CN116196468A - Dithiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel and application thereof in antibacterial aspect - Google Patents
Dithiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel and application thereof in antibacterial aspect Download PDFInfo
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- CN116196468A CN116196468A CN202310303999.6A CN202310303999A CN116196468A CN 116196468 A CN116196468 A CN 116196468A CN 202310303999 A CN202310303999 A CN 202310303999A CN 116196468 A CN116196468 A CN 116196468A
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- hydrogel
- folic acid
- thiosemicarbazide
- polydopamine
- ligand
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Abstract
The invention relates to a novel hydrogel synthesized by loading a bis-thiosemicarbazide ligand on folic acid hydrogel, wherein the bis-thiosemicarbazide ligand HL 1 =2, 6-diacetylpyridine bis-thiosemicarbazone; HL (HL) 2 =2, 6-diacetylpyridine-N 4‑ Methyl thiosemicarbazone; the invention utilizes transition metal ion Zn 2+ Crosslinked dopamine, bis-thiosemicarbazide ligand and folic acid synthesize an injectable hydrogel. The two carboxyl groups in the FA molecule and catechol in polydopamine are easy to combine with Zn 2+ A metal complex is formed to match the injectable hydrogel to the wound shape. The polydopamine modified folic acid material loads a double thiosemicarbazide ligand with an antibacterial effect through electrostatic interaction and hydrogen bonding. Experiments show that compared with blank hydrogel without the loaded ligand and the independent ligand, the antibacterial effect of the ligand-loaded hydrogel is improved remarkably, and a valuable reference is provided for the application of the ligand-loaded hydrogel in the antibacterial field.
Description
Technical Field
The invention belongs to the technical field of hydrogels, and particularly relates to a double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel and an application thereof in antibacterial aspect.
Background
Wound bacterial infections and inflammatory reactions caused by bacteria and fungi are severely threatening the life safety of humans. In order to solve a series of diseases caused by bacterial infection, a large number of antibiotics have been developed, but the overuse or improper use of antibiotics has resulted in the emergence of various resistant microorganisms in recent years. Accordingly, there is an urgent need to develop antibacterial biomaterials, which in some cases are used as alternatives to antibiotics to alleviate or solve the current problem of bacterial resistance. Among various antibacterial materials, the antibacterial hydrogel has a plurality of specific functions such as simple preparation process, various structures, excellent biocompatibility and oxidation resistance, and the like, and can replace antibiotics to treat bacterial infectious diseases, so that the antibacterial hydrogel attracts more and more attention.
Hydrogels are novel polymeric materials with three-dimensional network structures formed from hydrophilic polymer chains crosslinked by physical or covalent bonds. Hydrogels, whether formed from natural or synthetic polymers, have a three-dimensional network structure that absorbs a significant amount of moisture and retains a certain amount of moisture after swelling to equilibrium, and retains the original structure and properties without dissolving in water. Hydrogels have great advantages in wound healing due to their good biocompatibility, biodegradability, adjustable mechanical properties, high water content, control of tissue adhesion, maintenance of a moist environment at the wound site, and physical barrier to bacterial penetration. Therefore, hydrogel dressings have recently become a new type of medical dressing. Among them, the antibacterial function exhibited by the antibacterial hydrogel is the most needed in the medical field at present. The antibacterial hydrogel has good antibacterial activity, can provide a moist and massive hydrated environment for wounds, can effectively inhibit the growth of microorganisms such as bacteria on the wound surfaces of patients, and further can effectively reduce the infection probability of the wounds, so that the antibacterial hydrogel is widely applied to medical implant device coatings and skin infection treatment, replaces the traditional antibiotics for bacterial infection treatment, and can greatly relieve and eliminate the problems of bacterial drug resistance and the like.
Thiosemicarbazone is formed by thiosemicarbazone (NH) 2 -NH-CS-NH 2 ) Compounds condensed with aldehydes or ketones having a broad range of biological activity. Because the thiosemicarbazone compound contains N, S and other heteroatoms in the structure, the thiosemicarbazone compound has various biological activities such as bacteria resistance, fungi resistance, virus resistance, tumor resistance, parasite resistance and the like. In recent years, various thiosemicarbazone compounds have been studied, and among them, heterocyclic thiosemicarbazone compounds have been receiving a great deal of attention because of their excellent biological activity. A great deal of research shows that the biological activity of thiosemicarbazone compounds has high dependency on substituent groups, either by changing the structure of aldehyde ketone or by reacting with N 4 The optimization of the substituent groups can obtain compounds with different biological activities, so that the antibacterial and anticancer activities of the compounds are improved.
The invention develops the antibacterial hydrogel with good biocompatibility and high-efficiency antibacterial performance around the problem that bacterial infection affects wound healing. The invention utilizes two kinds of double thiosemicarbazide ligands to load on folic acid hydrogel to synthesize two kinds of novel hydrogels, two carboxyl groups in Folic Acid (FA) molecules and catechol in Polydopamine (PDA) are easy to combine with Zn 2+ Forming a metal complex, wherein electrostatic interaction and hydrogen bonding occur between the polydopamine modified folic acid material and the double thiosemicarbazide ligand. Experiments prove that compared with the blank hydrogel without the loaded ligand and the independent ligand, the antibacterial effect of the hydrogel with the loaded ligand is obviously improved. And is loaded with HL 2 Hydrogel specific loading HL of (C) 1 Has higher antibacterial activity. The invention is then subjected to MTT cytotoxicity test, and the test result shows that the hydrogel has smaller cytotoxicity, and the possible antibacterial mechanism is explored through experiments of cell membrane integrity, protein leakage, generation of Reactive Oxygen Species (ROS) and the like.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides the double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel which has good biocompatibility, excellent antibacterial performance and simple preparation method.
