Tannic acid-terephthalic acid polymer nanoparticles and their preparation and application

Abstract

This invention relates to tannic acid-terephthaloboric acid polymer nanospheres, their preparation, and applications. The preparation process involves adding tannic acid, terephthaloboric acid, and a surfactant to DMF, followed by heating under static conditions to obtain the target product, tannic acid-terephthaloboric acid polymer nanospheres. The tannic acid-terephthaloboric acid polymer nanospheres provided by this invention can be directly synthesized via a hydrothermal method, with sizes adjustable from tens to micrometers. The abundant phenolic hydroxyl groups and borate ester functional groups within the microspheres endow the material with superior reactive oxygen species scavenging ability and responsive drug release capacity, making it suitable for inflammation clearance and drug delivery targeting inflammatory environments.

Description

Technical Field

[0001] This invention belongs to the field of nanomaterials technology, and relates to a tannic acid-terephthalic acid polymer nanosphere and its preparation and application. Background Technology

[0002] Inflammation is a common symptom in many diseases, and alleviating inflammation is crucial for disease improvement and treatment. Targeting inflamed areas with nanomaterials to eliminate reactive oxygen species and free radicals is an effective way to improve the inflammatory environment.

[0003] Considering factors such as toxicity, efficacy, and drug delivery, nanomaterials that improve the inflammatory environment should not only possess highly efficient reactive oxygen species scavenging capabilities but also exhibit high drug loading capacity, biodegradability, low toxicity, and ease of preparation. Therefore, developing a novel nanomaterial for anti-inflammatory applications has significant scientific and practical value.

[0004] Although a series of nanomedicine carriers have been synthesized, such as the Chinese patent CN202111446379.5 which discloses a drug-loaded nanocomposite of a tannic acid-iron network modified with nanosilver, its preparation method, and its application in reversing tumor drug resistance, the drug-loaded nanocomposite comprises a core formed by doxorubicin linked to cell-penetrating peptides, an outer layer of a network structure formed by tannic acid and iron ions, and nanosilver particles modified on the outer layer of the network structure. However, previous related products often failed to simultaneously achieve the desired characteristics in terms of degradability, toxicity, responsiveness, drug delivery capacity, and ease of synthesis, thus limiting their practical application and commercial prospects. Summary of the Invention

[0005] The purpose of this invention is to provide tannic acid-terephthalic acid polymer nanospheres, their preparation and application, which have superior reactive oxygen species scavenging ability and responsive drug release ability, and can be used for inflammation clearance and drug delivery in inflammatory environments.

[0006] The objective of this invention can be achieved through the following technical solutions:

[0007] One technical solution of the present invention provides a method for preparing tannic acid-terephthalic acid polymer nanospheres. Tannic acid, terephthalic acid, and a surfactant are added to DMF, and the mixture is heated under static conditions to react, thereby obtaining the target product, tannic acid-terephthalic acid polymer nanospheres. Specifically, a sol containing tannic acid-terephthalic acid polymer nanospheres is obtained through a heating reaction, and the target product is obtained by centrifugation and freeze-drying.

[0008] The choice of solvent plays a crucial role in the synthesis results of this invention. Using DMF yields uniform nanospheres, while using water, DMSO, dioxane, or other solvents fails to produce similar results. Furthermore, the use of terephthaloboric acid in this invention is critical; without it, the product cannot be obtained. Replacing it with phenylboronic acid also fails to yield the product, and replacing it with phenyltriboronic acid fails to produce a controllable microsphere structure.

[0009] Furthermore, tannic acid, terephthalic acid, and surfactant are fed in a 1:1:1 mass ratio and synthesized directly in one step via a solvothermal method.

[0010] Furthermore, the surfactant is F127.

[0011] Furthermore, the heating reaction temperature is 80–120°C, and the time is 12–36 h. Adjusting the reaction temperature can also control the diameter of the obtained tannic acid-terephthalic acid polymer nanospheres. Products cannot be obtained below 60°C; as the reaction temperature increases, the diameter of the microspheres obtained between 80°C and 120°C gradually increases.

[0012] Furthermore, the total concentration of tannic acid and terephthalic acid in the reaction system was 0.2–1.5 mg / mL. Adjusting the concentrations of tannic acid and terephthalic acid allowed for precise control of the diameter of the obtained tannic acid-terephthalic acid polymer nanospheres; as the concentrations of tannic acid and terephthalic acid gradually increased, the diameter of the resulting microspheres gradually increased.

[0013] The second technical solution of this invention provides tannic acid-terephthalic acid (TBP) polymer nanospheres, which are prepared using any of the preparation methods described above. The particle size can be controllably adjusted from 20 nanometers to 1 micrometer. Furthermore, the nanospheres are completely degradable in water or physiological environments. When placed in water or PBS solution, the tannic acid-TBP polymer nanospheres completely degrade within approximately one week. Moreover, the tannic acid-TBP polymer nanospheres exhibit excellent biocompatibility. Co-incubation of 200 μg / mL particles with cells does not significantly reduce cell viability.

