CN112641951A - Bioactive supermolecule chiral hydrogel and preparation method and application thereof - Google Patents
Bioactive supermolecule chiral hydrogel and preparation method and application thereof Download PDFInfo
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- CN112641951A CN112641951A CN202011508561.4A CN202011508561A CN112641951A CN 112641951 A CN112641951 A CN 112641951A CN 202011508561 A CN202011508561 A CN 202011508561A CN 112641951 A CN112641951 A CN 112641951A
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- A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
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Abstract
The invention discloses a bioactive supermolecule chiral hydrogel and a preparation method and application thereof. The preparation method comprises the following steps: under the condition of physiological pH, mixing guanosine and/or guanosine derivatives and benzoxaborole drug molecules with an aqueous solution, heating the mixture to be completely dissolved, and then cooling the mixture to room temperature to prepare the bioactive supermolecule chiral hydrogel;wherein the molecule of the benzoxaborole drug has a structure represented by any one of the following formulas:
the invention combines benzoxaborole derivatives with guanosine compounds by using a dynamic covalent bond crosslinking strategy, and realizes the conversion of the benzoxaborole derivatives into supermolecule chiral hydrogel with high-efficiency biological activity under the physiological pH condition for the first time through a simple one-step heating-cooling process; the method is simple and green, convenient to operate and mild in reaction conditions, and the synthesized bioactive supramolecular chiral hydrogel can effectively solve the problems of low loading efficiency, complex synthesis and the like of other bioactive supramolecular hydrogels.
Description
Technical Field
The invention belongs to the technical field of supramolecular gel, and particularly relates to a bioactive supramolecular chiral hydrogel and a preparation method and application thereof, in particular to a bioactive supramolecular chiral hydrogel based on a dynamic covalent bond crosslinking strategy and a preparation method and application thereof.
Background
In recent years, supramolecular chiral hydrogel with biological activity has potential application in cell culture, tissue engineering, biological imaging, wound healing and the like. The most common strategy for preparing bioactive supramolecular chiral hydrogels is to physically encapsulate bioactive molecules into the hydrogel by non-covalent interactions, or to chemically modify bioactive molecules into the gel matrix by covalent cross-linking strategies. Such physical coating or covalent crosslinking may not only impart specific functions to the hydrogel, but may also enhance the activity of the biomolecules. However, the strategy of using hydrogels as carriers for physical encapsulation with weak non-covalent interactions has low loading efficiency and potential toxic side effects. The method of chemical modification by strong covalent bond is complex in synthesis and high in cost. Developing a simple and feasible strategy to prepare supramolecular chiral hydrogels with efficient bioactivity remains a great challenge.
The benzoxaborole derivatives are novel antifungal, antiviral and anti-inflammatory drugs, and have high biological activity. In the prior art, most of the research focuses on the interaction between the drug molecules and specific receptors, and the conversion of the benzoxaborole drug molecules into hydrogel agents with good solubility, stability and controlled release property is not explored. It is reported that natural guanosine can associate with different boronic acid compounds through the formation of dynamic boronic ester bonds and further self-assemble to form stable supramolecular hydrogels. The borate bond is a special dynamic covalent bond, the bond energy of the borate bond is between a non-covalent bond and a covalent bond, and the borate bond has the reversible characteristic of the non-covalent bond and the relative stability of the covalent bond, and has been widely used for constructing stimulus-responsive intelligent gel materials. In an alkaline environment, the o-diol reacts with boric acid to form a borate complex, and the stability of the borate complex is closely related to the pH value in a system. When the pH in the solution is above the pKa of the boronic acid compound, the vicinal diol complexes with the boronic acid. However, due to the relatively high pKa values of most boronic acids (8-9), guanosine-boronic acid hydrogels generally need to be prepared under strongly basic conditions (e.g., KOH or NaOH solutions) and thus do not meet the stringent requirements for biomedical applications.