The invention also provides a preparation method of the double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel and application of the double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel in antibacterial aspect.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the preparation method of the double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel comprises the following steps:
1) Mixing Folic Acid (FA) with water and alkali to obtain a solution A;
2) Ligand HL 1 And/or HL (HL) 2 Mixing with dopamine hydrochloride (DA), adding into alkali liquor, adding dimethyl sulfoxide, stirring and reacting for 20-40min to perform self-polymerization on PDA to obtain solution B;
3) Mixing the solution A and the solution B to obtain a solution C;
4) Mixing the soluble zinc salt solution with the solution C to obtain the zinc salt.
The injectable folic acid coupled polydopamine hydrogel modified by the double thiosemicarbazide provided by the invention has the advantages that two carboxyl groups in FA molecules and catechol in Polydopamine (PDA) can be easily combined with Zn 2+ Forming a metal complex, wherein electrostatic interaction and hydrogen bonding occur between the polydopamine modified folic acid material and the double thiosemicarbazide ligand.
The step 1) specifically comprises the following steps: mixing and stirring 0.1-0.4. 0.4 g folic acid, 4-8 mL distilled water and 0.05-0.10 g sodium hydroxide to obtain solution A.
Specifically, in step 2), the ligand HL 1 Is 2, 6-diacetylpyridine bis-thiosemicarbazone, the ligand HL 2 Is 2, 6-diacetylpyridine-N 4 -methyl thiosemicarbazone.
Further, the ligand HL 1 The mass ratio of the compound to dopamine hydrochloride is 1:1; the ligand HL 2 The mass ratio of the compound to the dopamine hydrochloride is 1:1-2.
Specifically, the dosage of dopamine hydrochloride is 0.02-0.04 g, and the dosage of dimethyl sulfoxide is 15-30 mu L.
Further, in the step 4), the soluble zinc salt is zinc acetate, and the concentration of the soluble zinc salt solution is 0.17-0.30mol/L.
Specifically, the volume ratio of the soluble zinc salt solution to the solution C is 1: 0.8-1.5.
Further, in the step 1) and the step 2), the alkali is sodium hydroxide, and the alkali liquor is sodium hydroxide aqueous solution with the concentration of 1-2 mol/L.
The invention provides the double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel prepared by the preparation method.
The invention also provides application of the double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel in antibacterial aspect.
The invention provides a preparation method of a preferable double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel, which comprises the following steps:
1) Mixing and stirring 0.1-0.4 g folic acid, 4-8 mL distilled water and 0.05-0.10 g sodium hydroxide for 10 min to obtain transparent brick red solution A;
2) Ligand HL 1 、HL 2 Mixing with 0.02-0.04 g dopamine hydrochloride (which can be dissolved by ultrasonic assistance), adding into 1-2 mL mol/L sodium hydroxide aqueous solution, adding 15-30 mu L dimethyl sulfoxide (DMSO) as a catalyst, stirring and reacting for 20-40min to perform self-polymerization on PDA to obtain black solution B;
3) Mixing the solution A and the solution B to obtain a reddish brown solution C;
4) Colorless transparent zinc acetate solution with the concentration of 0.17-0.30mol/L is prepared by the following steps of: mixing 0.8-1.5 with solution C.
Folic acid hydrogels are formed by crosslinking transition metal ions (i.e., zn 2+ ) Dopamine (DA) and Folic Acid (FA), and an injectable FA/PDA hydrogel is synthesized. The injectable hydrogel can be matched with the shape of a wound, and has good antibacterial effect on staphylococcus aureus (typical gram-positive bacteria) and escherichia coli (typical gram-negative bacteria). In addition, such hydrogels can release zinc ions within 12 days, thereby producing a sustained antimicrobial effect. Thus, such antimicrobial hydrogels have great potential in reconstructing bacterially infected tissue, particularly exposed wounds. Thiosemicarbazone has good antibacterial activity, and the ligand HL is adopted in the invention 1 =2, 6-diacetylpyridine bis-thiosemicarbazone; HL (HL) 2 =2, 6-diacetylpyridine-N 4 The folic acid hydrogel modified by the methyl thiosemicarbazone can obtain two types, and the antibacterial effect of the folic acid hydrogel is superior to that of the antibacterial hydrogel of a single substance.