[0014] The third technical solution of this invention provides an application of tannic acid-terephthalic acid polymer nanospheres, which are used to prepare anti-inflammatory drugs. At a concentration of 2 mg / mL, the tannic acid-terephthalic acid polymer nanospheres can scavenge more than 90% of hydrogen peroxide and free radicals.

[0015] The fourth technical solution of this invention provides an application of tannic acid-terephthalic acid polymer nanospheres, which are used to load small molecule drugs. Specifically, the loading rate reaches 10 wt%.

[0016] Furthermore, the small molecule drug is doxorubicin hydrochloride or docetaxel.

[0017] Furthermore, when polymer nanospheres are loaded with small molecule drugs, they respond to a 5 mM hydrogen peroxide concentration or an acidic environment of pH=5 and release more than 80% of the loaded small molecule drugs within 2 hours.

[0018] Compared with existing technologies, the tannic acid-terephthalic acid polymer nanospheres provided by this invention can be directly synthesized via a hydrothermal method, with sizes adjustable from tens to micrometers. The abundant phenolic hydroxyl groups and borate ester functional groups within the microspheres endow the material with superior reactive oxygen species scavenging ability and responsive drug release capability, making it suitable for inflammation clearance and drug delivery targeting inflammatory environments. Attached Figure Description

[0019] Figure 1 This is a schematic diagram of the process for synthesizing tannic acid-terephthalic acid polymer nanospheres according to the present invention;

[0020] Figure 2A Large-area scanning electron microscope images of the tannic acid-terephthalobolic acid polymer nanospheres prepared in this invention, and optical photographs of the resulting sol.

[0021] Figure 2B High-magnification scanning electron microscope images of the tannic acid-terephthalic acid polymer nanospheres prepared in this invention, and optical photographs of the obtained powder.

[0022] Figure 2C Transmission electron microscopy (TEM) image of the tannic acid-terephthalic acid polymer nanospheres prepared in this invention.

[0023] Figure 2D This is a statistical analysis of the particle size of the tannic acid-terephthalic acid polymer nanospheres prepared in this invention.

[0024] Figure 3 Scanning electron microscope (SEM) images of tannic acid-terephthalic acid polymer nanospheres prepared according to the preparation strategy of this invention, but without the addition of F127.

[0025] Figure 4A Optical photographs of the reaction solution prepared according to the preparation strategy of the present invention, but without the addition of terephthalic acid.

[0026] Figure 4B Optical photographs of the reaction solution prepared according to the preparation strategy of the present invention, but with phenylboronic acid replaced by terephthalic acid.

[0027] Figure 4C Optical photographs of the reaction solution prepared according to the preparation strategy of the present invention, but with terephthalic acid replaced by pyromellitic triboronic acid.

[0028] Figure 5A Optical photographs of the reaction solution prepared according to the preparation strategy of the present invention, but with DMF replaced by 1,4-dioxane.

[0029] Figure 5B Optical photographs of the reaction solution prepared according to the preparation strategy of the present invention, but with DMF replaced by toluene.

[0030] Figure 5C Optical photographs of the reaction solution prepared according to the preparation strategy of the present invention, but with DMF replaced by dimethyl sulfoxide.

[0031] Figure 6A Transmission electron microscopy image of 50 nm tannic acid-terephthalic acid polymer nanospheres prepared for this invention.

[0032] Figure 6B Transmission electron microscopy image of 400 nm tannic acid-terephthalic acid polymer nanospheres prepared for this invention.

[0033] Figure 6C Transmission electron microscopy image of 1-micrometer tannic acid-terephthalic acid polymer nanospheres prepared for this invention.

[0034] Figure 6D The particle size statistics of tannic acid-terephthalic acid polymer nanospheres with different particle sizes prepared in this invention are presented.

[0035] Figure 7A This invention describes the scavenging ability of tannic acid-terephthalic acid polymer nanospheres against hydroxyl radicals.

[0036] Figure 7B The statistical analysis of hydrogen peroxide removal by the tannic acid-terephthalic acid polymer nanospheres prepared in this invention is presented.

[0037] Figure 7C The ability of the tannic acid-terephthalic acid polymer nanospheres prepared in this invention to scavenge ABTS free radicals.

[0038] Figure 7D This invention demonstrates the ability of tannic acid-terephthalic acid polymer nanospheres prepared in response to hydrogen peroxide in releasing drugs. 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] In the following embodiments, unless otherwise specified, the raw materials or processing techniques are all commercially available materials or conventional processing techniques in the art.

