carrier:
hydroxyethyl methacrylate (HEMA, 2.2 mL) and N-vinyl pyrrolidone (NVP, 265. mu.L) were added to a 10mL centrifuge tube and mixed and shaken, and then azobenzene cross-linking agent (2.54 mg) was added to the mixture and shaken until the solid powder particles completely disappeared and the solution was clear and transparent; adding initiator ammonium persulfate (APS, 14 mg) and N, N, N ', N' -tetramethyl ethylenediamine (10 mu L) with equal molar ratio, finally adding 2mL of puerarin (3 mg/mL) aqueous solution into the solution, and uniformly stirring; injecting the mixture into a round model (0.3 mm thick), and then putting the round model into a constant-temperature drying oven at 60 ℃ for drying to form a film; after one hour, the shaped hydrogel was removed for use.
Example 5
S1, preparation of an azobenzene crosslinking agent:
p-dihydroxyazobenzene (265 mg, 1.25 mmol 1) was dissolved in dimethylformamide (DMF, 20 mL) and triethylamine (2.5 mmol) was added, followed by dropwise addition of acryloyl chloride (2.5 mmol) with a pipette and the reaction stirred at room temperature overnight; pouring the reacted solution into 600mL of water, and adjusting the pH of the mixed solution to 4 by dropwise adding a concentrated HCl aqueous solution; the precipitated orange solid was collected by suction filtration and washed with saturated NaHCO3And distilled water, and then freeze-dried with a freeze-dryer (-50 ℃, 7-8 Pa) to obtain the desired orange powder product, i.e., azobenzene cross-linker.
S2, preparation of a composite hydrogel drug carrier:
hydroxyethyl methacrylate (HEMA, 2.5 mL) is added into a 10mL centrifuge tube for mixing and shaking up, then azobenzene cross-linking agent (2.54 mg) is added into the mixture for shaking until solid powder particles completely disappear, and the solution is clear and transparent; then adding initiator ammonium persulfate (APS, 14 mg) and N, N, N ', N' -tetramethyl ethylenediamine (10 mu L) with equal molar ratio, finally adding 2mL of drug cyclosporine (2 mg/mL) aqueous solution into the solution, and uniformly stirring; injecting the mixture into a round model (0.3 mm thick), and then putting the round model into a constant-temperature drying oven at 60 ℃ for drying to form a film; after one hour, the shaped hydrogel was removed for use.
Example 6
S1, preparation of azobenzene cross-linking agent:
p-diaminoazobenzene (265 mg, 1.25mmo 1) was dissolved in dimethylformamide (DMF, 20 mL) and triethylamine (3.5 mmol) was added, followed by dropwise addition of acryloyl chloride (3.5 mmol) with a pipette and stirring of the reaction at room temperature overnight; pouring the reacted solution into 600mL of water, and adjusting the pH of the mixed solution to 4 by dropwise adding a concentrated HCl aqueous solution; the precipitated orange solid was collected by suction filtration and washed with saturated NaHCO3And distilled water, and then freeze-dried with a freeze-dryer (-50 ℃, 7-8 Pa) to obtain the desired orange powder product, i.e., azobenzene cross-linker.
S2, preparation of a composite hydrogel drug carrier:
hydroxyethyl methacrylate (HEMA, 2 mL) and N-vinyl pyrrolidone (NVP, 465 μ L) are added into a 10mL centrifuge tube to be mixed and shaken evenly, and then azobenzene cross-linking agent (2.54 mg) is added into the mixture to be shaken until solid powder particles completely disappear, and the solution is clear and transparent; adding initiator ammonium persulfate (APS, 14 mg) and N, N, N ', N' -tetramethylethylenediamine (10 mu L) with the same molar ratio, finally adding 2mL of norfloxacin (1 mg/mL) aqueous solution into the solution, and uniformly stirring; injecting the mixture into a round model (0.3 mm thick), and then putting the round model into a constant-temperature drying oven at 60 ℃ for drying to form a film; after one hour, the shaped hydrogel was removed for use.
