CN112480389B - Low-oxygen responsive injectable hydrogel and preparation method thereof - Google Patents
Low-oxygen responsive injectable hydrogel and preparation method thereof Download PDFInfo
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- CN112480389B CN112480389B CN201910854490.4A CN201910854490A CN112480389B CN 112480389 B CN112480389 B CN 112480389B CN 201910854490 A CN201910854490 A CN 201910854490A CN 112480389 B CN112480389 B CN 112480389B
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33303—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group
- C08G65/33306—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing amino group acyclic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
Abstract
The invention discloses a hypoxia-responsive injectable hydrogel and a preparation method thereof. Specifically, amino on ethylenediamine and double bonds on 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate and polyethylene glycol diacrylate (PEGDA) are subjected to Michael addition reaction to obtain metronidazole-terminated hyperbranched polyamino ester (HB-PBAE-MNZ). HB-PBAE-MNZ and thiolated hyaluronic acid (HS-HA) are blended to obtain the injectable hydrogel with low-oxygen responsiveness. The gel has the advantages of simple preparation method, mild reaction conditions, good biocompatibility and low oxygen responsiveness.
Description
Technical Field
The invention relates to a low-oxygen-responsiveness injectable hydrogel and a preparation method thereof, in particular to a method for constructing a gel system by utilizing the Michael addition reaction between unreacted double bonds on a hyperbranched polymer and sulfydryl on sulfydryl hyaluronic acid, and nitroimidazole is used as an end capping group to ensure that the hydrogel has low-oxygen responsiveness.
Background
The hydrogel means a crosslinked polymer having a three-dimensional network structure in which a main chain or a branch chain contains a large amount of hydrophilic groups and is swollen with water, which is not dissolved in water, and which contains a large amount of water while maintaining a certain shape. Under the stimulation of external physical and chemical factors such as temperature, light, electricity, magnetism, sound, force, pH value, chemical substances and the like, the self properties of some polymer hydrogels such as phase, volume, shape, optics, electric field, mechanics, surface area, reaction rate, identification performance and the like change accordingly, and do work outwards simultaneously, and the hydrogel with stimulation responsiveness to the external environment change is called intelligent hydrogel. The intelligent hydrogel integrates perception, driving and information processing into a whole, and forms a functional material which is similar to an organism and has intelligent properties. The hydrogel materials with the environmental stimulus response behavior characteristics have wide application prospects in the field of microenvironment sensing.
The nitroimidazole group has low oxygen responsiveness, can be reduced into the aminoimidazole group by a reducing agent under the low oxygen condition, and can utilize hydrophilic and hydrophobic change to regulate and control the drug release.
The synthesis of the hyperbranched polymer is difficult to control, the proportion, the temperature and the reaction time need to be controlled to achieve the expected hyperbranched structure, and the structure of the polyurethane is degradable and has good biocompatibility.
Hyaluronic acid is used as a natural macromolecule, has good biocompatibility and is often used as a biomedical material. The thiolated hyaluronic acid can react with double bonds linked with ester bonds at room temperature to form a gel network system.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and aims to construct a gel system by utilizing the Michael addition reaction of the sulfydryl of the sulfhydrylated hyaluronic acid and unreacted active double bonds in the hyperbranched polymer, and the hydrogel has low-oxygen responsiveness by taking nitroimidazole as an end capping group.
The purpose of the invention is realized by the following technical scheme.
