Potassium ion responsive hydrogel based on imidoboronic acid ester bond and preparation method and application thereof

Abstract

This invention relates to a potassium ion-responsive hydrogel based on iminoboronic ester bonds, its preparation method, and its applications. The hydrogel is prepared using guanosine, 2-formylphenylboronic acid, and polyoxyethylenediamine. The diol of guanosine forms a borate ester bond with 2-formylphenylboronic acid, and the primary amine in the polyoxyethylenediamine forms an imino group with the aldehyde group of 2-formylphenylboronic acid. The bases of guanosine form a G-quadruplex under the influence of potassium ions. The hydrogel has a porous network structure. The preparation method is as follows: A mixed aqueous solution of guanosine, 2-formylphenylboronic acid, and polyoxyethylenediamine is heated to boiling to obtain a clear solution. After cooling, the solution is mixed with a potassium ion solution to prepare the potassium ion-responsive hydrogel based on iminoboronic ester bonds. Compared with the prior art, the hydrogel prepared by this invention exhibits both temperature and potassium ion responsive characteristics.

Description

Technical Field

[0001] This invention relates to the field of ion-responsive hydrogel preparation, and in particular to a potassium ion-responsive hydrogel based on iminoboronic ester bonds, its preparation method, and its application. Background Technology

[0002] Environmentally sensitive hydrogels, capable of responding to factors such as temperature, light, and ions, exhibit sol-gel transformation properties and have garnered widespread attention in the biomedical field. Among them, ion-responsive hydrogels, due to metal-ligand coordination and hydrogen bonding interactions, possess strong mechanical strength and are polymer networks capable of altering their physical or chemical properties in response to changes in ionic strength, pH, or specific ion concentrations. These hydrogels have broad applications in biomedicine, environmental engineering, and drug delivery. This is advantageous when applied to the eye, as they can withstand the loads of eye movements, thereby improving lubrication. Ion-responsive hydrogels possess ion-responsive, tunable mechanical strength, and can be administered intraocularly as a flowable solution. The rapidly forming hydrogel can resist tear washout, prolonging the drug's residence time in front of the cornea, and can withstand the loads of eye movements when applied to the eye, thus improving lubrication. Furthermore, the combination of high water content and excellent lubrication properties makes ion-responsive hydrogels an excellent ophthalmic medical material. Ion-responsive hydrogels are typically composed of a hydrogel matrix and an ionic liquid phase, and are a type of polymer network structure formed by interactions such as metal-ligand coordination.

[0003] Generally, ion-responsive hydrogels, such as sodium alginate hydrogels, require high ion concentrations to rapidly form suitable hydrogels with high mechanical strength and ion-responsive sol-gel transition. In addition, there is currently little research on hydrogel systems where temperature and ions can simultaneously regulate the sol-gel transition, which limits the application of ion-responsive hydrogels. Summary of the Invention

[0004] The purpose of this invention is to provide a potassium ion-responsive hydrogel based on iminoboronic acid ester bonds, its preparation method and application, wherein the prepared hydrogel has both temperature and potassium ion responsive characteristics.

[0005] The objective of this invention can be achieved through the following technical solutions:

[0006] In a first aspect, the present invention provides a potassium ion-responsive hydrogel based on iminoboronic acid ester bonds, wherein the hydrogel is prepared using guanosine, 2-formylphenylboronic acid and polyoxyethylenediamine, and the hydrogel has a porous network structure and contains iminoboronic acid ester bonds.

[0007] Preferably, the molar ratio of guanosine, 2-formylphenylboronic acid, and polyoxyethylene diamine is (1.5-2.5):(1.7-2.3):1.

[0008] Preferably, the diol of the guanosine forms a borate ester bond with 2-formylphenylboronic acid, the primary amine in the polyoxyethylene diamine forms an imino group with the aldehyde group of 2-formylphenylboronic acid, and the bases of the guanosine form a G-tetrachain under the action of potassium ions.

[0009] Preferably, the structural formula of the iminoboronic ester bond is:

[0010]

[0011] Preferably, the hydrogel has potassium ion responsive properties; it is in a sol state when potassium ions are absent and in a gel state when potassium ions are present at room temperature.

[0012] Preferably, the hydrogel has temperature-responsive characteristics, being in a gel state when the temperature is below the gel-sol transition temperature and in a sol state when the temperature is above the gel-sol transition temperature.

