CN111621038A - Albumin hydrogel, and preparation method and application thereof - Google Patents
Albumin hydrogel, and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides an albumin hydrogel which is prepared by mixing albumin, a cross-linking agent and a solvent; the cross-linking agent comprises a repeating unit with a structure shown in a formula (I) and a terminal group with a structure shown in a formula (II). The invention develops an albumin hydrogel which is fast in crosslinking, low in gelling concentration and free of biotoxicity, and is applied to the fields of cell culture, tissue engineering and drug delivery. In addition, as a good paclitaxel local treatment drug carrier, the invention solves the defect of poor paclitaxel solubility, does not introduce polyoxyethylene castor oil with biotoxicity, and effectively reduces the administration times, increases the drug concentration at the tumor and reduces the systemic toxicity compared with a systemic preparation. The nanometer particle coating the taxol is used as the gel forming component of the gel, so that the taxol can be uniformly distributed in the gel, and the stable and continuous release can be realized.
Description
Technical Field
The invention belongs to the technical field of high polymer materials, and particularly relates to an albumin hydrogel, and a preparation method and application thereof.
Background
Chemically crosslinked hydrogels are materials that are crosslinked by covalent bonds, have a three-dimensional (3D) network structure, and contain a large amount of water or biological fluids, and generally have good stability, durability, and mechanical properties. The hydrogel can be divided into two categories, namely natural polymer and synthetic polymer according to different sources of the components. The natural polymer mainly comprises polysaccharides such as chitosan and hyaluronic acid, and proteins such as collagen, gelatin and albumin; the synthetic polymer mainly comprises polymethacrylic acid derivatives, polyester, polyether, polyamino acid materials and the like. Among such a wide variety of hydrogels, protein-based hydrogels constructed using natural proteins as basic structural units have a wide application prospect in the aspects of sensing, drug delivery, tissue engineering, artificial organs, and the like due to good biocompatibility, viscoelasticity, and in-vivo degradability, and among them, albumin is often used in the biomedical field as a protein-based gel material due to its characteristics of good solubility, good stability, in-tumor accumulation, easy availability, biodegradability, nontoxicity, and the like.
International cancer research machine according to 2018Recent data from the Institute of America (IARC) survey showed that breast cancer has an incidence of 24.2% in female cancers worldwide, and is the first place for female cancers. Paclitaxel, one of the most excellent natural anticancer drugs found at present, has been widely used for treating breast cancer clinically. However, paclitaxel has very poor water solubility, which greatly affects its therapeutic efficiency. Therefore, it is commonly used in clinic
A preparation with polyoxyethylated castor oil and ethanol as solvent for improving solubility of paclitaxel is provided. However, the introduction of polyoxyethylated castor oil may cause allergic reactions in the body. In order to reduce the toxicity and increase the therapeutic efficacy of paclitaxel, researchers have developed a number of carriers for the delivery of drugs, such as paclitaxel lipid physically pamoate, micellar paclitaxel, which have been used clinically
And albumin-bound paclitaxel
However, the paclitaxel preparations are systemic therapeutic preparations and have the disadvantages of more administration times and large systemic toxicity. Therefore, it is important to develop new topical therapeutic formulations that can reduce the number of administrations, increase the drug concentration at the tumor, and reduce systemic toxicity. Injectable hydrogels are a commonly used local treatment carrier, and have received extensive attention in the local drug release and tumor treatment fields with the advantages of being minimally invasive, site-specific, prolonging drug release time, low systemic toxicity, and being capable of delivering hydrophilic and hydrophobic agents.
The prior art discloses a variety of albumin-based hydrogels, such as those prepared using disulfide bonds in BSA for redox stimuli responsive hydrogels (Scientific Reports,2015,5:15977), prepared for drug delivery by reacting tyrosine residues in BSA with epoxy moieties of epichlorohydrin (ACS substinable chem. eng.,2018,6:3321-3330) and prepared for cancer therapy and luminescence imaging by reacting amino groups in BSA with glutaraldehyde to encapsulate ruthenium-polypyridine complexes (Journal of organic Biochemistry,2019,194:19-25), all of which have good biocompatibility and in vivo degradability. However, these hydrogels reported to date have certain disadvantages in preparation, such as long gelling time, high gelling concentration and the need for potentially toxic small molecules as cross-linking agents, which greatly limits their application in cell culture and tissue engineering.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a fast-crosslinking, low-gel-forming concentration, non-biotoxic albumin hydrogel, which is applied in the fields of cell culture, tissue engineering and drug delivery.