In the preparation process of the composite hydrogel, the first step comprises the steps of mixing a polydopamine solution and a folic acid solution. The second step is that the ligand thiosemicarbazide compound can be added into the polydopamine solution with the assistance of ultrasound, and the polydopamine/thiosemicarbazide mixed solution is formed through ultrasonic dissolution. The third step is Zn 2+ Coordination gelation with folic acid and polydopamine. Since hydrogels disrupt the integral cell membrane of bacterial cell membranes, the occurrence of intracellular tissue outflow from cells is likely to lead to bacterial death. Second, excess Reactive Oxygen Species (ROS) in bacterial cells can cause a series of oxidative stress reactions that lead to bacterial death. After the hydrogel prepared by the invention is loaded with different thiosemicarbazones, the formed composite hydrogel material has a sterilization effect and smaller cytotoxicity, and the actual antibacterial efficacy of the hydrogel is improved. . The invention also carries out a thiazole blue colorimetric Method (MTT) cytotoxicity test, which shows that the hydrogel has smaller cytotoxicity; and possible antibacterial mechanisms are explored through experiments of cell membrane integrity, protein leakage, reactive Oxygen Species (ROS) production and the like.
The invention discloses and reports that two kinds of bis-thiosemicarbazide ligands are loaded on folic acid hydrogel to synthesize two kinds of novel hydrogels. Taking into consideration the excellent biological activity of thiosemicarbazide and the injectability characteristic of polydopamine modified folic acid hydrogel, the obtained composite hydrogel is reasonably assumed to have dual advantages, high-efficiency antibacterial property and excellent injectability, and simultaneously has better cell activity, and the thiosemicarbazide is loaded on polydopamine modified folic acid and Zn is added 2+ The complex hydrogel subjected to the complex gelation was then subjected to an antibacterial test and a cell compatibility study.
The invention generates HL/PDA solution by mixing and self-polymerizing DA and HL; mixing the solution with FA solution to obtain FA/HL/PDA solution, and synthesizing Zn by one-step synthesis method 2+ Mixing and coordinating the solution with the FA/HL/PDA solution to obtain FA/HL/PAD hydrogel, and respectively applying the FA/HL/PAD hydrogel to the large intestineThe antibacterial efficacy of bacillus, bacillus cereus, staphylococcus aureus, agrobacterium tumefaciens, bacillus subtilis and the like is evaluated, the action mechanism of the antibacterial efficacy is explored, and the cell activity is tested. Compared with the prior art, the invention has the following beneficial effects:
1) The invention develops a method for introducing transition metal ion Zn for the first time 2+ Gelation is carried out as coordination ions, and efficient antibacterial ligands are added into the hydrogel, so that a novel green synthesis strategy of the injectable folic acid coupled polydopamine hydrogel modified by the double thiosemicarbazide is constructed;
2) The folic acid FA selected by the invention is a natural substance necessary for human body, and has anti-tumor effect and G-quadruple formation property. In addition, another natural substance, dopamine (DA) and its polymeric form, polydopamine (PDA), has found wide application in the fields of tissue engineering and other biomedical fields. PDA is often used to prepare hydrogels with self-healing function due to its highly reactive catechol groups, zinc ions (Zn 2+ ) The compound hydrogel has excellent antibacterial performance, synergistic and tissue repairing capacity, and wide pharmacological activity, such as antitumor, antibacterial, antiviral, antimalarial and the like, so that the synthesized compound hydrogel has excellent antibacterial property, injectability, wound healing promotion and other properties, and is used for preparing the hydrogel prepared from transition metal ions (Zn 2 + ) The cross-linked bis-thiosemicarbazide ligand (HL), dopamine (PDA) and Folic Acid (FA) synthesize an injectable composite hydrogel, which provides a realistic basis;
3) The composite hydrogel prepared by the invention has higher sterilization efficiency and good biocompatibility, and can maintain high-efficiency treatment effect in a certain time;
4) The double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel prepared by the invention has a certain antibacterial effect on gram-positive bacteria and bacterial gram-negative bacteria, and the antibacterial activity of a series of hydrogels with different ligand and polydopamine ratios is explored and compared. The invention systematically clarifies the possible bacteriostasis mechanism. The composite hydrogel has great application prospect in the biomedical field;
5) The double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel prepared by the method has injectability, can be perfectly attached to a wound, and has application prospects in the field of rapid wound repair.