Disclosure of Invention
The invention mainly aims to provide a bioactive supermolecular chiral hydrogel and a preparation method and application thereof, so as to overcome the defects of the prior art.
In order to achieve the purpose, the technical scheme adopted by the invention comprises the following steps:
the embodiment of the invention provides a preparation method of a bioactive supramolecular chiral hydrogel, which comprises the following steps:
under the condition of physiological pH, mixing guanosine and/or guanosine derivatives and benzoxaborole drug molecules with an aqueous solution, heating the mixture to be completely dissolved, and then cooling the mixture to room temperature to prepare the bioactive supermolecule chiral hydrogel; in the process, the benzoxaborole drug molecules and the guanosine compound are mutually combined through forming dynamic borate bonds, and further self-assembled to form stable supermolecular chiral hydrogel with intrinsic bioactivity. Wherein the benzoxaborole drug molecule has a structure represented by any one of formula (I) to formula (IV):
further, the aqueous solution includes any one of a DMEM solution and a PBS solution, and is not limited thereto.
In the invention, the bioactive supermolecule chiral hydrogel is prepared based on a dynamic covalent bond crosslinking strategy.
The embodiment of the invention also provides the bioactive supermolecular chiral hydrogel prepared by the method.
The embodiment of the invention also provides application of the bioactive supramolecular chiral hydrogel in the field of biomedicine.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention provides a simple and feasible method for preparing supermolecule chiral hydrogel with high-efficiency biological activity by a dynamic covalent bond crosslinking strategy; the benzoxaborole derivatives are a special class of cyclic half-boric acid compounds, and have a low pKa value (7.2); the invention combines the benzoxaborole derivatives with guanosine compounds, and directly converts the benzoxaborole drug molecules into supermolecule chiral hydrogel with high-efficiency bioactivity by a simple one-step heating-cooling process under the physiological pH condition for the first time; the method is simple and green, convenient to operate, mild in reaction conditions, simple and efficient, does not need complicated synthesis and purification steps, and is easy to popularize;
(2) due to the reversible characteristic of a dynamic covalent bond, the bioactive supramolecular chiral hydrogel prepared by the invention has better self-healing property and injectability, has gel-sol response characteristics to various stimuli such as temperature, shearing force, hydrogen peroxide, ATP and the like, and can be used as a novel drug molecule release platform;
(3) the supermolecule chiral hydrogel prepared by the invention is based on natural base guanosine and benzoxaborole type pharmaceutically active molecules, has good biocompatibility, lower cytotoxicity and antibacterial property, has high-efficiency bactericidal activity on gram-positive bacteria and gram-negative bacteria, and has good application prospect in the field of biomedicine.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments described in the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a physical diagram of the bioactive supramolecular chiral hydrogel prepared in example 1 of the invention;
fig. 2 is a self-healing performance test chart of the bioactive supramolecular chiral hydrogel prepared in example 1 of the invention;
fig. 3a-3c are graphs of the rheological test of frequency scan, strain scan and time scan of the bioactive supramolecular chiral hydrogel prepared in example 1 of the invention;
FIGS. 4 a-4 b are nuclear magnetic representations of the bioactive supramolecular chiral hydrogel prepared in example 1 of the invention;
FIG. 5 is a circular dichroism chromatogram representation of the bioactive supramolecular chiral hydrogel prepared in example 1 of the invention;
FIG. 6 shows cytotoxicity tests of bioactive supramolecular chiral hydrogels prepared in example 1 of the present invention;
FIGS. 7 a-7 b show the in vitro antibacterial activity test of the bioactive supramolecular chiral hydrogel prepared in example 1 of the invention on Escherichia coli and Staphylococcus aureus, respectively;
fig. 8 is a graph showing the stimulus response of the bioactive supramolecular chiral hydrogel prepared in example 1 to temperature, shear force and ATP.