The invention provides an albumin hydrogel which is prepared by mixing albumin, a cross-linking agent and a solvent;
the cross-linking agent comprises a repeating unit with a structure shown in a formula (I) and an end group with a structure shown in a formula (II);
preferably, the crosslinking agent is selected from one or more compounds with structures from formula (III) to formula (V);
wherein n is the degree of polymerization, and n is more than or equal to 50 and less than or equal to 100; m is polymerization degree, and m is more than or equal to 25 and less than or equal to 50; p is polymerization degree, and p is more than or equal to 67 and less than or equal to 133.
Preferably, the albumin is selected from bovine serum albumin, human serum albumin, bovine serum albumin nanoparticles, human serum albumin nanoparticles, bovine serum albumin/paclitaxel nanoparticles or human serum albumin/paclitaxel nanoparticles.
Preferably, the bovine serum albumin nanoparticles, the human serum albumin nanoparticles, the bovine serum albumin/paclitaxel nanoparticles or the human serum albumin/paclitaxel nanoparticles are prepared by a desolvation method.
Preferably, the solvent is selected from water, physiological saline, a buffer solution, a tissue culture solution or a body fluid.
The invention also provides a preparation method of the albumin hydrogel, which comprises the following steps:
and mixing the albumin solution with the cross-linking agent solution to obtain the albumin hydrogel.
Preferably, the albumin solution is a mixture of albumin and a solvent, and the mass volume concentration of albumin in the albumin solution is 4-20%.
Preferably, the cross-linking agent solution is a mixture of a cross-linking agent and a solvent, and the mass volume concentration of the cross-linking agent in the cross-linking agent solution is 4-20%.
Preferably, the mixing temperature is 25-37 ℃.
The invention also provides application of the albumin hydrogel in tissue engineering and drug delivery.
Compared with the prior art, the invention provides the albumin hydrogel which is prepared by mixing albumin, a cross-linking agent and a solvent; the cross-linking agent comprises a repeating unit with a structure shown in a formula (I) and a terminal group with a structure shown in a formula (II). The invention develops an albumin hydrogel which is fast in crosslinking, low in gelling concentration and free of biotoxicity, and is applied to the fields of cell culture, tissue engineering and drug delivery. In addition, as a good paclitaxel local treatment drug carrier, the invention solves the defect of poor paclitaxel solubility, does not introduce polyoxyethylene castor oil with biotoxicity, and effectively reduces the administration times, increases the drug concentration at the tumor and reduces the systemic toxicity compared with a systemic preparation. The nanometer particle coating the taxol is used as the gel forming component of the gel, so that the taxol can be uniformly distributed in the gel, and the stable and continuous release can be realized.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of an o-phthalaldehyde derivative prepared in example 9 of the present invention;
FIG. 2 is a NMR spectrum of 4aPEG-OPA prepared in example 10 of the present invention;
FIG. 3 shows the results of mechanical strength tests of albumin hydrogel with a mass concentration of 4%;
FIG. 4 shows the results of mechanical strength tests of albumin hydrogel with a mass concentration of 8%;
FIG. 5 shows the results of the measurement of the mechanical strength of the hydrogel composed of albumin-paclitaxel nanoparticles with mass concentrations of 8%, 10%, and 12%;
FIG. 6 shows the results of testing the mechanical strength of hydrogels composed of albumin-paclitaxel nanoparticles at 8%, 10% and 12% by mass concentration;
FIG. 7 is a scanning electron microscope photograph of the gel prepared in example 17;
FIG. 8 is a scanning electron microscope photograph of the gel prepared in example 18;
FIG. 9 shows the results of an in vitro degradation experiment for the gel prepared in example 19;
FIG. 10 shows the cytotoxicity results of gel materials at different concentrations on L929 cells.
Detailed Description
The invention provides an albumin hydrogel which is prepared by mixing albumin, a cross-linking agent and a solvent;
the cross-linking agent comprises a repeating unit with a structure shown in a formula (I) and an end group with a structure shown in a formula (II);
in some embodiments of the invention, the crosslinking agent is selected from one or more compounds having the structures of formula (III) to formula (v);
wherein n is the degree of polymerization, and n is more than or equal to 50 and less than or equal to 100; m is polymerization degree, and m is more than or equal to 25 and less than or equal to 50; p is polymerization degree, and p is more than or equal to 67 and less than or equal to 133.