Drawings
FIG. 1 is a schematic depiction of the synthetic route of the composite hydrogel according to the present invention;
in FIG. 2 (a) is HL 1 、FA/PDA、FA/HL 1 An infrared spectrum of PDA, (b) is HL 1 、FA/PDA、FA/HL 1 X-ray powder diffraction of PDA, (c) is HL 2 、FA/PDA、FA/HL 2 /PDA1、FA/HL 2 /PDA 1.5、FA/HL 2 An infrared spectrum of PDA 2, (d) is HL 2 、FA/PDA、FA/HL 2 /PDA1、FA/HL 2 /PDA 1.5、FA/HL 2 X-ray powder diffraction of PDA 2;
a, b, c, d in FIG. 3 are FA/PDA, FA/HL, respectively 1 /PDA、FA/HL 2 /PDA 1、FA/HL 2 SEM image of PDA 1.5 hydrogel;
FIG. 4 is FA/HL 2 Mapping diagram of PDA1 hydrogel;
FIG. 5 is FA/HL 2 X-ray photoelectron spectroscopy (XPS) of PDA1 hydrogel;
FIG. 6 is FA/PDA, FA/HL 1 /PDA、FA/HL 2 /PDA 1、FA/HL 2 /PDA 1.5、FA/HL 2 The PDA 2 hydrogel has a graph of the disc antibacterial effect on escherichia coli, staphylococcus aureus, bacillus cereus and agrobacterium tumefaciens;
FIG. 7 is FA/PDA, HL 1 、FA/HL 1 /PDA、HL 1 、FA/HL 2 /PDA 1、FA/HL 2 The PDA 2 hydrogel has a bacterial colony bacteriostasis effect graph for bacillus subtilis, agrobacterium tumefaciens, pseudomonas aeruginosa, escherichia coli, staphylococcus aureus and bacillus cereus;
FIG. 8 is a diagram of a warp FA/HL 2 PDA1 hydrogel treated escherichia coli antibacterial mechanism; (a) The effect of the composite material on bacterial cell membrane damage at optical density 260nm, (b) the leakage of protein in the cell membrane by the composite material at optical density 595 nm)An effect, (c) an effect of the composite on the activity of intracellular respiratory chain dehydrogenase at optical density 490, nm, (d) a generation of intracellular active oxygen content by the composite at optical density 575nm, (e) an effect of the composite on a change in intracellular Glutathione (GSH) content at optical density 412 nm;
FIG. 9 is FA/PDA, FA/HL 1 /PDA、FA/HL 2 Cytotoxicity of PDA1 hydrogel;
FIG. 10 is FA/HL 2 Injectability map of PDA1 hydrogel.
Detailed Description
The following describes the technical scheme of the present invention in further detail with reference to examples, but the scope of the present invention is not limited thereto.
In the examples described below, folic acid and dopamine hydrochloride were used as purchased from the technical company, budweiser, beijing, and 2, 6-diacetylpyridine was used as purchased from J & K chemical Co. 4-methyl-3-thiosemicarbazide and thiosemicarbazide were purchased from the Beijing carbofuran technologies Co. The detection tests of the antibacterial property, mechanism and the like are all determined by adopting the conventional technology in the field unless detailed description is given.
Example 1:
bis-thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel (FA/HL/PDA), wherein the chemical name of the bis-thiosemicarbazide ligand is: HL (HL) 1 =2, 6-diacetylpyridine bis-thiosemicarbazone; HL (HL) 2 =2, 6-diacetylpyridine-N 4 The hydrogen bond formed by the amino group in FA and the catechol group in PDA is connected with the PDA chain, in addition, the primary amino group in FA and the quinone group in PDA can also form the hydrogen bond, the amino group in the bis-thiosemicarbazide can form the hydrogen bond with the catechol group in PDA, and two carboxyl groups in FA molecules and catechol in polydopamine PDA can easily react with Zn 2+ Forming a metal complex, thereby forming a composite hydrogel material (FA/HL/PDA).
(1) Ligand bis (thiosemicarbazide) (HL) 1 、HL 2 ) Is prepared from
HL 1 Preparation method of =2, 6-diacetylpyridine bis-thiosemicarbazone: weighing 2, 6-diacetylpyrazolePyridine 0.2 g and thiocarbamide 0.22 g are dissolved in a 50 mL round bottom flask containing 30 mL absolute ethanol, 110 mu L of glacial acetic acid is added dropwise as a catalyst, stirred for 4 hours at 70 ℃ on a reflux heating stirrer, cooled to room temperature, filtered, and the product is collected after being dried to obtain the ligand.
HL 2 =2, 6-diacetylpyridine-N 4 -a process for the preparation of methyl thiosemicarbazone: 2, 6-diacetylpyridine (0.2 g,2 mmol) and 4-methyl-3-thiocarbamide (0.22 g,2 mmol) were weighed into a 50 mL round bottom flask, 30 mL ethanol was added thereto, 110. Mu.L glacial acetic acid was added dropwise thereto, the mixture was stirred and refluxed at 70℃for 4 hours, and the mixture was cooled to room temperature and filtered to obtain a pale yellow powdery solid, i.e., a ligand.
(2) The invention provides a preparation method of an injectable folic acid coupled polydopamine hydrogel modified by double thiosemicarbazide, which specifically comprises the following steps (the synthetic route is shown in figure 1):
1) Adding folic acid FA of 0.18 and g into distilled water of 4 mL, adding sodium hydroxide of 0.05 and g into the mixture, and stirring the mixed solution for 10 min until the solution is transparent to obtain transparent brick red solution A; in the step, FA is dissolved in alkaline water to generate folate, and folic acid molecules form a long chain through the hydrogen bonding action between folic acid molecules;
2) Ligand HL prior to gelation 1 (0.02g)、HL 2 (0.02 g) and dopamine hydrochloride DA (0.02 g, 0.03g, 0.04 g) were combined as HL, respectively 1 :DA=1:1、HL 2 Da=1: 1. 1:1.5, 1:2 into 1 mol/L sodium hydroxide aqueous solution of 1 mL, adding 20 mu L dimethyl sulfoxide (DMSO) as a catalyst into the mixed solution, stirring for 20 min to perform self-polymerization of HL/PDA solution (the solution is black after stirring), and obtaining black solution B; the step is the polymerization process of D, namely catechol groups and quinone groups in DA molecules react with each other to form PDA chains;
3) Mixing the solution A and the solution B to obtain a reddish brown solution C; adding the FA solution prepared in the first step into a PDA reagent, and connecting each FA long chain to form a net structure, namely the FA-PDA complex;
4) 0.385 and g zinc acetate is dissolved in 10 and mL distilled water and stirred to form colorless and transparent zinc acetate solution (concentration 0.21 mol/L).