[0041] Example 1:

[0042] This embodiment provides a specific method for preparing tannic acid-terephthalic acid polymer nanospheres. (See [link to relevant documentation]). Figure 1 As shown, the specific steps are as follows:

[0043] (1) Add tannic acid, terephthalic acid and F127 to DMF solution and stir until all three are completely dissolved. After dissolution, the mass concentration of each of the three is 5 mg / mL, and a clear solution is obtained.

[0044] (2) Pour the clear solution obtained in step (1) into a hydrothermal reactor and hydrothermally heat it at 100°C for 24 hours under static conditions. A flesh-colored sol is obtained.

[0045] (3) Centrifuge the flesh-colored sol obtained in step (2) and freeze-dry it. The resulting powder is the target tannic acid-terephthalic acid polymer nanospheres.

[0046] Figure 2A The images show large-area scanning electron microscope (SEM) images of the tannic acid-terephthalic acid polymer nanospheres prepared in Example 1, as well as optical photographs of the resulting sol. It can be seen that the obtained tannic acid-terephthalic acid polymer nanospheres are of uniform size, and the synthesized solution is also a homogeneous sol, which is easy to store.

[0047] Figure 2B The images show high-magnification scanning electron microscope (SEM) images of the tannic acid-terephthalic acid polymer nanospheres prepared in Example 1, and optical photographs of the obtained powder. It can be seen that the diameter of the obtained tannic acid-terephthalic acid polymer nanospheres is about 500 nm, and after lyophilization, they are light yellowish-brown powders that are easy to store.

[0048] Figure 2C The image shows a transmission electron microscope (TEM) image of the tannic acid-terephthalic acid polymer nanospheres prepared in Example 1. It can be seen that the diameter of the obtained tannic acid-terephthalic acid polymer nanospheres is approximately 500 nm, which is consistent with the scanning electron microscope (SEM) results.

[0049] Figure 2D The particle size distribution of the tannic acid-terephthalic acid polymer nanospheres prepared in Example 1 is shown; it can be seen that the diameter of the obtained tannic acid-terephthalic acid polymer nanospheres is approximately 500 nm, which is consistent with the results of scanning electron microscopy and transmission electron microscopy.

[0050] Figure 3Scanning electron microscopy (SEM) images of tannic acid-terephthalobolic acid polymer nanospheres prepared according to the preparation strategy of this invention, but without the addition of F127. It can be seen that the absence of F127 does not affect the formation of the microspheres, but the resulting microspheres are more aggregated and their dispersibility is limited.

[0051] Figure 4A This is an optical photograph of the reaction solution when prepared according to the preparation strategy of this invention, but without the addition of terephthalic acid. It can be seen that the product cannot be obtained without the addition of terephthalic acid.

[0052] Figure 4B Optical photographs of the reaction solution when terephthaloboric acid is replaced with phenylboronic acid according to the preparation strategy of this invention. It can be seen that when terephthaloboric acid is replaced with phenylboronic acid, the product cannot be obtained.

[0053] Figure 4C Optical photographs of the reaction solution when terephthalic acid is replaced with pyromellitic triboronic acid according to the preparation strategy of this invention. It can be seen that replacing terephthalic acid with pyromellitic triboronic acid only yields a large amount of flocculent precipitate, and a controllable microsphere structure cannot be obtained.

[0054] Figure 5A Optical photographs of the reaction solution when DMF is replaced with 1,4-dioxane according to the preparation strategy of this invention. It can be seen that when DMF is replaced with 1,4-dioxane, a controllable microsphere structure cannot be obtained.

[0055] Figure 5B Optical photographs of the reaction solution when DMF is replaced with toluene according to the preparation strategy of this invention. It can be seen that when DMF is replaced with toluene, a controllable microsphere structure cannot be obtained.

[0056] Figure 5C Optical photographs of the reaction solution when DMF is replaced with dimethyl sulfoxide (DMSO) according to the preparation strategy of this invention. It can be seen that when DMF is replaced with DMSO, a controllable microsphere structure cannot be obtained.

[0057] Figure 6A Transmission electron microscopy (TEM) image of the prepared 50 nm tannic acid-terephthalobolic acid polymer nanospheres; small-sized tannic acid-terephthalobolic acid polymer nanospheres can be obtained by reducing the concentration of tannic acid and terephthalobolic acid to 2.5 mg / mL.

[0058] Figure 6B Transmission electron microscopy (TEM) image of the 500 nm tannic acid-terephthalobolic acid polymer nanospheres prepared; tannic acid-terephthalobolic acid polymer nanospheres of this size can be obtained by setting the concentration of tannic acid and terephthalobolic acid to 5 mg / mL.

[0059] Figure 6CTransmission electron microscopy (TEM) image of the prepared 1-micron tannic acid-terephthalobolic acid polymer nanospheres; large-sized tannic acid-terephthalobolic acid polymer nanospheres can be obtained by increasing the concentration of tannic acid and terephthalobolic acid to 10 mg / mL.