[0013] Preferably, the gel-sol transition temperature is 25–60°C.

[0014] More preferably, the gel-sol transition temperature is 43–60°C.

[0015] Secondly, the present invention also provides a method for preparing the above-mentioned potassium ion-responsive hydrogel based on iminoboronic ester bonds, comprising the following steps:

[0016] S1: Guanosine, 2-formylphenylboronic acid, and polyoxyethylene diamine are mixed in proportion and dissolved in deionized water to obtain solution A;

[0017] S2: Heat solution A to boiling point to obtain solution B;

[0018] S3: After solution B cools, it is mixed with potassium ion solution to obtain potassium ion responsive hydrogel based on iminoboronic ester bond.

[0019] Preferably, in step S1, the molar concentration of guanosine in solution A is 25-75 mM, the molar concentration of 2-formylphenylboronic acid is 25-75 mM, and the molar concentration of polyoxyethylene diamine is 12.5-37.5 mM.

[0020] Preferably, in step S2, the heating is to heat the solution A to boiling point to obtain a clear solution B, and the boiling is maintained for 1 to 4 minutes.

[0021] Preferably, in step S3, the concentration of the potassium ion solution is 15–100 μM.

[0022] Preferably, in step S3, the potassium ion solution is mixed with solution B in equal volume.

[0023] More preferably, the potassium ion solution is an aqueous solution of potassium ions.

[0024] Thirdly, the present invention also provides an application of the above-mentioned potassium ion-responsive hydrogel based on iminoboronic ester bonds, including its application in the preparation of ophthalmic drugs.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] (1) The present invention obtains a potassium ion responsive hydrogel based on iminoboronic acid ester bond by physically blending a mixture of guanosine, 2-formylphenylboronic acid and polyoxyethylene diamine with a solution containing potassium ions. This hydrogel system has potassium ion responsive characteristics and can coordinate with potassium ions under the coordination of metal ions, thereby realizing the sol-gel transition.

[0027] (2) The potassium ion responsive hydrogel based on iminoboronic acid ester bond prepared by the present invention can achieve a reversible transition from gel to sol in the temperature range of 25 to 60°C, showing a precisely regulated temperature response capability.

[0028] (3) The hydrogel prepared by the present invention can rapidly form a hydrogel with high mechanical strength and ion-responsive sol-gel transition at a low ion concentration.

[0029] (4) The hydrogel prepared by the present invention can be used to prepare ophthalmic drugs. Guanosine, 2-formylphenylboronic acid and polyoxyethylenediamine can form a stable hydrogel in the presence of artificial tears. Attached Figure Description

[0030] Figure 1 The nuclear magnetic resonance spectrum of the potassium ion-responsive hydrogel based on iminoboronic ester bonds obtained in Example 1 of this invention is shown.

[0031] Figure 2 The NMR spectrum of the spontaneous and synergistic formation of iminoboronic acid ester bonds between guanosine, polyoxyethylene diamine and 2-formylphenylboronic acid in Example 1 of the present invention is shown in the figure. (a) is 2-formylphenylboronic acid and (b) is polyoxyethylene diamine and 2-formylphenylboronic acid.

[0032] Figure 3 The infrared spectrum of the potassium ion-responsive hydrogel based on iminoboronic ester bonds obtained in Example 1 of this invention.

[0033] Figure 4The infrared spectrum of the spontaneous and synergistic formation of iminoboronic acid ester bonds between guanosine, polyoxyethylene diamine and 2-formylphenylboronic acid obtained in Example 1 of the present invention;

[0034] Figure 5 The rheological properties of the potassium ion-responsive hydrogels based on iminoboronic ester bonds obtained in Examples 1-3 of this invention are shown in the diagram.

[0035] Figure 6 These are porous morphology images of potassium ion-responsive hydrogels based on iminoboronic ester bonds obtained in Examples 1-3 of the present invention, wherein (a): Example 1, (b): Example 2, (c): Example 3;

[0036] Figure 7 This is a temperature-dependent frequency scan of the potassium ion-responsive hydrogel based on iminoboronic ester bonds obtained in Example 1 of the present invention.