5) Zinc acetate solution and solution C are mixed according to the volume ratio of 1:1. is mixed according to the proportion to form the sample hydrogel FA/HL containing the polydopamine with different mass concentrations 1 /PDA、 FA/HL 2 /PDA(FA/HL 2 /PDA 1、 FA/HL 2 /PDA 1.5、FA/HL 2 /PDA 2)。
In addition, the invention researches the injectability of the hydrogel, and the FA/HL prepared by the method 2 The relevant experiments were carried out for the example of the PDA1 hydrogel product: firstly, adopting a syringe to absorb a proper amount of FA/HL 2 PDA1 hydrogel sample, then slowly pushing the syringe to observe the phenomenon. FIG. 10 shows FA/HL 2 Injectability map of PDA1 hydrogel. As shown in FIG. 10, at 0S, FA/HL is shown as being inhaled into the syringe but not starting injection 2 Partial volume FA/HL can be seen in PDA1 hydrogel sample at 5S 2 PDA1 hydrogel samples were pushed out via syringe, the results showed that: FA/HL of the invention 2 The PDA1 hydrogel has certain injectability.
By way of contrast, the present application provides a synthesis of folic acid hydrogels, which are prepared specifically by the following steps:
1) Adding folic acid of 0.18 and g into distilled water of 4 mL, adding sodium hydroxide of 0.05 and g into the mixture, and stirring the mixed solution for 10 min until the solution is transparent to obtain transparent brick red solution A;
2) Adding 0.02g dopamine hydrochloride into 1 mol/L sodium hydroxide aqueous solution of 1 mL, adding 20 mu L dimethyl sulfoxide (DMSO) into the mixed solution, stirring for 20 min to perform self-polymerization of PDA (the solution after stirring is black), and obtaining black solution B;
3) Mixing the solution A and the solution B to obtain a reddish brown solution C;
4) Dissolving 0.385 and g zinc acetate in 10 mL distilled water, and stirring to form colorless and transparent acetic acid solution (0.21 mol/L);
5) Zinc acetate and solution C are mixed according to the volume ratio of 1:1. is mixed in a ratio of (2) to form a folic acid hydrogel (FA/PDA hydrogel).
A-d in FIG. 3 are FA/PDA, FA/HL, respectively 1 /PDA、FA/HL 2 /PDA 1、FA/HL 2 SEM image of PDA 1.5 hydrogel. As can be seen from fig. 3, the individual FA/PDA hydrogels shown in fig. 3 a show smooth surfaces and stacked nanoplatelets as well as a larger porous structure. FA/HL 1 PDA hydrogel and FA// HL 2 The surface of the PDA1 hydrogel (b, c in fig. 3) all showed significant wrinkling due to electrostatic interactions between the carboxyl groups of the hydrogel and the imino groups of the bis-thiosemicarbazide. In addition, SEM element mapping of C, O, N, S is shown in fig. 4, demonstrating successful formation of the composite.
In FIG. 2, a and b are FA/PDA and HL, respectively 1 、FA/HL 1 Infrared spectrum and X-ray powder diffraction of PDA, c and d are respectively HL 2 、FA/PDA、FA/HL 2 /PDA1、FA/HL 2 /PDA 1.5、FA/HL 2 Infrared spectrum and X-ray powder diffraction of PDA 2. As shown in FIG. 2 a, the FA/PDA hydrogel is at 1654 cm -1 A broad peak appears at 1577 cm due to c=o stretching vibrations -1 The absorption peak at this point is attributed to the N-H bending vibration. In HL 1 In the spectrum of 1586cm -1 The absorption peak of (2) is attributed to c=n stretching vibration, 1163 cm -1 The absorption peak of (2) belongs to N-N stretching vibration 821 cm -1 The absorption peak of (C) belongs to the c=s stretching vibration. At FA/HL 1 1185cm in PDA Spectrum −1 The characteristic signal spectrum at is due to HL 1 N-N in (A) indicating FA/HL 1 Successful synthesis of PDA. HL (HL) 2 、FA/PDA、FA/HL 2 /PDA1、FA/HL 2 /PDA 1.5、FA/HL 2 FT-IR spectrum of PDA 2 as shown in FIG. 2 c, HL 2 The absorption peaks at 1554, 1103 and 867cm-1 in the middle are respectively attributed tov(C=N))、v(N-N) andv(c=s). For FA/PDA hydrogels, at 1586cm -1 The absorption peak at the site is attributed tov((N-H) & lt/EN & gt at FA/HL) 2 In the PDA 1.5 hydrogel, HL 2 The N-N and N-H telescopic vibration bands of (a) are shifted by 1094cm -1 And 1586cm -1 This is due to the action of hydrogen bonding. Furthermore, HL 2 And typical characteristic absorption peaks of FA/PDA hydrogels appear at FA/HL 2 PDA hydrogelIn (a), show HL 2 And successful binding of FA/PDA hydrogel. The positions of the corresponding diffraction peaks were compared by XRD spectrum to further demonstrate the phase purity and similarity of the resulting crystalline compounds. For confirming the phase purity of the hydrogel. As can be seen from FIG. 2 b, FA/HL 1 Appearance of PDA hydrogel similar to HL 1 Is shown in the diffraction peak of FA/HL 1 HL in PDA hydrogel 1 . As shown in FIG. 2 d, for HL 2 Is observed to be located at 2θ=12.33 0 , 14.99 0 Is a peak of the same. Such as FA/HL 2 XRD spectrum of/PDA showed 2θ=9.98 0 A broad peak appears at this point, indicating FA/HL 2 The preparation of the PDA hydrogel was successful and was not doped with other impurities.