The invention relates to a hypoxia-responsive injectable hydrogel and a preparation method thereof, which are carried out according to the following steps:
(1) uniformly mixing dimethyl sulfoxide (DMSO) solution of polyethylene glycol diacrylate (PEGDA) and dimethyl sulfoxide (DMSO) solution of Ethylenediamine (EDA), wherein the molar ratio of double bonds of the polyethylene glycol diacrylate to active hydrogen of the ethylenediamine is 1 (1.1-1.4), and reacting in an oil bath to enable the double bonds on the polyethylene glycol diacrylate (PEGDA) and amino groups on the Ethylenediamine (EDA) to perform Michael addition reaction to obtain hyperbranched polyamino ester (HB-PBAE);
(2) adding a dimethyl sulfoxide (DMSO) solution of 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate into the reaction solution in the step (1), wherein the molar ratio of the double bond of the 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate to the active hydrogen of the ethylenediamine in the step (1) is (0.2-0.8): (1.1-1.4), continuing the reaction in an oil bath to react the double bond on the 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate with the unreacted amino in the reaction solution in the step (1) to obtain the hyperbranched polyamino ester (HB-PBAE-MNZ) terminated by the nitroimidazole group;
after the reaction in the step (1) is finished, purifying is not carried out, and 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate is directly added for reaction, so that the molar ratio of the sum of double bonds on polyethylene glycol diacrylate (PEGDA) and 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate to active hydrogen on ethylenediamine is more than 1, preferably 1.5: 1.25;
(3) uniformly mixing the aqueous solution of the nitroimidazole group-terminated hyperbranched polyaminoester (HB-PBAE-MNZ) prepared in the step (2) with the aqueous solution of the thiolated hyaluronic acid (HA-SH), wherein the mass ratio of the nitroimidazole group-terminated hyperbranched polyaminoester to the thiolated hyaluronic acid is (10-20): 1, fully reacting to enable unreacted double bonds on the nitroimidazole group-terminated hyperbranched polyaminoester (HB-PBAE-MNZ) and sulfydryl on the sulfhydrylated hyaluronic acid (HA-SH) to generate Michael addition reaction to generate the three-dimensional network stereo polymer.
In the step (1), the polyethylene glycol diacrylate (PEGDA) and the Ethylenediamine (EDA) react for 5-7h in oil bath at the temperature of 70-90 ℃.
In the step (2), 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate and hyperbranched polyamino ester (HB-PBAE) continue to react for 3-5H in an oil bath at 70-90 ℃; the molar ratio of the double bond of the 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate to the active hydrogen of the ethylenediamine in the step (1) is (0.2-0.5): (1.1-1.4).
After the reaction in the step (2) is finished, the reaction solution is purified by more than 5 times of diethyl ether.
In the step (3), the mass percentage concentration of the aqueous solution of the nitroimidazole group-terminated hyperbranched polyaminoester (HB-PBAE-MNZ) is 20 wt%, the mass percentage concentration of the aqueous solution of the thiolated hyaluronic acid (HA-SH) is 1 wt%, and the two are blended according to the volume ratio of 1: 1; fully carrying out the reaction by vortex stirring; the gelling temperature is room temperature, and the gelling time is 3-4 min.
The invention has the beneficial effects that: the hydrogel prepared by the invention has the advantages of simple preparation method, mild reaction conditions, good biocompatibility and low-oxygen responsiveness, and can be applied to the medical fields of drug sustained release and the like.
Drawings
FIG. 1 is a diagram of HB-PBAE-MNZ prepared in the example of the invention1H-NMR spectrum;
FIG. 2 is a gel-forming picture of 20 wt% HB-PBAE-MNZ and 1 wt% HA-SH;
FIG. 3 is a graph showing the UV absorption spectrum of an aqueous solution of HB-PBAE-MNZ with a mass fraction of 0.2% after reduction for 4 hours under normoxic and hypoxic conditions with an equal volume of an aqueous solution of 0.1mg/ml sodium bisulfite;
FIG. 4 is an injectable schematic of hydrogel formed by 20 wt% HB-PBAE-MNZ and 1 wt% HA-SH;
FIG. 5 shows the preparation of 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate according to an example of the present invention1H-NMR spectrum.
Detailed Description
The following is a further description of the invention and is not intended to limit the scope of the invention.