Comparative example 1
Hydroxyethyl methacrylate (HEMA, 2 mL) and N-vinyl pyrrolidone (NVP, 465 μ L) were added to a 10mL centrifuge tube and mixed and shaken; adding initiator ammonium persulfate (APS, 14 mg) and N, N, N ', N' -tetramethylethylenediamine (10 mu L) with the same molar ratio, finally adding 2mL of aqueous solution of the drug levofloxacin (1 mg/mL), and uniformly stirring; injecting the mixture into a round model (0.3 mm thick), and then putting the round model into a constant-temperature drying oven at 60 ℃ for drying to form a film; after one hour, the shaped hydrogel was removed for use.
Comparative example 2
Hydroxyethyl methacrylate (HEMA, 2 mL) and N-vinyl pyrrolidone (NVP, 465 μ L) are added into a 10mL centrifuge tube to be mixed and shaken evenly, and then azobenzene acrylate (2 mg) is added into the mixture to be shaken until solid powder particles completely disappear, and the solution is clear and transparent; then the initiator ammonium persulfate (APS, 14 mg) and N, N, N ', N' -tetramethylethylenediamine (10 μ L) in equimolar ratio were added; finally, 2mL of levofloxacin (1 mg/mL) aqueous solution is added into the solution and stirred uniformly; injecting the mixture into a round model (0.3 mm thick), and then putting the round model into a constant-temperature drying oven at 60 ℃ for drying to form a film; after one hour, the shaped hydrogel was removed for use.
Comparative example 3
Hydroxyethyl methacrylate (HEMA, 2.5 mL) was added to a 10mL centrifuge tube, followed by the initiator ammonium persulfate (APS, 14 mg) and N, N, N ', N' -tetramethylethylenediamine (10 μ L) in equimolar ratio, and finally 2mL of aqueous solution of the drug levofloxacin (1 mg/mL) was added to the solution and stirred well; injecting the mixture into a round model (0.3 mm thick), and then putting the round model into a constant-temperature drying oven at 60 ℃ for drying to form a film; after one hour, the shaped hydrogel was removed for use.
The experimental method comprises the following steps:
1. nuclear magnetic characterization:
chloroform was used as a solvent, and a nuclear magnetic resonance apparatus (NMR, Bruker, AV 300) was used as the apparatus.
Nuclear magnetic H spectrum and structure of azobenzene crosslinker prepared in step S1 of example 1 referring to fig. 1, assignment of the position of H on fig. 1 confirms successful synthesis of azobenzene crosslinker of example 1 of the present invention.
SEM characterization
Putting the hydrogel prepared in the example 1, the comparative example 1 and the comparative example 2 into a glass dish, adding water into the glass dish to completely soak the hydrogel film, and putting the hydrogel film into a refrigerator for freezing; then putting the frozen sample into a freeze dryer for freeze drying (-50 ℃, 7-8 Pa) for 24 hours, and then cutting the hydrogel membrane completely frozen and dried into samples of 5 x 5mm by using scissors; adhering the freeze-dried hydrogel film membrane on a metal sample table by using conductive adhesive, and then spraying a layer of metal film, aiming at preventing the hydrogel membrane from being damaged by heat or radiation; and finally, placing the film into a high-resolution field emission Scanning Electron Microscope (SEM) instrument, and observing the surface structure of the film.
Referring to fig. 2, wherein a is an SEM photograph of the lyophilized hydrogel of comparative example 1, b is an SEM photograph of the lyophilized hydrogel of example 1, and c is an SEM photograph of the lyophilized hydrogel of comparative example 2. As can be seen from fig. 2, example 1 of the present invention has a finer mesh structure.