The chemical components and the related elements are subjected to valence state research by using an X-ray photoelectron spectroscopy (XPS) technology. As shown in FIG. 5, the prepared FA/HL 2 PDA1 hydrogel samples consisted of C, N, O, S and Zn elements uniformly dispersed in the prepared hydrogels, and XPS spectra of N1 s showed two distinct peaks at 398.7 and 399.4 eV, which were respectively of pyridine-N and triazine-N. Furthermore, two Wei Feng appeared at 163.1 eV and 164.1 eV in the S2 p XPS spectrum, ascribed to c=s, further demonstrating FA/HL 2 Successful preparation of the PDA1 hydrogel.
Example 2:
study of antibacterial Properties: the antibacterial properties were first evaluated by disc diffusion using a typical gram-negative bacterium (E.coliE.coiAgrobacterium tumefaciensA.tumefaciena) And gram positive bacteria (staphylococcus aureus)S.aureusBacillus cereusB.cereu) FA/PDA, FA/HL for the present invention 1 /PDA、FA/HL 2 /PDA 1、FA/HL 2 /PDA 1.5、FA/HL 2 The antibacterial properties of the PDA 2 hydrogel were evaluated. FA/PDA hydrogel was used as a blank control group and an experimental group loaded with different mass dopamine. As shown in FIG. 6, under the same experimental conditions, FA/HL 1 PDA hydrogel and FA/HL 2 The antibacterial performance of the PDA hydrogel is superior to that of the FA/PDA hydrogel, which shows that the ligand-loaded hydrogel has good antibacterial activity. And with FA/HL 1 /PDA comparison, FA/HL 2 The PDA hydrogel has better antibacterial performance, FA/HL 1 PDA and FA/HL 2 PDA has better antibacterial activity to staphylococcus aureus and bacillus cereus. And explore how much of the loaded dopamine content is for FA/HL 2 Impact of antibacterial Properties of PDA hydrogel, experimental results show that: along with the increase of the dopamine content, the inhibition zone has no obvious change, which indicates that the antibacterial effect of the composite hydrogel is not obviously enhanced.
Example 3:
the antibacterial properties of the composite hydrogels were evaluated using colony counting. The invention explores HL 1 、HL 2 、FA/PDA、FA/ HL 1 /PDA、FA/ HL 2 /PDA 1、FA/ HL 2 PDA 2 pair bacillus subtilisB.subtilis) Agrobacterium tumefaciens @A.tumefaciena) Pseudomonas aeruginosaP. aeruginosa) And bacillus cereusB.cereu) Coli @E.coi) And staphylococcus aureus @ sS.aureus) Is effective in inhibiting bacteria. As shown in FIG. 7, by exploring HL 1 、HL 2 And FA/PDA, the results show that the three hydrogel materials have a certain antibacterial effect on escherichia coli, agrobacterium tumefaciens, bacillus subtilis, staphylococcus aureus and bacillus cereus. Secondly explore FA/HL 1 /PDA、FA/HL 2 /PDA 1、FA/HL 2 The antibacterial effect of PDA 2 hydrogel on enterobacteria, rhizobium, bacillus subtilis, staphylococcus aureus and bacillus cereus, and the result shows that the FA/HL is carried out 1 /PDA、FA/ HL 2 /PDA 1、FA/ HL 2 The colony number of the escherichia coli, the agrobacterium tumefaciens, the bacillus subtilis, the staphylococcus aureus and the bacillus cereus cultured by the PDA 2 is greatly reduced, and the antibacterial effect is obviously enhanced. For E.coli (gram-negative bacteria) and Staphylococcus aureus (gram-positive bacteria), ligand HL was loaded 2 FA/HL of (a) 2 The antibacterial effect of the PDA hydrogel is obviously higher than that of the loading ligand HL 1 FA/HL of (a) 1 PDA hydrogel.
Example 4:
antibacterial mechanism experiment: bacteria and method for producing sameCell membrane integrity assay. The antimicrobial agent may interact directly with the cell membrane of the bacteria, thereby destroying the integrity of the cell membrane, potentially leading to leakage of nutrients and ultimately cell death. Release of small components and low molecular weight substances, including K+, PO 4 2− DNA and RNA, disrupting or impairing the function of the cell. The efflux of intracellular components, such as DNA and RNA, may exhibit specific absorption at 260 nm. Thus, an optical density value of 260nm can be determined as an indicator of bacterial membrane integrity. Coli group without composite hydrogel treatment is used as blank control group and is processed by FA/HL 2 As experimental groups, the E.coli group treated with PDA1 was cultured for 0min, 15min, and the optical density values at 260nm were not much different in the post-control group, as shown in FIG. 8 a. Optical Density value (OD) at 260nm in the experimental group compared with the control group 260 nm ) Obviously raise, and shows that the composite hydrogel FA/HL 2 PDA1 can cause severe damage to the bacterial membrane, and the integrity of the cell membrane is compromised resulting in leakage of some components within the bacterial body.