Putting 4g of metronidazole into a round-bottom flask, adding magnetons, adding 70ml of dichloromethane, adding 3ml of triethylamine into the solution, and uniformly mixing. Adding 10ml of chloroform into a constant pressure dropping funnel, adding 4ml of acryloyl chloride into the constant pressure dropping funnel, uniformly mixing, dropwise adding into the solution after preparation, and starting dropwise adding after gently stirring by a dropper.
Preparing broken ice blocks in advance, putting the broken ice blocks into an aluminum basin, adding a proper amount of water, and carrying out an ice-water bath reaction. And (3) putting the reaction system into an ice water bath for reaction for 12 hours, and then reacting at room temperature for 12 hours.
After the reaction is finished, the round-bottom flask is taken out by wearing a cloth glove, the round-bottom flask is wiped dry by using clean toilet paper, and each bottle mouth is opened to suck out small magnetons by using a magnet. Pouring off ice water for reaction, filtering the reaction solution, carrying out rotary evaporation on the filtrate for concentration, adding 50ml of chloroform for dilution after the filtrate is concentrated to about 15ml, washing with ultrapure water for three times, adding anhydrous calcium chloride particles into an organic phase for overnight drying after liquid separation, and carrying out rotary evaporation on the filtrate after filtration to obtain a light yellow solid product, namely the 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate.
By using1H NMR pairThe chemical structure of the 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate prepared in the example of the present invention is characterized, and from FIG. 5, it is clear that an absorption peak at 8.2ppm of hydrogen atoms on imidazole groups, an absorption peak at 2.3ppm of methyl groups on imidazole groups, an absorption peak at 5.9-6.6ppm of double bonds, and an absorption peak at 3.8-4.3ppm of methylene groups are observed, and the structure of 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate is well characterized, thereby proving that the 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate is successfully synthesized.
The low-oxygen responsive injectable hydrogel and the preparation method thereof are illustrated by taking the active hydrogen on the ethylenediamine and the double bond on the PEGDA-700 as 1.25:1 as an example.
1.56ml of polyethylene glycol diacrylate (PEGDA, number average molecular weight 700) was added to 3.7ml of DMSO and stirred until dispersed uniformly. 0.067ml of ethylenediamine was added to 1ml of DMSO. The two solutions were mixed in a round bottom flask and reacted for 6h at 80 ℃ in an oil bath. 0.8g of 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate (active hydrogen on ethylenediamine: the double bond of 2- (2-methyl-5-nitro-1H-imidazol-1-yl) ethyl acrylate is 1.25:0.5) was dissolved in 2ml of DMSO, and added to the above reaction solution to continue the reaction for 4 hours to obtain a nitroimidazole group-terminated hyperbranched polyamino ester (HB-PBAE-MNZ). After cooling, the product is purified three times by using more than five times of diethyl ether. The product was collected and stored at-20 ℃.
Preparing HB-PBAE-MNZ into 20 wt% aqueous solution, preparing thiolated hyaluronic acid into 1 wt% aqueous solution, blending according to the volume ratio of 1:1, performing vortex stirring to fully react, and standing at room temperature for 3min to obtain the hydrogel.
By using1H NMR shows the chemical structure of the nitro imidazole group-terminated hyperbranched polyaminoester (HB-PBAE-MNZ) prepared by the embodiment of the invention, as can be seen from figure 1, a peak with chemical shift of about 8.0ppm is a peak corresponding to hydrogen on imidazole, and the existence of the nitro imidazole group in HB-PBAE-MNZ is proved; in addition, the hydrogen on the double bond had three peaks at chemical shifts of about 6.2ppm, 6.3ppm and 6.0ppm, demonstrating that there were still unreacted double bonds, and thusThe successful synthesis of HB-PBAE-MNZ was demonstrated.