In some embodiments of the invention, the crosslinking agent is selected from compounds having the structure of formula (III).
In the present invention, the albumin is selected from bovine serum albumin, human serum albumin, bovine serum albumin nanoparticles, human serum albumin nanoparticles, bovine serum albumin/paclitaxel nanoparticles or human serum albumin/paclitaxel nanoparticles.
Wherein the bovine serum albumin nanoparticles, the human serum albumin nanoparticles, the bovine serum albumin/paclitaxel nanoparticles or the human serum albumin/paclitaxel nanoparticles are prepared by a desolvation method.
Specifically, a certain amount of bovine serum albumin or human serum albumin is dissolved in deionized water, and after stirring and dissolving, the pH is adjusted to 7.0-9.0, preferably 7.7, so as to obtain a protein solution.
Dissolving a certain amount of paclitaxel in anhydrous ethanol to obtain paclitaxel ethanol solution.
Wherein the mass ratio of albumin to paclitaxel is 20: 1-10: 1, and the volume ratio of deionized water to absolute ethyl alcohol is 1: 2-1: 4
Then, setting the rotating speed at 400-600 rpm, dropwise adding the absolute ethyl alcohol or paclitaxel ethanol solution into the protein solution, and stirring for 24 hours at room temperature. Dialyzing for 3 days after the reaction, and freeze-drying to obtain bovine serum albumin nanoparticles or human serum albumin nanoparticles or bovine serum albumin/paclitaxel nanoparticles or human serum albumin/paclitaxel nanoparticles.
In the present invention, the solvent is selected from water, physiological saline, a buffer solution, a tissue culture solution or a body fluid, and preferably a buffer solution.
The invention also provides a preparation method of the albumin hydrogel, which comprises the following steps:
and mixing the albumin solution with the cross-linking agent solution to obtain the albumin hydrogel.
Specifically, albumin is dissolved in a solvent to obtain an albumin solution. The solvent is selected from water, physiological saline, buffer solution, tissue culture solution or body fluid, preferably buffer solution. The mass volume concentration of albumin in the albumin solution is 4-20%, preferably 5-15%.
And dissolving the crosslinking agent in a solvent to obtain a crosslinking agent solution. The solvent is selected from water, physiological saline, buffer solution, tissue culture solution or body fluid, preferably buffer solution. The mass volume concentration of the cross-linking agent in the cross-linking agent solution is 4-20%, preferably 5-15%.
And then mixing the albumin solution with the cross-linking agent solution to obtain the albumin hydrogel. The mixing temperature is 25-37 ℃.
The invention also provides application of the albumin hydrogel in tissue engineering and drug delivery.
The albumin hydrogel provided by the invention has the following beneficial effects:
1. the invention has short gelling time and low gelling concentration, can realize quick crosslinking gelling without other crosslinking agents, and can conveniently regulate and control the gelling time and the mechanical strength of the gel by changing the concentration ratio of the components. When the albumin component is the drug-loaded nano-particles, the drug-loaded amount of the gel can be changed by changing the concentration of the nano-particles, so that the subsequent medical application is facilitated.
2. The invention takes the drug-loaded nano particles as the gel-forming component of the gel, can uniformly distribute the paclitaxel in the gel, and is beneficial to realizing the stable and long-term release of the paclitaxel.
3. The invention is a local therapeutic preparation, which avoids the use of toxic solvent, reduces the administration times, increases the drug concentration at the tumor and reduces the systemic toxicity.
In order to further understand the present invention, the albumin hydrogel, the preparation method and the application thereof provided by the present invention are illustrated below with reference to the following examples, and the scope of the present invention is not limited by the following examples.
Example 1
300mg of bovine serum albumin was added to deionized water, dissolved by stirring, and the pH was adjusted to 7.0 with 0.2mol/L sodium hydroxide solution. Add 15mg of paclitaxel into absolute ethanol, stir and dissolve. The bovine serum albumin solution was stirred at 500r/min, and the paclitaxel ethanol solution was added dropwise to the bovine serum albumin solution at 0.5mL/min, and stirred at room temperature for 24 h. After the reaction is finished, adding the reaction solution into a dialysis bag, dialyzing with deionized water for three days, and then freeze-drying to obtain bovine serum albumin/paclitaxel nanoparticles.