Antibacterial mechanism experiment: protein leakage test. Once the bacterial cell wall/membrane is destroyed, proteins within the bacterial cells can leak out of the cell. Thus, leakage of protein can be an indicator of disruption of cell wall/membrane integrity. Based on OD 595 nm Absorbance at the site, leakage of the protein was assessed to monitor cell membrane integrity. As shown in fig. 8 b, the optical density values (OD) at 595 and nm after incubation for 15, 30, 45, 60 min were observed for the control group 595 nm ) The changes were not significant, but the experimental group was significantly elevated, which also indicated that 2, 6-diacetylpyridine N was added 4 After the folic acid coupled polydopamine hydrogel modified by the methyl thiosemicarbazone, protein leakage is obviously increased, which also proves that the folic acid coupled polydopamine hydrogel can damage cell membranes of bacteria, thereby leading to bacterial death. This is consistent with the measurement of bacterial cell membrane integrity.
Antibacterial mechanism experiment: activity assay of respiratory chain dehydrogenase. Under physiological conditions, bacterial respiratory chain dehydrogenases can reduce colorless Iodonitrotetrazolium (INT) to dark red water insoluble Iodonitrotetrazolium (INF). Thus, it is possible toDetermination of optical Density value (OD) 490 nm ) To determine respiratory chain dehydrogenase activity via FA/HL as shown in FIG. 8 c 2 After treatment of the PDA1 composite hydrogel, the enzyme activity of the escherichia coli is far lower than that of the control group, and the respiratory chain dehydrogenase activity of normal cells is increased along with the incubation process, and the results prove that the FA/HL is proved 2 The PDA1 complex hydrogel may inhibit the activity of respiratory chain dehydrogenase.
Antibacterial mechanism experiment: reactive Oxygen Species (ROS) content. Reactive Oxygen Species (ROS) when in excess in cells cause a series of reactions leading to bacterial death such as oxidative damage and oxidative stress. In addition, ROS can also affect the proteins and nucleic acids of bacterial cells. The invention further learns about FA/HL by measuring the ROS content in bacterial cells 2 Bacteriostatic mechanism of PDA1 composite hydrogel. At O 2– Under the action of (a ROS), nitroblue tetrazolium (NBT) can be reduced to bluish violet formaldehyde. Thus, the amount of bluish violet formaldehyde produced can be used to indicate the level of ROS in bacterial cells. Therefore, the invention measures the change of the active oxygen content in bacterial cells by a nitroblue tetrazolium (NBT) reduction method. As shown in fig. 8 d, ROS production by untreated e.coli cells remained essentially unchanged after 15min incubation. However, in FA/HL 2 In the presence of the PDA1 complex hydrogel, ROS production increased significantly with increasing incubation time. If not discarded in time, it can lead to the accumulation of ROS, which can lead to a series of oxidative stress reactions, ultimately leading to cell death.
Antibacterial mechanism experiment: glutathione (GSH) oxidation test. GSH is a thiol-containing tripeptide that can act as an antioxidant in bacteria to prevent oxidative stress-induced damage to cellular components. Sulfhydryl groups (-SH) in GSH can be converted to disulfide bonds (-S-), thereby converting GSH to glutathione disulfide bonds. Therefore, glutathione (GSH) has been used as an indicator of intracellular oxidative stress. The concentration of thiol groups in GSH can be quantitatively determined by the Ellman method. The formation of glutathione disulfide may serve as an indicator of GSH loss. As shown in FIG. 8 e, after 1h of incubation, a significant decrease in absorbance at 412nm indicates a significant decrease in GSH content, oxidation process of GSHThe degree is obviously increased, and the result shows that the FA/HL 2 PDA1 hydrogels either directly convert GSH to GSSG or induce ROS formation, thereby converting GSH to GSSG. Finally, GSH consumption is responsible for bacterial cell damage.
Example 5:
MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-dipheny tetrazolium assay to detect cytotoxicity. The principle of detection of MTT involves succinate dehydrogenase in the mitochondria of living cells converting the water-soluble dye MTT into insoluble formazan and depositing in the cells, whereas dead cells do not. Formazan was then dissolved in DMSO and the optical density at 490 nm was measured. The invention detects the composite hydrogel, FA/HL 1 /PDA1、FA/HL 2 PDA1 toxicity to lung cancer cells (a 594) and neuroblastoma cells (SK-N-SH) cells. As shown in fig. 9, the cell viability of the thiosemicarbazide-loaded hydrogel was only slightly reduced compared to the blank (FA/PDA). This suggests that the locally sustained action of the thiosemicarbazide-functionalized polydopamine-coupled hydrogel may lead to a certain toxicity, but does not cause serious damage.