As can be seen from FIG. 2, after a 20 wt% HB-PBAE-MNZ aqueous solution and a 1 wt% thiolated hyaluronic acid aqueous solution were blended in a volume ratio of 1:1 and left standing for 3min, the mixed solution therein after the tube was turned over did not flow, thereby demonstrating that the mixed aqueous solution of HB-PBAE-MNZ and thiolated hyaluronic acid formed a hydrogel.
The Hypoxia responsiveness of the hyperbranched polyaminoester (HB-PBAE-MNZ) terminated by the nitroimidazole group prepared by the embodiment of the invention is tested according to the reference (Hypoxia-reactive block copolymers as anti-cancer drugs for enhanced chemoradiotherapeutics of bulk solid tumors, Biomaterials,181(2018): 360-371). In FIG. 3, curves (1) and (2) are UV curves after an aqueous solution of HB-PBAE-MNZ with a mass fraction of 0.2% was reduced by an equal volume of an aqueous solution of 0.1mg/ml sodium bisulfite under normoxic and hypoxic conditions for 4h, respectively. As can be seen from FIG. 3, the absorption peak at 310nm representing the nitroimidazole group is still high under the normoxic condition; under the condition of low oxygen, the peak of the nitroimidazole is obviously reduced, so that the nitroimidazole is reduced by a reducing agent under the condition of low oxygen, namely, the nitroimidazole group-terminated hyperbranched polyamino ester (HB-PBAE-MNZ) prepared by the embodiment of the invention has low-oxygen responsiveness. The subsequent hydrogel obtained by the same method is subjected to a hypoxia responsiveness test, and a similar result is obtained, namely the hydrogel prepared by the embodiment of the invention has hypoxia responsiveness.
As can be seen from FIG. 4, the hydrogel prepared in the example of the present invention has injectability.
The preparation of the natural polymer-based injectable hydrogel can be realized by adjusting the process parameters according to the content of the invention, and the performance of the hydrogel is basically consistent with that of the embodiment of the invention.
The invention has been described in an illustrative manner, and it is to be understood that any simple variations, modifications or other equivalent changes which can be made by one skilled in the art without departing from the spirit of the invention fall within the scope of the invention.
Claims (8)
1. A hypoxia-responsive injectable hydrogel, comprising: the preparation method comprises the following steps:
(1) uniformly mixing a dimethyl sulfoxide solution of polyethylene glycol diacrylate and a dimethyl sulfoxide solution of ethylenediamine, wherein the molar ratio of double bonds of the polyethylene glycol diacrylate to active hydrogen of the ethylenediamine is 1 (1.1-1.4), and reacting in an oil bath to enable the double bonds of the polyethylene glycol diacrylate and amino groups of the ethylenediamine to generate Michael addition reaction to obtain hyperbranched polyamino ester;
(2) adding a dimethyl sulfoxide solution of 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate into the reaction solution in the step (1), wherein the molar ratio of the double bonds of the 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate to the active hydrogen of the ethylenediamine in the step (1) is (0.2-0.8): (1.1-1.4), continuing to react in an oil bath to react double bonds on the 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate with unreacted amino in the reaction solution in the step (1) to obtain hyperbranched polyamino ester terminated by nitroimidazole groups;
(3) uniformly mixing the aqueous solution of the nitroimidazole group-terminated hyperbranched polyaminoester prepared in the step (2) with the aqueous solution of the thiolated hyaluronic acid, wherein the mass ratio of the nitroimidazole group-terminated hyperbranched polyaminoester to the thiolated hyaluronic acid is (10-20): 1, fully reacting to enable unreacted double bonds on the nitroimidazole group-terminated hyperbranched polyaminoester to generate Michael addition reaction with sulfydryl on the sulfhydrylated hyaluronic acid, and generating the three-dimensional reticular stereo polymer.
2. The hypoxia-responsive injectable hydrogel of claim 1, wherein: in the step (1), the polyethylene glycol diacrylate and the ethylenediamine react for 5-7 hours in an oil bath at the temperature of 70-90 ℃.