Study on photo-responsiveness of hydrogel
(1) Response performance: irradiating the azobenzene hydrogel film by ultraviolet light to convert the azobenzene hydrogel film from a trans-structure to a cis-structure, and observing the response change process of a characteristic absorption peak at the wavelength of 358nm by an ultraviolet-visible spectrophotometer (Cary 50).
(2) Recovery performance: when the azobenzene hydrogel film is reduced to the lowest point under the induction of purple light and does not change any more, a daylight lamp is used for irradiating the azobenzene hydrogel film to ensure that the azobenzene hydrogel film is converted from a cis structure to a trans structure, and an ultraviolet-visible spectrophotometer (Cary 50) is used for observing the reversion change process of a characteristic absorption peak at the wavelength of 358 nm.
(3) Effect of light intensity on the photoresponsive properties of hydrogels: slowly sticking the aminoazobenzene hydrogel film on the smooth surface of a cuvette by using tweezers at room temperature (25 ℃), respectively testing the positions with the illumination intensities of 500LUX, 1000LUX and 2000LUX by using a digital illumination meter (TA 8130), placing the cuvette stuck with the aminoazobenzene hydrogel film at the position with the calibrated light intensity, recording the illumination time by using a meter, and testing the ultraviolet response and the recovery performance of the azobenzene hydrogel film.
(4) Influence of temperature on the photoresponsive properties of the hydrogel: slowly attaching the amino azobenzene hydrogel film to the smooth surface of a cuvette by using tweezers under the illumination of 1000LUX at the temperature of 25 ℃, 50 ℃ and 80 ℃, placing the cuvette attached with the amino azobenzene hydrogel film in a water bath kettle with a preset temperature, recording the illumination time by using a meter, and testing the ultraviolet response and the recovery time of the azobenzene hydrogel film.
Referring to fig. 3-6, it can be seen that azobenzene in the hydrogel has a controlled response process (uv effect) and recovery process (white light effect) with very stable periodic changes, manifested as stable absorbance value changes and stable response time and recovery time.
In FIG. 3, curves of the variation of the ultraviolet spectrum with response time 0S, 30S, 60S, 90S, 120S, 150S, 180S, 210S are shown in sequence from top to bottom at 373 nm; in FIG. 4, at 373 nm, the change curves of the ultraviolet spectrum with the recovery time of 30min, 20min, 15min, 5min and 0min are shown from top to bottom.
Referring to FIG. 7, wherein a is the change of the recovery time of the hydrogel in example 1 with the intensity of light; b is the change of the recovery time of the hydrogel in example 1 with the ambient temperature.
As can be seen from fig. 7, the recovery time gradually decreases as the white light intensity increases; the recovery time was gradually shortened with increasing temperature, indicating the controllability of the hydrogel.
In vitro release behavior
The prepared hydrogel film in example 1 and the hydrogel film in example 1 irradiated under ultraviolet condition and placed under dark condition are immersed in PBS buffer solution with pH =7.4, and placed in a constant temperature shaking incubator for drug release at a rotation speed of 100r/min, a constant temperature of 37 ℃, 2ml of release solution is taken out from the centrifuge tube at intervals of 5min, and then new 2ml of the same PBS buffer solution is added into the centrifuge tube. And then, the above operation steps are carried out according to the 10, 15, 20, 25, 30, 40, 60, 90, 150, 270, 510 and 1030 minutes respectively, the absorbance of the solution is measured, and the cumulative release amount of the drug levofloxacin is calculated according to a plotted levofloxacin concentration-absorbance standard curve. In order to reduce experimental error, the above drug loading experiment was performed in duplicate.
Referring to fig. 8, wherein a is the release profile of the carrier gel in PBS of example 1; b is the release profile of the carrier gel in PBS in example 1 under dark conditions after irradiation under UV conditions. As can be seen from FIG. 8, the drug was gradually released from the hydrogel, which had a more compact structure after light irradiation, resulting in slower drug release and less drug release.