Detailed Description
In view of the defects of the prior art, the inventor of the present invention has long studied and largely practiced to propose the technical solution of the present invention, which will be clearly and completely described below, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
One aspect of the embodiments of the present invention provides a method for preparing a bioactive supramolecular chiral hydrogel, which includes:
under the condition of physiological pH, mixing guanosine and/or guanosine derivatives and benzoxaborole drug molecules with an aqueous solution, heating the mixture to be completely dissolved, and then cooling the mixture to room temperature to prepare the bioactive supermolecule chiral hydrogel; in this process, the benzoxaborole drug molecules and the guanosine compound are combined with each other through forming a dynamic borate bond, and further self-assemble to form a stable supramolecular chiral hydrogel with intrinsic bioactivity, wherein the benzoxaborole drug molecules have a structure shown in any one of formula (I) to formula (IV):
in some more specific embodiments, the guanosine and/or guanosine derivative includes any one or a combination of two or more of guanosine, isoguanosine, 8-bromoguanosine, and 8-aminoguanosine, without being limited thereto.
In some specific embodiments, the mole ratio of the guanosine and/or guanosine derivative to the benzoxaborole drug molecules is 2: 1-2.
Further, the mass ratio of the guanosine and/or the guanosine derivative to the aqueous solution is 1-8: 100.
In some specific embodiments, the temperature of the heating treatment is 90-100 ℃ and the time is 5-30 min.
In some more specific embodiments, the aqueous solution includes any one of a DMEM solution and a PBS buffer solution, but is not limited thereto.
Further, the pH value of the aqueous solution is 6-10.
Further, the pH value of the PBS solution is 6-10, and the preferable pH value is 7.4.
Further, the pH of the DMEM solution is 7.0.
Further, the PBS solution was prepared by a conventional method.
The invention provides a dynamic covalent bond synthesis strategy, which directly converts benzoxaborole drug molecules into supramolecular chiral hydrogel with bioactivity under the condition of physiological pH by forming guanosine cis-diol-boric acid ester bonds.
In the invention, the inventor also proves that the prepared bioactive supermolecule chiral hydrogel has lower cytotoxicity on human liver cancer cells (HEPG-2).
In the invention, the inventor also proves that the prepared bioactive supermolecular chiral hydrogel has high bactericidal activity on gram-positive bacteria and gram-negative bacteria.
Another aspect of embodiments of the invention also provides bioactive supramolecular chiral hydrogels prepared by the foregoing methods.
Further, the bioactive supramolecular chiral hydrogel has low cytotoxicity.
Furthermore, the bioactive supermolecule chiral hydrogel has antibacterial property.
Further, the bioactive supramolecular chiral hydrogel has bactericidal activity against both gram-positive and gram-negative bacteria.
Further, the supramolecular hydrogel has bioactivity and chirality.
Further, the bioactive supramolecular chiral hydrogel exhibits multiple response characteristics to temperature, shear force, ATP, etc., and has high bactericidal activity against both gram-positive and gram-negative bacteria.
Another aspect of the embodiments of the present invention also provides a use of the aforementioned bioactive supramolecular chiral hydrogel in the biomedical field.
The technical solutions of the present invention are further described in detail below with reference to several preferred embodiments and the accompanying drawings, which are implemented on the premise of the technical solutions of the present invention, and a detailed implementation manner and a specific operation process are provided, but the scope of the present invention is not limited to the following embodiments.
The experimental materials used in the examples used below were all available from conventional biochemical reagents companies, unless otherwise specified.
Example 1
Accurately weighing 30.0mg of guanosine, 18.5mg of benzoxaborole drug molecules (having a structure shown in a formula (III)), 1000mg of PBS (pH value of 7.4) buffer solution into a glass vial, heating at 95 ℃ for 20min until the drugs are completely dissolved, and naturally cooling to obtain a bioactive supramolecular chiral hydrogel sample (shown in figure 1). In the bioactive supermolecule chiral hydrogel, the molar ratio of guanosine to benzoxaborole drug molecules is 2:1, and the weight of guanosine accounts for 3% of the weight of a PBS (pH value is 7.4) buffer solution.