3. The hypoxia-responsive injectable hydrogel of claim 1, wherein: in the step (2), 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate and hyperbranched polyamino ester continuously react for 3-5H in an oil bath at the temperature of 70-90 ℃; the molar ratio of the double bond of the 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate to the active hydrogen of the ethylenediamine in the step (1) is (0.2-0.5): (1.1-1.4).
4. The hypoxia-responsive injectable hydrogel of claim 1, wherein: in the step (3), the mass percentage concentration of the nitroimidazole group-terminated hyperbranched polyaminoester aqueous solution is 20 wt%, the mass percentage concentration of the thiolated hyaluronic acid aqueous solution is 1 wt%, and the nitroimidazole group-terminated hyperbranched polyaminoester aqueous solution and the thiolated hyaluronic acid aqueous solution are mixed according to the volume ratio of 1: 1; fully carrying out the reaction by vortex stirring; the gelling temperature is room temperature, and the gelling time is 3-4 min.
5. A method for preparing a hypoxia-responsive injectable hydrogel, comprising: the method comprises the following steps:
(1) uniformly mixing a dimethyl sulfoxide solution of polyethylene glycol diacrylate and a dimethyl sulfoxide solution of ethylenediamine, wherein the molar ratio of double bonds of the polyethylene glycol diacrylate to active hydrogen of the ethylenediamine is 1 (1.1-1.4), and reacting in an oil bath to enable the double bonds of the polyethylene glycol diacrylate and amino groups of the ethylenediamine to generate Michael addition reaction to obtain hyperbranched polyamino ester;
(2) adding a dimethyl sulfoxide solution of 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate into the reaction solution in the step (1), wherein the molar ratio of the double bonds of the 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate to the active hydrogen of the ethylenediamine in the step (1) is (0.2-0.8): (1.1-1.4), continuing to react in an oil bath to react double bonds on the 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate with unreacted amino in the reaction solution in the step (1) to obtain hyperbranched polyamino ester terminated by nitroimidazole groups;
(3) uniformly mixing the aqueous solution of the nitroimidazole group-terminated hyperbranched polyaminoester prepared in the step (2) with the aqueous solution of the thiolated hyaluronic acid, wherein the mass ratio of the nitroimidazole group-terminated hyperbranched polyaminoester to the thiolated hyaluronic acid is (10-20): 1, fully reacting to enable unreacted double bonds on the nitroimidazole group-terminated hyperbranched polyaminoester to generate Michael addition reaction with sulfydryl on the sulfhydrylated hyaluronic acid, and generating the three-dimensional reticular stereo polymer.
6. The method of preparing a hypoxia-responsive injectable hydrogel according to claim 5, wherein: in the step (1), the polyethylene glycol diacrylate and the ethylenediamine react for 5-7 hours in an oil bath at the temperature of 70-90 ℃.
7. The method of preparing a hypoxia-responsive injectable hydrogel according to claim 5, wherein: in the step (2), 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate and hyperbranched polyamino ester continuously react for 3-5H in an oil bath at the temperature of 70-90 ℃; the molar ratio of the double bond of the 2- (2-methyl-5-nitro-1H-imidazole-1-yl) ethyl acrylate to the active hydrogen of the ethylenediamine in the step (1) is (0.2-0.5): (1.1-1.4).
8. The method of preparing a hypoxia-responsive injectable hydrogel according to claim 5, wherein: in the step (3), the mass percentage concentration of the nitroimidazole group-terminated hyperbranched polyaminoester aqueous solution is 20 wt%, the mass percentage concentration of the thiolated hyaluronic acid aqueous solution is 1 wt%, and the nitroimidazole group-terminated hyperbranched polyaminoester aqueous solution and the thiolated hyaluronic acid aqueous solution are mixed according to the volume ratio of 1: 1; fully carrying out the reaction by vortex stirring; the gelling temperature is room temperature, and the gelling time is 3-4 min.
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