The above is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention, it should be noted that, for those skilled in the art, several modifications and decorations without departing from the principle of the present invention should be regarded as the protection scope of the present invention.

Claims (10)

1. A preparation method of hydrogel drug carrier with light control characteristics is characterized in that p-diaminoazobenzene is dissolved in dimethylformamide, and triethylamine and acryloyl chloride are added to react to generate azobenzene cross-linking agent; and mixing the prepared azobenzene cross-linking agent with hydroxyethyl methacrylate monomer and N-vinyl pyrrolidone, adding an initiator to form a composite hydrogel drug carrier, and finally loading the drug into the hydrogel drug carrier in an adsorption mode or copolymerization mode.
2. The method of making a light management feature hydrogel drug carrier of claim 1, comprising the steps of:
s1, preparation of an azobenzene crosslinking agent:
dissolving p-diaminoazobenzene in dimethylformamide, adding triethylamine, dropwise adding acryloyl chloride by using a pipette, and stirring the reaction at room temperature overnight; adding water to the reacted solution, dropwise adding concentrated HCl aqueous solution to adjust the pH of the mixed solution to 4, collecting precipitated orange solid by suction filtration, and using saturated NaHCO3Washing with distilled water once respectively, and then freeze-drying to obtain orange azobenzene cross-linking agent powder;
s2, preparation of a composite hydrogel drug carrier:
adding hydroxyethyl methacrylate and N-vinyl pyrrolidone into a centrifuge tube, mixing and shaking up, then adding the azobenzene cross-linking agent prepared in S1 into the mixture, oscillating until solid powder particles completely disappear, and the solution is clear and transparent, then adding an initiator, finally adding a medicinal aqueous solution or water into the solution, and stirring uniformly; and (3) injecting the mixture into a mold, then placing the mold into a constant-temperature drying oven for drying to form a film, and finally taking out the formed hydrogel for later use.
3. The method of claim 1, wherein the concentration of dimethylformamide in S1 is in the range of 0.1 to 5 mol/L.
4. The preparation method of the hydrogel drug carrier with the light control characteristics according to claim 1, wherein the molar ratio of triethylamine to p-diaminoazobenzene added in S1 is 5: 1-1: 1; the molar ratio of the acryloyl chloride to the p-diaminoazobenzene is 5: 1-1: 1.
5. The method for preparing a hydrogel drug carrier with light control characteristics according to claim 1, wherein the molar ratio of the hydroxyethyl methacrylate to the N-vinyl pyrrolidone added in S2 is 10: 1-3: 1.
6. The method for preparing a hydrogel drug carrier with light control characteristics as claimed in claim 1, wherein the azobenzene crosslinking agent is added in S2 in an amount of 0.01 to 1% by mole based on the mixture of hydroxyethyl methacrylate and N-vinylpyrrolidone.
7. The method for preparing a hydrogel drug carrier with light control characteristics according to claim 1, wherein in S2, the initiator is one of ammonium persulfate/tetramethylethylenediamine, potassium persulfate/tetramethylethylenediamine, and vitamin C/hydrogen peroxide, wherein the molar number of the oxidant and the reducing agent is equal; the concentration of the initiator is 2 mM-10 mM.
8. The method of making a photo controlled feature hydrogel drug carrier of claim 1 wherein the para-diaminoazobenzene is replaced with para-dihydroxyazobenzene or meta-diaminoazobenzene.
9. The method of claim 1, wherein in S2, the drug has a molecular weight of less than ten thousand, and the drug includes but is not limited to norfloxacin, ofloxacin, puerarin, and cyclosporine.
10. The method for preparing the hydrogel drug carrier with the light control characteristics according to claim 1, wherein in S2, the drug is loaded in a manner that the hydrogel is soaked in a drug solution of 1.5-3 mg/ml, so that the drug permeates into a hydrogel network; or the dosage of the drug is 1-5 mg/g of monomer by a mode of copolymerizing the drug and the monomer.
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