Example 2
Accurately weighing 10.0mg of guanosine, 12.4mg of benzoxaborole drug molecules (with the structure shown in formula (III)), 1000mg of DMEM solution in a glass vial, heating at 90 ℃ for 30min until the drug molecules are completely dissolved, and naturally cooling to obtain the bioactive supramolecular chiral hydrogel sample. In the bioactive supermolecule chiral hydrogel, the molar ratio of guanosine to benzoxaborole drug molecules is 1:1, and the weight of guanosine accounts for 1% of that of a DMEM solution.
Example 3
Accurately weighing 80.0mg of isoguanosine and 42.9mg of benzoxaborole drug molecules (having a structure shown in formula (I)), putting 1000mg of DMEM solution into a glass vial, heating at 100 ℃ for 5min until the drug molecules are completely dissolved, and naturally cooling to obtain the bioactive supramolecular chiral hydrogel sample. In the bioactive supermolecule chiral hydrogel, the molar ratio of isoguanosine to benzoxaborole drug molecules is 1:1, and the mass of isoguanosine accounts for 8% of the mass of a DMEM solution.
Example 4
Accurately weighing 30.0mg of isoguanosine, 14.2mg of benzoxaborole drug molecules (with a structure shown in a formula (II)), 1000mg of PBS (with a pH value of 7.4) buffer solution into a glass vial, heating at 96 ℃ for 25min until the buffer solution is completely dissolved, and naturally cooling to obtain the bioactive supermolecule chiral hydrogel sample. In the bioactive supermolecule chiral hydrogel, the molar ratio of isoguanosine to benzoxaborole drug molecules is 1:1, and the mass of isoguanosine accounts for 3% of the mass of a PBS (pH 7.4) buffer solution.
Example 5
Accurately weighing 50.0mg of 8-bromoguanosine and 15.0mg of benzoxaborole drug molecules (having a structure shown in formula (IV)), putting 1000mg of DMEM solution into a glass vial, heating at 97 ℃ for 15min until the DMEM solution is completely dissolved, and naturally cooling to obtain the bioactive supramolecular chiral hydrogel sample. In the bioactive supermolecule chiral hydrogel, the molar ratio of 8-bromoguanosine to benzoxaborole drug molecules is 2:1, and the mass of 8-bromoguanosine accounts for 5% of the mass of a DMEM solution.
Example 6
Accurately weighing 50.0mg of 8-aminoguanosine, 29.3mg of benzoxaborole drug molecules (having a structure shown in a formula (III)), 1000mg of PBS (with the pH value of 7.4) solution in a glass vial, heating at 92 ℃ for 28min until the drugs are completely dissolved, and naturally cooling to obtain the bioactive supramolecular chiral hydrogel sample. In the bioactive supermolecule chiral hydrogel, the molar ratio of 8-aminoguanosine to benzoxaborole drug molecules is 2:1, and the mass of 8-aminoguanosine accounts for 5% of the mass of a PBS (pH value is 7.4) solution.
To verify the beneficial effects of the present invention, the inventors of the present application tested the bioactive supramolecular chiral hydrogel prepared in example 1 as an example:
1. self-healing performance test of bioactive supermolecule chiral hydrogel
The block of bioactive supramolecular chiral hydrogel prepared in example 1 (see fig. 2) was cut into three sections, one of the sections was stained for easy observation, three gels were then allowed to contact each other, and after 2h, the gel block did not fall off after the two ends of the gel were lifted, and it was seen that the gel had good self-healing properties.
2. Rheological testing of bioactive supramolecular chiral hydrogels
Bioactive supramolecular chiral hydrogels were prepared and subjected to rheological testing as in example 1 (as shown in figures 3a-3 c), and the storage modulus (G') of the hydrogels was observed to be higher than the loss modulus (G ") in the dynamic frequency sweep, indicating the presence of a solid-like viscoelastic hydrogel network. The strain scan demonstrated the presence of a linear viscoelastic region in the hydrogel. The gradual strain scanning test shows that the prepared bioactive supermolecule chiral hydrogel has good thixotropy and can be quickly restored to a gel state after being damaged by larger stress.