[0060] Figure 6D The figure shows the particle size statistics of tannic acid-terephthalic acid polymer nanospheres with different particle sizes prepared in Example 1; the milligrams marked in the figure represent the amount of tannic acid and terephthalic acid added in 10 mL of DMF solution. This result shows that the particle size of the obtained tannic acid-terephthalic acid polymer nanospheres can be controlled within a very wide range.

[0061] Figure 7A The ability of the tannic acid-terephthalic acid polymer nanospheres prepared in Example 1 to scavenge hydroxyl radicals indicates that the synthesized tannic acid-terephthalic acid polymer nanospheres can effectively scavenge hydroxyl radicals generated by the Fenton reaction of iron ions and hydrogen peroxide. The test method is Fe... 2+ Ions (2×10) -2 After incubating the mixture of 50 μL of M-H2O2 (0.1 M) and 150 μL of H2O2 (0.1 M) with different concentrations of tannic acid-terephthalic acid polymer nanospheres (5 μg / mL, 25 μg / mL, 50 μg / mL) and 50 μL of DMPO for 1 min, the EPR spectrum was measured.

[0062] Figure 7B The statistical analysis of hydrogen peroxide removal by the tannic acid-terephthalic acid polymer nanospheres prepared in Example 1 was conducted by mixing tannic acid-terephthalic acid polymer nanospheres of different concentrations with a 5 mM hydrogen peroxide solution, and then detecting the hydrogen peroxide concentration using a hydrogen peroxide detection kit. The bar chart in the figure represents the relative values ​​of hydrogen peroxide concentration output by the kit. A tannic acid-terephthalic acid polymer nanosphere concentration of 10 μg / mL can remove 50% of the hydrogen peroxide.

[0063] Figure 7C The scavenging ability of the tannic acid-terephthalic acid polymer nanospheres prepared in Example 1 against ABTS free radicals was demonstrated. Different concentrations of tannic acid-terephthalic acid polymer nanospheres were mixed with a 5 mM hydrogen peroxide solution, and the hydrogen peroxide concentration was then detected using an ABTS free radical detection kit. The vertical axis in the figure represents the scavenging efficiency of ABTS free radicals.

[0064] Figure 7DThis study investigated the ability of tannic acid-terephthalobolic acid polymer nanospheres prepared in Example 1 to release drug in response to hydrogen peroxide. The tannic acid-terephthalobolic acid polymer nanospheres were mixed with a DMSO solution of doxorubicin hydrochloride and stirred for 24 hours, followed by centrifugation and freeze-drying. The doxorubicin loading rate was determined based on the change in material mass. The doxorubicin-loaded tannic acid-terephthalobolic acid polymer nanospheres were then dispersed in aqueous solutions with different hydrogen peroxide concentrations. Samples were periodically taken and centrifuged, and the concentration of doxorubicin in the solution was detected by fluorescence to determine the release rate. It was observed that doxorubicin was not released under neutral conditions. Under acidic conditions, doxorubicin was rapidly released, reaching a release rate of approximately 80% after about 2 hours.

[0065] 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. A method for preparing tannic acid-terephthalic acid polymer nanospheres, characterized in that, Tannic acid, terephthalic acid and surfactant F127 are added to DMF and heated under static conditions to react, thus obtaining the target product, tannic acid-terephthalic acid polymer nanospheres.

2. The method for preparing tannic acid-terephthalic acid polymer nanospheres according to claim 1, characterized in that, Tannic acid, terephthalic acid, and surfactant were fed in a mass ratio of 1:1:1 and synthesized directly in one step via a solvothermal method.

3. The method for preparing tannic acid-terephthalic acid polymer nanospheres according to claim 1, characterized in that, The heating reaction is carried out at a temperature of 80~120℃ for 12~36 hours.

4. The method for preparing tannic acid-terephthalic acid polymer nanospheres according to claim 1, characterized in that, The total concentration of tannic acid and terephthalic acid in the reaction system was 0.2~1.5 mg / mL.

5. A tannic acid-terephthalic acid polymer nanosphere, which is prepared by the preparation method according to any one of claims 1-4.

6. The application of the tannic acid-terephthalic acid polymer nanospheres as described in claim 5 in the preparation of anti-inflammatory drugs.

7. The use of the tannic acid-terephthaloboric acid polymer nanospheres as described in claim 5 in the preparation of drugs loaded with doxorubicin hydrochloride or docetaxel.

8. The application of the tannic acid-terephthalic acid polymer nanospheres as described in claim 7, characterized in that, When polymer nanospheres are loaded with doxorubicin hydrochloride, they respond to a 5 mM hydrogen peroxide concentration or an acidic environment with pH=5 and release more than 80% of the loaded doxorubicin hydrochloride within 2 hours.

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