The high performance liquid chromatography analysis of the obtained nanoparticles shows that the paclitaxel is successfully encapsulated in the bovine serum albumin, and the drug loading is 2.0%.
Example 2
300mg of bovine serum albumin was added to deionized water, dissolved by stirring, and the pH was adjusted to 7.7 with 0.2mol/L sodium hydroxide solution. Add 15mg of paclitaxel into absolute ethanol, stir and dissolve. The bovine serum albumin solution was stirred at 500r/min, and the paclitaxel ethanol solution was added dropwise to the bovine serum albumin solution at 0.5mL/min, and stirred at room temperature for 24 h. After the reaction is finished, adding the reaction solution into a dialysis bag, dialyzing with deionized water for three days, and then freeze-drying to obtain bovine serum albumin/paclitaxel nanoparticles.
The high performance liquid chromatography analysis of the obtained nanoparticles shows that the paclitaxel is successfully encapsulated in the bovine serum albumin, and the drug loading is 3.9%.
Example 3
300mg of bovine serum albumin was added to deionized water, dissolved by stirring, and the pH was adjusted to 8.0 with 0.2mol/L sodium hydroxide solution. Add 15mg of paclitaxel into absolute ethanol, stir and dissolve. The bovine serum albumin solution was stirred at 500r/min, and the paclitaxel ethanol solution was added dropwise to the bovine serum albumin solution at 0.5mL/min, and stirred at room temperature for 24 h. After the reaction is finished, adding the reaction solution into a dialysis bag, dialyzing with deionized water for three days, and then freeze-drying to obtain bovine serum albumin/paclitaxel nanoparticles.
The high performance liquid chromatography analysis of the obtained nano particles shows that the taxol is successfully encapsulated in the bovine serum albumin, and the drug loading is 0.019%.
Example 4
300mg of bovine serum albumin was added to deionized water, dissolved by stirring, and the pH was adjusted to 9.0 with 0.2mol/L sodium hydroxide solution. Add 15mg of paclitaxel into absolute ethanol, stir and dissolve. The bovine serum albumin solution was stirred at 500r/min, and the paclitaxel ethanol solution was added dropwise to the bovine serum albumin solution at 0.5mL/min, and stirred at room temperature for 24 h. After the reaction is finished, adding the reaction solution into a dialysis bag, dialyzing with deionized water for three days, and then freeze-drying to obtain bovine serum albumin/paclitaxel nanoparticles.
The high performance liquid chromatography analysis of the obtained nano particles shows that the taxol is successfully encapsulated in the bovine serum albumin, and the drug loading is 0.00023%.
Example 5
300mg of bovine serum albumin was added to deionized water, dissolved by stirring, and the pH was adjusted to 7.7 with 0.2mol/L sodium hydroxide solution. Add 15mg of paclitaxel into absolute ethanol, stir and dissolve. The bovine serum albumin solution was stirred at 500r/min, and the paclitaxel ethanol solution was added dropwise to the bovine serum albumin solution at 1mL/min, and stirred at room temperature for 24 h. After the reaction is finished, adding the reaction solution into a dialysis bag, dialyzing with deionized water for three days, and then freeze-drying to obtain bovine serum albumin/paclitaxel nanoparticles.
The high performance liquid chromatography analysis of the obtained nanoparticles shows that the paclitaxel is successfully encapsulated in the bovine serum albumin, and the drug loading is 1.0%.
Example 6
300mg of bovine serum albumin was added to deionized water, dissolved by stirring, and the pH was adjusted to 7.7 with 0.2mol/L sodium hydroxide solution. 30mg of paclitaxel was added to the absolute ethanol, and dissolved with stirring. The bovine serum albumin solution was stirred at 500r/min, and the paclitaxel ethanol solution was added dropwise to the bovine serum albumin solution at 0.5mL/min, and stirred at room temperature for 24 h. After the reaction is finished, adding the reaction solution into a dialysis bag, dialyzing with deionized water for three days, and then freeze-drying to obtain bovine serum albumin/paclitaxel nanoparticles.