3. Structural characterization of bioactive supramolecular chiral hydrogel
In the preparation method of example 1, guanosine and compound III first form a dynamic boronic ester compound and further aggregate to form a supramolecular chiral hydrogel. The formation of the borate compound can be verified by boron nuclear magnetic spectrum. As shown in FIG. 4a, the boron signal for the free compound III molecule in DMSO solution appeared at 24.51ppm, whereas in PBS solution, the signal shifted to 26.97ppm with a new boron signal appearing at 6.18ppm, demonstrating the formation of the new compound, guanosine- (bis) benzoxaboronate. After hydrogel formation, the boron signal of free compound III shifted to 29.38ppm and the signal of guanosine- (bis) benzoxaboronate shifted to 11.31 ppm. The bioactive supramolecular chiral hydrogel prepared in example 1 is lyophilized, and the obtained xerogel powder is subjected to high-resolution mass spectrometry, and the result is shown in fig. 4b, wherein the peak 878.28 in the spectrogram is the molecular ion peak of the guanosine- (bis) benzoxaboronate compound. These results fully demonstrate that the cis diol in guanosine ribose reacts with the cyclic hemi boronic acid group in compound III to form a dynamic boronic ester bond at physiological pH (7.4).
4. Circular dichroism characterization of bioactive supermolecule chiral hydrogel
Bioactive supramolecular chiral hydrogels were prepared and characterized by circular dichroism according to the method of example 1 (fig. 5). As shown in fig. 5, the supramolecular chiral hydrogel prepared in example 1 showed a strong negative circular dichroism signal at 324nm at room temperature, and the signal intensity gradually decreased with increasing temperature (accompanied by gel-sol conversion), indicating that a wide range of left-handed helical supramolecular chiral structures are present in the hydrogel.
5. Cytotoxicity testing of bioactive supramolecular chiral hydrogels
Bioactive supramolecular chiral hydrogels were prepared according to the method of example 1 and analyzed for cellular compatibility with HEPG-2 cells by MTT cytotoxicity assay. The specific experimental process is as follows: a suspension of human hepatoma cells (HEPG-2) was prepared in DMEM medium containing 10% (V/V) PBS and 1% penicillin/streptomycin, then 100. mu.L of the cells were seeded in a 96-well cell culture plate, and placed in an incubator to incubate for 24 hours, then the solution in the 96-well plate was removed, then 100. mu.L of DMEM solution containing hydrogels (0-4000. mu.g/mL) of different concentrations were added, incubation was continued for 24 hours, then MTT (5mg/mL) was added to each well, after incubation for 4 hours, the solution in the plate was discarded, 100. mu.L of DMSO solution was added to each well, and after shaking, the absorbance of MTT at 570nm was measured using a microplate reader. The experimental results are shown in fig. 6, and the results show that the activity of the HEPG-2 cells is maintained between 85% and 100% after 48 hours of incubation, which indicates that the bioactive supramolecular chiral hydrogel has excellent cell compatibility.
6. Antibacterial property test of bioactive supermolecule chiral hydrogel
Bioactive supramolecular chiral hydrogels were prepared according to the method of example 1 and tested against gram-negative escherichia coli and gram-positive bacteria staphylococcus aureus by agar pore diffusion experimentsThe antimicrobial activity of (1). The specific experimental process is as follows: the concentration of the used bacteria is 1x106CFU/mL cell suspension was spread on the surface of the solidified medium, perforated with a 0.9mm diameter punch, and 200ul of hydrogel precursor solution (0.7% W/V) was injected into the hole and the hot precursor solution gelled within 20 minutes. The medium was then incubated at 37 ℃ for 24 h. The experimental results are shown in figures 7 a-7 b, and the results show that the inhibition zone of the bioactive supramolecular chiral hydrogel sample on escherichia coli is 28mm, and the inhibition zone on staphylococcus aureus is 21 mm.