In conclusion, the invention develops the thiosemicarbazide-modified dopamine-coupled folic acid hydrogel with high antibacterial property around the problems of bacterial infection and wound infection. Zinc ion (Zn) 2+ ) Is a transition metal ion, has higher binding constant with FA or catechol, and has good coordination and antibacterial performance and tissue repair capability. The present invention uses two carboxyl groups in FA molecule or catechol in PDA to chelate Zn easily 2+ The formation of metal ligand coordination allows the FA/PDA hydrogel to form in only a few seconds. Thiosemicarbazide is a N, N, S tridentate schiff base ligand, which has good antibacterial performance. The PDAs and the thiosemicarbazide components can form hydrogen bonds, the thiosemicarbazide is successfully modified on the polydopamine through the hydrogen bond effect, then an antibacterial property test is carried out, and the synthesized thiosemicarbazide modified dopamine coupling folic acid hydrogel can release zinc ions within a certain time, so that the folic acid hydrogel synthesized by the invention has a certain wound repair capability. The composite hydrogel has injectability and maintains certain stability; in addition, in the case of the optical fiber,the composite hydrogel has the advantages of injectability, low toxicity, easiness in operation and the like, and provides a valuable reference for the application in the bacteriostasis field. The synthesis route of the thiosemicarbazide functionalized poly-dopamine coupled folic acid hydrogel is as follows: the first step is to dissolve FA in alkaline water (brown), converting the two carboxyl groups of FA into carboxylic acid functions. The hydrogen bonding interactions of the FA molecules also combine the two FA molecules, forming a long chain of FA molecules. DA is introduced to connect each long chain to form a network structure. The second step is the polymerization process of DA, namely catechol and quinone groups in DA molecules react with each other to form a PDA chain, and the third step is the thiosemicarbazide functional polydopamine, and hydrogen bonds are formed between the thiosemicarbazide and polydopamine. And the fourth step is to add zinc ions, wherein the zinc ions and two carboxyl groups in FA molecules or catechol in PDA form coordination, and hydrogel is formed in a few seconds. Because the thiosemicarbazide functionalized polydopamine has excellent antibacterial performance, the hydrogel composite material is endowed with stronger antibacterial effect. The polydopamine coupled folic acid hydrogel modified by thiosemicarbazide has good injectability, and can cause physical damage to cell membranes of the polydopamine coupled folic acid hydrogel by direct contact with bacterial suspension, so that the integrity of the cell membranes of bacteria is damaged, and components in cytoplasm leak. The prepared composite material has a certain wound repair capability due to the sustainable release of zinc ions. In a word, the composite hydrogel prepared by the invention has high-efficiency antibacterial capability, good injectability, certain wound repair capability and small cytotoxicity, and is expected to be an efficient antibacterial biological material.
Claims (10)
1. The preparation method of the double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel is characterized by comprising the following steps of:
1) Mixing folic acid with water and alkali to obtain a solution A;
2) Ligand HL 1 And/or HL (HL) 2 Mixing with dopamine hydrochloride, adding into alkali liquor, adding dimethyl sulfoxide, and stirring for reacting for 20-40min to obtain solution B;
3) Mixing the solution A and the solution B to obtain a solution C;
4) Mixing the soluble zinc salt solution with the solution C to obtain the zinc salt.
2. The method for preparing the double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel according to claim 1, wherein the step 1) is specifically as follows: mixing and stirring 0.1-0.4. 0.4 g folic acid, 4-8 mL distilled water and 0.05-0.10 g alkali to obtain solution A.
3. The method for preparing a bis-thiosemicarbazide-modified injectable folic acid coupled polydopamine hydrogel according to claim 2, wherein in step 2), the ligand HL 1 Is 2, 6-diacetylpyridine bis-thiosemicarbazone, the ligand HL 2 Is 2, 6-diacetylpyridine-N 4 -methyl thiosemicarbazone.
4. A method for preparing a bis-thiosemicarbazide-modified injectable folic acid coupled polydopamine hydrogel according to claim 3, wherein the ligand HL 1 The mass ratio of the compound to dopamine hydrochloride is 1:1; the ligand HL 2 The mass ratio of the compound to the dopamine hydrochloride is 1:1-2.
5. The method for preparing the double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel according to claim 4, wherein the amount of dopamine hydrochloride is 0.02-0.04 g and the amount of dimethyl sulfoxide is 15-30 mu L.
6. The method for preparing the double thiosemicarbazide-modified injectable folic acid coupled polydopamine hydrogel according to claim 5, wherein in the step 4), the soluble zinc salt is zinc acetate, and the concentration of the soluble zinc salt solution is 0.17-0.30mol/L.
7. The method for preparing the double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel, as set forth in claim 5, wherein the volume ratio of the soluble zinc salt solution to the solution C is 1: 0.8-1.5.
8. The method for preparing the double thiosemicarbazide-modified injectable folic acid coupled polydopamine hydrogel, as claimed in claim 1, wherein in the step 1) and the step 2), the alkali is sodium hydroxide, and the alkali solution is sodium hydroxide aqueous solution with the concentration of 1-2 mol/L.
9. The double thiosemicarbazide modified injectable folic acid coupled polydopamine hydrogel prepared by the preparation method of any one of claims 1 to 8.
10. Use of the bis-thiosemicarbazide-modified injectable folic acid coupled polydopamine hydrogel according to claim 9 in antibacterial aspect.
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