The high performance liquid chromatography analysis of the obtained nanoparticles shows that the paclitaxel is successfully encapsulated in the bovine serum albumin, and the drug loading is 8.9%.
Example 7
300mg of bovine serum albumin was added to deionized water, dissolved by stirring, and the pH was adjusted to 7.7 with 0.2mol/L sodium hydroxide solution. 30mg of paclitaxel was added to the absolute ethanol, and dissolved with stirring. The bovine serum albumin solution was stirred at 500r/min, and the paclitaxel ethanol solution was added dropwise to the bovine serum albumin solution at 1mL/min, and stirred at room temperature for 24 h. After the reaction is finished, adding the reaction solution into a dialysis bag, dialyzing with deionized water for three days, and then freeze-drying to obtain bovine serum albumin/paclitaxel nanoparticles.
The high performance liquid chromatography analysis of the obtained nanoparticles shows that the paclitaxel is successfully encapsulated in the bovine serum albumin, and the drug loading is 6.3%.
Example 8
300mg of bovine serum albumin was added to deionized water, dissolved by stirring, and the pH was adjusted to 7.7 with 0.2mol/L sodium hydroxide solution. The bovine serum albumin solution was stirred at 500r/min, and the absolute ethanol solution was added dropwise to the bovine serum albumin at 0.5mL/min, followed by stirring at room temperature for 24 hours. After the reaction is finished, adding the reaction solution into a dialysis bag, dialyzing with deionized water for three days, and then freeze-drying to obtain the bovine serum albumin nano particles.
Example 9
12g of 3, 4-dimethylbenzoic acid and 57g N-bromosuccinimide were dissolved in 200mL of warm carbon tetrachloride. 1.62g of benzoyl peroxide was added to the reaction mixture and refluxed at 81 ℃ for 15 h. The resulting white precipitate was filtered while hot and washed three times with benzene (3X 100mL) and diethyl ether (3X 100mL), respectively. The combined filtrates were evaporated and the residue was dissolved in 300mL of 10% sodium carbonate solution. The solution was washed with dichloromethane and acidified to pH 1 with concentrated hydrochloric acid, then extracted with ethyl acetate (4 × 60 mL). The organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo. The light yellow solid was purified by crystallization in acetonitrile to obtain 3, 4-bis (dibromomethyl) benzoic acid.
Mixing 3, 4-bis (II)Bromomethyl) benzoic acid was dissolved in 180mL of 10% sodium carbonate solution and reacted at 70 ℃ for 4 hours the reaction mixture was acidified to pH 1 with hydrochloric acid in an ice-water bath and extracted with ethyl acetate (5 × 40mL), the organic phase was washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo, the yellow solid thus obtained was dissolved in 100mL of anhydrous methanol and used with 750mg of Sc (OTf) at room temperature3The treatment was carried out overnight. Then, methanol was evaporated, the mixture was dissolved in 100mL of acetonitrile, and 4.8g of NHS and 8.1g of EDC · HCl were added. The mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was dissolved in dichloromethane, washed three times with saturated brine, and dried over magnesium sulfate. The crude product was purified by silica gel chromatography in n-hexane/ethyl acetate to give the o-phthalaldehyde derivative.
The obtained o-phthalaldehyde derivative was subjected to nuclear magnetic resonance analysis, and fig. 1 is a nuclear magnetic resonance hydrogen spectrum of the o-phthalaldehyde derivative prepared in example 9 of the present invention.
Example 10
2g of amino-terminated four-arm polyethylene glycol (4 aPEG-NH)2) With 514mg of the o-phthalaldehyde derivative prepared in example 8 dissolved in 25mL of anhydrous dichloromethane, 0.5mL of pyridine was added. The mixture was stirred at room temperature for 2 days and precipitated in cold ether to give a four-arm polyethylene glycol terminated with an o-phthalaldehyde derivative. Then it was dissolved in 5mL of deionized water, and 5mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 1 hour and diluted to 50 mL. The mixture was dialyzed for 2 days and lyophilized to give a phthalic aldehyde terminated four-arm polyethylene glycol (4 aPEG-OPA).
The obtained 4aPEG-OPA was subjected to nuclear magnetic resonance analysis, and FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the 4aPEG-OPA prepared in example 10 of the present invention.