7. Stimulus responsiveness test of bioactive supramolecular chiral hydrogel
Bioactive supramolecular chiral hydrogels prepared according to example 1 were sensitive to various external stimuli (e.g. temperature, shear forces, ATP, H)2O2Etc.) has a gel-sol response characteristic (as shown in fig. 8). As the temperature increases, the supramolecules dissociate and the hydrogel transforms into a solution; in the presence of low concentrations of adenosine triphosphate (ATP, 10mM), the hydrogel was completely dissociated within 8h due to its competition; at H2O2Under the oxidation action, the hydrogel is rapidly degraded; under the action of shearing force, the hydrogel is changed into free flowing liquid, and can be recovered to a stable gel state after standing for a period of time (2h40min), which indicates that the hydrogel has excellent thixotropy.
In addition, the inventors of the present invention have also made experiments with other materials, process operations, and process conditions described in the present specification with reference to the above examples, and have obtained preferable results.
The aspects, embodiments, features and examples of the present invention should be considered as illustrative in all respects and not intended to be limiting of the invention, the scope of which is defined only by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.
The use of headings and chapters in this disclosure is not meant to limit the disclosure; each section may apply to any aspect, embodiment, or feature of the disclosure.
Throughout this specification, where a composition is described as having, containing, or comprising specific components or where a process is described as having, containing, or comprising specific process steps, it is contemplated that the composition of the present teachings also consist essentially of, or consist of, the recited components, and the process of the present teachings also consist essentially of, or consist of, the recited process steps.
It should be understood that the order of steps or the order in which particular actions are performed is not critical, so long as the teachings of the invention remain operable. Further, two or more steps or actions may be performed simultaneously.
While the invention has been described with reference to illustrative embodiments, it will be understood by those skilled in the art that various other changes, omissions and/or additions may be made and substantial equivalents may be substituted for elements thereof without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims. Moreover, unless specifically stated any use of the terms first, second, etc. do not denote any order or importance, but rather the terms first, second, etc. are used to distinguish one element from another.
Claims (10)
1. A preparation method of a bioactive supramolecular chiral hydrogel is characterized by comprising the following steps:
under the condition of physiological pH, mixing guanosine and/or guanosine derivatives and benzoxaborole drug molecules with an aqueous solution, heating the mixture to be completely dissolved, and then cooling the mixture to room temperature to prepare the bioactive supermolecule chiral hydrogel; wherein the benzoxaborole drug molecule has a structure represented by any one of formula (I) to formula (IV):
2. the method of claim 1, wherein: the guanosine and/or guanosine derivative comprises any one of guanosine, isoguanosine, 8-bromoguanosine and 8-aminoguanosine.
3. The method of claim 1, wherein: the mole ratio of the guanosine and/or the guanosine derivative to the benzoxaborole drug molecules is 2: 1-2.
4. The method of claim 1, wherein: the weight ratio of the guanosine and/or the guanosine derivative to the aqueous solution is 1-8: 100.
5. The method of claim 1, wherein: the temperature of the heating treatment is 90-100 ℃, and the time is 5-30 min.
6. The method of claim 1, wherein: the aqueous solution comprises a DMEM solution and/or a PBS buffer solution; preferably, the pH value of the aqueous solution is 6-10.
7. The method of claim 6, wherein: the DMEM solution had a pH of 7.0.
8. The method of claim 6, wherein: the pH of the PBS buffer solution was 7.4.
9. A bioactive supramolecular chiral hydrogel prepared by the method of any one of claims 1-8;
preferably, the bioactive supramolecular chiral hydrogel has low cytotoxicity; preferably, the bioactive supramolecular chiral hydrogel has antibacterial property; preferably, the bioactive supramolecular chiral hydrogel has bactericidal activity against both gram-positive and gram-negative bacteria.
10. Use of the bioactive supramolecular chiral hydrogel according to claim 9 in the biomedical field.
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