[0037] Figure 8 An optical photograph of the potassium ion-responsive hydrogel based on iminoboronic ester bonds obtained in Example 1 of this invention;

[0038] Figure 9 This is a diagram illustrating the synthesis mechanism of the potassium ion-responsive hydrogel based on iminoboronic ester bonds according to the present invention. Detailed Implementation

[0039] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. These embodiments are based on the technical solution of the present invention and provide detailed implementation methods and specific operating procedures. However, the scope of protection of the present invention is not limited to the following embodiments.

[0040] This invention provides a potassium ion-responsive hydrogel based on iminoboronic ester bonds. The hydrogel is prepared using guanosine, 2-formylphenylboronic acid, and polyoxyethylenediamine. Figure 9 As shown, the diol of the guanosine forms a borate ester bond with 2-formylphenylboronic acid, the primary amine in the polyoxyethylene diamine forms an imino group with the aldehyde group of 2-formylphenylboronic acid, and the bases of the guanosine form a G-tetrachain under the action of potassium ions. The hydrogel has a porous network structure.

[0041] The hydrogel exhibits potassium ion responsiveness, remaining in a sol state when potassium ions are absent and in a gel state at room temperature when potassium ions are present. It also exhibits temperature responsiveness, remaining in a gel state when the temperature is below the gel-sol transition temperature and in a sol state when the temperature is above the gel-sol transition temperature, which is 25–60°C.

[0042] The above hydrogel was prepared by the following method:

[0043] S1: Guanosine, 2-formylphenylboronic acid, and polyoxyethylene diamine are mixed and dissolved in deionized water at a molar ratio of (1.5-2.5):(1.7-2.3):1 to obtain solution A. The molar concentrations of guanosine, 2-formylphenylboronic acid, and polyoxyethylene diamine in solution A are 25-75 mM, 25-75 mM, and 12.5-37.5 mM, respectively.

[0044] S2: Heat solution A to boiling and maintain for 1–4 minutes until a clear solution B is obtained;

[0045] S3: After solution B cools, it is mixed with an equal volume of potassium ion solution with a concentration of 15-100mM to prepare a potassium ion responsive hydrogel based on iminoboronic ester bonds.

[0046] Unless otherwise specified, the reagents, methods, instruments, and equipment used in this invention are conventional in the art. Unless otherwise specified, the reagents and materials used in the following examples are all commercially available.

[0047] The polyoxyethylene diamine used in the following examples has a molecular weight of 1000.

[0048] Example 1

[0049] 7 mg of guanosine (25 mM), 3.8 mg of 2-formylphenylboronic acid (25 mM), and 12.3 mg of polyoxyethylene diamine (12.5 mM) were placed together in a clean test tube. Then, 1 ml of deionized water was added to the test tube to obtain solution A. This mixture was heated to boiling and maintained at boiling for 2 minutes until homogeneous and a clear solution was obtained, yielding solution B. After allowing it to cool naturally, it was slowly poured into 1 ml of a potassium ion solution (18.8 mM), finally yielding the solution shown below. Figure 8 The G-Quadruplex Hydrogel shown is shown.

[0050] Example 2

[0051] 14 mg of guanosine (50 mM), 7.6 mg of 2-formylphenylboronic acid (50 mM), and 24.6 mg of polyoxyethylene diamine (25 mM) were placed together in a clean test tube. Then, 1 ml of deionized water was added to the test tube to obtain solution A. This mixture was heated to boiling and maintained at boiling for 2 minutes until homogeneous and a clear solution was obtained, yielding solution B. After being allowed to cool naturally, it was slowly poured into 1 ml of a potassium ion solution (18.8 mM) to finally obtain G-quadruplex hydrogel.

[0052] Example 3

[0053] 21 mg of guanosine (75 mM), 11.4 mg of 2-formylphenylboronic acid (75 mM), and 36.9 mg of polyoxyethylene diamine (37.5 mM) were placed together in a clean test tube. Then, 1 ml of deionized water was added to the test tube to obtain solution A. This mixture was heated to boiling and maintained at boiling for 2 minutes until homogeneous and a clear solution was obtained, yielding solution B. After being allowed to cool naturally, it was slowly poured into 1 ml of a potassium ion solution (18.8 mM) to finally obtain G-quadruplex hydrogel.