Example 11
The crosslinking agent prepared in example 10 and bovine serum albumin were prepared into a 4% solution by using a PBS buffer solution with a pH of 7.4, the two solutions were mixed in equal volumes, the gel formation time was measured by a tubule inversion method after being mixed uniformly by using a vortex apparatus, the gelation was determined without flowing within 30s when the tubule was inverted, the gel formation time was recorded, and the gel formation time of the albumin hydrogel with a mass concentration of 4% at 37 ℃ was 309 ± 6 s.
Example 12
The crosslinking agent prepared in example 10 and bovine serum albumin were prepared into 8% by mass concentration using PBS buffer solution with pH 7.4, and the two solutions were mixed in equal volumes, and after being mixed uniformly by a vortex apparatus, gel formation time was measured by a small tube inversion method, and gel formation time was recorded as no flow within 30s when the small tube was inverted, and gel formation time of 8% by mass albumin hydrogel at 37 ℃ was 151 ± 6 s.
Example 13
The crosslinking agent prepared in example 10 and bovine serum albumin were prepared into a 4% solution by mass concentration using a PBS buffer solution with pH 7.4, and the two solutions were mixed in equal volumes, and after being uniformly mixed by a vortex apparatus, the mixture was rapidly transferred to a rotational rheometer to measure the mechanical strength, and as a result, referring to fig. 3, the mechanical strength of the 4% albumin hydrogel was 600 Pa.
Example 14
The crosslinking agent prepared in example 10 and bovine serum albumin were prepared into a solution having a mass concentration of 8% using a PBS buffer solution having a pH of 7.4, respectively, and the two were mixed in equal volumes, and after being uniformly mixed by using a vortex apparatus, the mixture was rapidly transferred to a rotational rheometer to measure the mechanical strength thereof, and as a result, referring to fig. 4, the mechanical strength of the albumin hydrogel having a mass concentration of 8% was 13000 Pa.
Example 15
The cross-linking agent prepared in example 10 and the bovine serum albumin/paclitaxel nanoparticles prepared in example 2 were mixed in equal volumes with PBS buffer solution with pH of 7.4 to obtain solutions with mass concentrations of 6% (cross-linking agent concentration) and 8% -12% (nanoparticle concentration), and the solutions were rapidly transferred to a rotational rheometer to measure the mechanical strength after being mixed uniformly with a vortex instrument, and as a result, referring to fig. 5, the mechanical strengths of hydrogels consisting of albumin and paclitaxel nanoparticles with mass concentrations of 8%, 10%, and 12% were 900Pa, 2100Pa, and 4900Pa, respectively.
Example 16
The cross-linking agent prepared in example 10 and the bovine serum albumin/paclitaxel nanoparticles prepared in example 6 were mixed in equal volumes with PBS buffer solution with pH of 7.4 to obtain solutions with mass concentrations of 6% (cross-linking agent concentration) and 8% -12% (nanoparticle concentration), and the solutions were rapidly transferred to a rotational rheometer to measure the mechanical strength after being uniformly mixed by using a vortex instrument, and as a result, referring to fig. 6, the mechanical strengths of hydrogels consisting of albumin and paclitaxel nanoparticles with mass concentrations of 8%, 10%, and 12% were 300Pa, 1000Pa, and 2800Pa, respectively.
Example 17
The cross-linking agent prepared in example 10 and bovine serum albumin were prepared into a 4% solution by mass concentration using PBS buffer solution with pH 7.4, and the two solutions were mixed in equal volumes, mixed uniformly by a vortex apparatus, gelled at 37 ℃, and lyophilized, and then the scanning electron microscope image is shown in fig. 7. As can be seen from fig. 7, the gel has a porous structure, is beneficial to the transmission of nutrients and the embedding of drugs, and can be applied to the fields of tissue engineering and drug delivery.
Example 18
The cross-linking agent prepared in example 10 and bovine serum albumin were prepared into 8% solutions by mass concentration using PBS buffer solution with pH 7.4, and the two solutions were mixed in equal volumes, mixed uniformly by a vortex apparatus, gelled at 37 ℃, and lyophilized, and then the scanning electron microscope image is shown in fig. 8. As can be seen from fig. 8, the gel has a porous structure, is beneficial to the transmission of nutrients and the embedding of drugs, and can be applied to the fields of tissue engineering and drug delivery.