[0054] Example 4

[0055] 8.4 mg of guanosine (30 mM), 4.56 mg of 2-formylphenylboronic acid (30 mM), and 14.76 mg of polyoxyethylene diamine (15 mM) were placed together in a clean test tube. Then, 1 ml of deionized water was added to the test tube to obtain solution A. This mixture was heated to boiling and maintained at boiling for 2 minutes until homogeneous and a clear solution was obtained, yielding solution B. After being allowed to cool naturally, it was slowly poured into 1 ml of artificial tears (potassium ion concentration 18.8 mM) to finally obtain G-quadruplex hydrogel.

[0056] Performance testing:

[0057] like Figure 1 As shown, the hydrogel prepared in Example 1 was subjected to nuclear magnetic resonance (NMR) testing. The figure shows that the 1H NMR spectrum of 2-formylphenylboronic acid (2-FPBA) exhibits a distinct peak (-CHO) at 9.79 ppm. This peak is replaced by the 8.45 ppm peak (-CH=N-) in the G-Quadruplex Hydrogel prepared in Example 1, which indicates the formation of imine bonds.

[0058] like Figure 2 As shown, NMR spectroscopy was performed on the hydrogel prepared in Example 1. The results show that when 2-FPBA and polyoxyethylene diamine were mixed together without guanosine, no C=N bond formation was detected, indicating that the imine bond and cycloboronic acid bond are formed cooperatively. This is likely because nitrogen atoms are electron-rich, while boron atoms are electron-deficient, and their adjacent positions favor N→B coordination. Due to their mutual cooperation and reinforcement, they are collectively referred to as imine-boronic acid bonds.

[0059] like Figure 3As shown, the hydrogel prepared in Example 1 was subjected to infrared spectroscopy. In the figure, Gq is G-quadruplex hydrogel, G is guanosine, and 2-FPBA is 2-formylphenylboronic acid. It can be observed from the figure that free υ in 2-FPBA C＝0 =1674cm -1 The band disappears, and υ appears in the hydrogel. C＝N =1694cm -1 This indicates that the aldehyde group on 2-FPBA reacted with the amino group on polyethylene glycol diamine.

[0060] like Figure 3 and Figure 4 As shown, the infrared spectrum of the hydrogel prepared in Example 1 was tested. It can be observed from the figure that the υ of 2-FPBA... O-H =3340cm -1 3070cm -1 It disappears after gelation, and the prepared hydrogel has a diameter of 10¹⁴ cm⁻¹. -1 (υ B-OC An absorption band appears near 1296 cm⁻¹, instead of at 1296 cm⁻¹. -1 (υ B-OH The vibration at the ) position supports the formation of cyclic borate ester bonds.

[0061] The hydrogels prepared in Examples 1-3 were subjected to frequency scanning tests using an MCR302 rheometer to examine their rheological properties. The tests were conducted at a frequency range of 0.1–100 rad / s under 1% strain.

[0062] from Figure 5 As can be seen from the data, the storage modulus G' of the hydrogels prepared in Examples 1-3 is greater than their loss modulus G", indicating that the hydrogels are viscoelastic and in a gel state. Furthermore, within the frequency range of 0.1–100 rad / s, the storage modulus of the hydrogels prepared in this invention is above 10. 2 ~10 4 Within the Pa range. Storage modulus can be used to measure the mechanical properties of a material; the larger the storage modulus, the better the mechanical properties of the material. As can be seen from the figure, with the increase of concentration (from 25 mM to 75 mM), both the storage modulus G' and the loss modulus G” increase significantly. This indicates that the elasticity and viscosity of the material increase with increasing concentration, demonstrating that the hydrogels prepared in Examples 1-3 of this invention have good mechanical properties. Among them, the G' and G” curves of the hydrogel prepared in Example 3 (75 mM) are in the highest range, which means that the material exhibits stronger mechanical strength and viscosity at this concentration.

[0063] like Figure 6As shown in the figure, the hydrogels prepared in Examples 1-3 were subjected to scanning electron microscopy (SEM) testing. It can be seen from the figure that the hydrogels prepared in Examples 1-3 have a porous network structure.

[0064] like Figure 7 As shown, the hydrogels prepared in Examples 1-3 were placed on a rheometer for variable temperature frequency scanning. The scanning temperature range was 25-45℃. As can be seen from the figure, the hydrogels were in a gel state at the initial temperature of 25℃. As the temperature increased, the storage modulus and loss modulus of the hydrogels decreased, indicating that the increase in temperature would affect the hydrogen bonds in the hydrogels, thereby reducing the mechanical properties of the hydrogels.

[0065] In summary, the hydrogel prepared by this invention exhibits potassium ion responsiveness and temperature responsiveness, can rapidly form a hydrogel at low ion concentrations, and possesses excellent mechanical properties. Furthermore, mixing guanosine, 2-formylphenylboronic acid, and polyoxyethylene diamine with artificial tears can form a stable hydrogel, which also exhibits potassium ion responsiveness and temperature responsiveness, indicating that the hydrogel prepared by this invention can be used in the preparation of ophthalmic drugs.

[0066] The hydrogel prepared by this invention can be further applied to the preparation of ophthalmic drugs, as follows:

[0067] (1) Based on Example 1, dexamethasone sodium phosphate, an anti-inflammatory drug, was effectively loaded into a hydrogel using an immersion method. After appropriate molding and sterilization, the drug-loaded hydrogel was used in an anti-inflammatory experiment in a rat model. The results showed that the hydrogel could continuously release the drug when applied to the eye, effectively reducing ocular inflammation, and no obvious adverse reactions were observed during the experiment.

[0068] (2) Based on Example 1, chloramphenicol was successfully loaded into a hydrogel using an immersion method, and microgel particles suitable for use in eye drops were prepared by cutting and sterilization. Clinical trials showed that this drug-loaded microgel eye drops exhibited good antibacterial effects in the treatment of bacterial keratitis in rats, with no significant side effects.

[0069] Therefore, the potassium ion responsive hydrogel based on iminoboronic ester bonds prepared in this invention has broad application prospects in the preparation of ophthalmic drugs.

[0070] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. An imino boronic acid ester bond-based potassium ion-responsive hydrogel, characterized by, The hydrogel was prepared using guanosine, 2-formylphenylboronic acid and polyoxyethylene diamine. The hydrogel has a porous network structure and contains iminoboronic acid ester bonds. The structural formula of the iminoboronic ester bond is: ； The hydrogel has potassium ion responsive characteristics; it is in a sol state when potassium ions are absent and in a gel state when potassium ions are present at room temperature. The hydrogel described above has temperature-responsive characteristics; it is in a gel state when the temperature is below the gel-sol transition temperature and in a sol state when the temperature is above the gel-sol transition temperature. The gel-sol transition temperature is 25~60℃; The molar ratio of guanosine, 2-formylphenylboronic acid, and polyoxyethylene diamine is (1.5~2.5):(1.5~2.5):

1.

2. The potassium ion-responsive hydrogel based on iminoboronic ester bonds according to claim 1, characterized in that, The gel-sol transition temperature of the hydrogel is 43~60 ℃.

3. A method for preparing a potassium ion-responsive hydrogel based on iminoboronic ester bonds as described in any one of claims 1 to 2, comprising the following steps: S1: Guanosine, 2-formylphenylboronic acid, and polyoxyethylene diamine are mixed in proportion and dissolved in deionized water to obtain solution A; S2: Heat solution A to boiling point to obtain solution B; S3: After solution B is cooled, it is mixed with potassium ion solution to obtain potassium ion responsive hydrogel based on iminoboronic ester bond.

4. The method for preparing a potassium ion-responsive hydrogel based on iminoboronic ester bonds according to claim 3, characterized in that, In step S1, the molar concentration of guanosine in solution A is 25~75 mM, the molar concentration of 2-formylphenylboronic acid is 25~75 mM, and the molar concentration of polyoxyethylene diamine is 12.5~37.5 mM.

5. The method for preparing a potassium ion-responsive hydrogel based on iminoboronic ester bonds according to claim 3, characterized in that, In step S2, the heating is to heat the solution A to boiling point to obtain a clear solution B, and the boiling is maintained for 1 to 4 minutes.

6. The method for preparing a potassium ion-responsive hydrogel based on iminoboronic ester bonds according to claim 3, characterized in that, In step S3, the concentration of the potassium ion solution is 15~100 mM.

7. The method for preparing a potassium ion-responsive hydrogel based on iminoboronic ester bonds according to claim 3, characterized in that, In step S3, the potassium ion solution is mixed with solution B in equal volume.

8. Use of the imino boronic acid ester bond-based potassium ion-responsive hydrogel according to any one of claims 1 to 2, characterized in that, Used in the preparation of ophthalmic medications.

Images