Example 19
The crosslinking agent prepared in example 10 and the bovine serum albumin nanoparticles prepared in example 8 were prepared into solutions with mass concentrations of 6% (crosslinking agent concentration) and 8% -12% (nanoparticle concentration) respectively using a PBS buffer solution with pH of 7.4, the two solutions were mixed in equal volumes, and after being uniformly mixed by a vortex apparatus, the mixture was left to stand at 37 ℃ to form gel. After the gel was stabilized, a PBS buffer solution having a pH of 7.4 and a PBS buffer solution having a concentration of elastase of 1U/mL were added thereto, respectively, and incubated at 37 ℃. At a specific time point the liquid was blotted dry and the gel mass was weighed. Then, PBS buffer solution with pH of 7.4 and PBS buffer solution of elastase with concentration of 1U/mL were added, and incubation was continued at 37 ℃. The degradation curve is shown in figure 9, and the in vitro degradation experiment result shows that the gel has certain stability and can be degraded under the simulated in vivo condition in the presence of elastase, so that the biodegradability of the gel is proved, and the gel is beneficial to biomedical application.
Example 20
Mouse fibroblasts L929 were seeded at 8000 cells/well in 96-well plates, 200 μ L of complete medium (90% DMEM medium + 10% newborn bovine serum) per well, and incubated in an incubator for 24 h. After 24 hours, the culture plate is taken out, 20 mu L of PBS buffer solution with the pH value of 7.4, 10-0.625 mg/mL of bovine serum albumin nano particles prepared by the embodiment 8 and the cross-linking agent 4aPEG-OPA prepared by the embodiment 10 are respectively added into the culture plate to reach the final concentration of 1-0.0625 mg/mL, and the culture plate is placed in an incubator to be incubated for 24 hours. And taking out the culture plate after 24h, sucking the culture medium, washing the culture plate for 2-3 times by using PBS (phosphate buffer solution), adding 10% CCK-8 solution in a dark place, placing the culture plate in an incubator for incubation for 1h, and testing the absorbance of the culture plate at 450nm and 630nm by using an enzyme-labeling instrument. The cytotoxicity of the materials with different concentrations on L929 cells is shown in figure 10, and the experimental result shows that the materials have no cytotoxicity on normal fibroblasts, so that the gel is proved to have no biological toxicity and can be applied to the field of biomedicine.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. An albumin hydrogel is characterized by being prepared by mixing albumin, a cross-linking agent and a solvent;
the cross-linking agent comprises a repeating unit with a structure shown in a formula (I) and an end group with a structure shown in a formula (II);
2. the albumin hydrogel of claim 1, wherein the cross-linking agent is selected from one or more compounds having the structures of formula (III) to formula (v);
wherein n is the degree of polymerization, and n is more than or equal to 50 and less than or equal to 100; m is polymerization degree, and m is more than or equal to 25 and less than or equal to 50; p is polymerization degree, and p is more than or equal to 67 and less than or equal to 133.
3. The albumin hydrogel of claim 1, wherein the albumin is selected from the group consisting of bovine serum albumin, human serum albumin, bovine serum albumin nanoparticles, human serum albumin nanoparticles, bovine serum albumin/paclitaxel nanoparticles, and human serum albumin/paclitaxel nanoparticles.
4. The albumin hydrogel of claim 3, wherein the bovine serum albumin nanoparticles, human serum albumin nanoparticles, bovine serum albumin/paclitaxel nanoparticles, or human serum albumin/paclitaxel nanoparticles are prepared by a desolvation method.
5. The albumin hydrogel of claim 1, wherein the solvent is selected from the group consisting of water, physiological saline, a buffer solution, a tissue culture solution, and a body fluid.
6. A method of preparing an albumin hydrogel according to any one of claims 1 to 5, comprising the steps of:
and mixing the albumin solution with the cross-linking agent solution to obtain the albumin hydrogel.
7. The method according to claim 6, wherein the albumin solution is a mixture of albumin and a solvent, and the albumin solution has a mass volume concentration of 4% to 20%.
8. The method according to claim 6, wherein the crosslinking agent solution is a mixture of a crosslinking agent and a solvent, and the mass volume concentration of the crosslinking agent in the crosslinking agent solution is 4 to 20%.
9. The method according to claim 6, wherein the mixing temperature is 25 to 37 ℃.
10. Use of the albumin hydrogel of any one of claims 1 to 5 in tissue engineering and drug delivery.
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