A unimicellar metal-polyphenol nanomaterial and preparation and application thereof

Abstract

This invention relates to a single-micelle metal-polyphenol nanomaterial, its preparation, and its application. The preparation method of the single-micelle metal-polyphenol nanomaterial is as follows: a polybasic acid and a surfactant are dispersed in an organic solvent to obtain a clear solution, which is then added dropwise to a soluble metal salt aqueous solution under stirring. The resulting mixed solution is dialyzed and freeze-dried to obtain the target product, the single-micelle metal-polyphenol nanomaterial. Compared with the prior art, this invention provides a single-micelle metal-polyphenol nanomaterial with controllable particle size, which can be well adjusted from 8 nanometers to 200 nanometers. The single-micelle metal-polyphenol nanomaterial of this invention can efficiently carry various therapeutic substances, is easily modified by antibodies, and possesses highly efficient acid-responsive degradation characteristics and excellent biocompatibility, showing great application potential in the field of nanomedicine.

Description

Technical Field

[0001] This invention relates to the field of nanomaterials, and in particular to a single micelle metal-polyphenol nanomaterial and its preparation and application. Background Technology

[0002] The rapid development of clinical diagnostic and treatment technologies has placed higher demands on the field of nanomedicine, especially the design and synthesis of novel nanomedicine carriers, which are of great significance for the diagnosis and treatment of diseases.

[0003] Considering factors such as toxicity, efficacy, and drug delivery, an ideal nanomedicine carrier should possess characteristics such as simple synthesis, low toxicity and side effects, biodegradability, small size, and high loading capacity. Therefore, developing a novel nanomedicine carrier has significant scientific research and application value.

[0004] Although a series of nanomedicine carriers have been synthesized, previous products often failed to achieve the characteristics of small size, responsiveness, drug loading rate and ease of synthesis, thus limiting their practical application and commercial prospects.

[0005] For example, Chinese patent CN202111446379.5 discloses a drug-loaded nanocomposite of tannic acid-iron network modified with nanosilver, its preparation method, and its application in reversing tumor drug resistance. The drug-loaded nanocomposite includes a core formed by doxorubicin linked to cell-penetrating peptides, surrounded by a network structure layer formed by tannic acid and iron ions, with nanosilver particles modified outside the network structure layer. This synthesis process is relatively complex and makes it difficult to balance drug loading rate and size. Summary of the Invention

[0006] The purpose of this invention is to overcome the defects of the prior art by providing a single micelle metal-polyphenol nanomaterial and its preparation and application. This nanomaterial has the characteristics of high loading efficiency, easy modification, degradability and low biocompatibility, and can be used for efficient drug delivery, in vivo imaging and other applications.

[0007] The objective of this invention can be achieved through the following technical solutions:

[0008] One of the technical solutions of the present invention provides a method for preparing single micelle metal-polyphenol nanomaterials. A polybasic acid and a surfactant are dispersed in an organic solvent to obtain a clear solution, which is then added dropwise to an aqueous solution of a soluble metal salt under stirring conditions. The resulting mixed solution is dialyzed and freeze-dried to obtain the target product, single micelle metal-polyphenol nanomaterials.

[0009] In this invention, the preparation process of dispersing the raw materials separately in an organic solvent and an aqueous solution, and then adding the organic solvent dropwise into the aqueous solution, is crucial. Directly mixing the raw materials will not yield controllable micro / nano structures.

[0010] Furthermore, in the mixed solution, the concentration of the polybasic acid is 10–100 mg / mL, the concentration of the surfactant is 0.1–1 g / mL, and the concentration of the soluble metal salt is 5–50 mg / mL.

[0011] Furthermore, the polybasic acid is tannic acid, pyromellitic acid, or terephthalic acid.

[0012] Furthermore, the surfactant is F127, F108, F68, or P123.

[0013] Furthermore, the organic solvent is dimethyl sulfoxide (DMSO), or a mixture thereof with a water-insoluble solvent. When the organic solvent is DMSO, the resulting material is nanodots; when a water-insoluble solvent is introduced into DMSO, the nanomaterial transforms from nanodots into hollow nanospheres (water-insoluble solvent, such as 1,3,5,-trimethylbenzene to DMSO in a volume ratio of 2:8). Further increasing the content of the water-insoluble solvent yields micron-sized vesicles (1,3,5,-trimethylbenzene to DMSO in a volume ratio of 1:1).

[0014] Furthermore, the water-insoluble solvent is one or a mixture of two of mesitylene or cyclohexane.

[0015] Furthermore, the metal ions in the soluble metal salt are iron ions, copper ions, zinc ions, or magnesium ions, and the anions are chloride ions, sulfate ions, nitrate ions, or acetate ions. Specifically, the soluble metal salt is a metal chloride such as ferric chloride, zinc chloride, or copper chloride, and the metal chloride can also be replaced by nitrates or sulfates.

[0016] Furthermore, the single-micelle metal-polyphenol nanomaterials can also be surface-modified using a simple method. The resulting single-micelle metal-polyphenol nanodots are directly mixed with the antibody or other material to be modified, thus completing the modification. Therefore, the obtained single-micelle metal-polyphenol nanomaterials can easily achieve targeting specific diseases and organs, improving in vivo drug delivery efficiency.

[0017] A second technical solution of the present invention provides a single-micelle metal-polyphenol nanomaterial, which is prepared using any of the preparation methods described above. The particle size of the obtained nanomaterial product can be controlled by the concentrations of three feed ingredients during the synthesis process. For example: increasing the concentration of tannic acid in the dimethyl sulfoxide solution increases the particle size of the obtained single-micelle metal-polyphenol nanodots. Increasing the concentration of F127 in the dimethyl sulfoxide solution decreases the particle size of the obtained single-micelle metal-polyphenol nanodots. Increasing the concentration of iron ions in the aqueous solution increases the particle size of the obtained single-micelle metal-polyphenol nanodots.

[0018] The third technical solution of this invention provides an application of a single-micelle metal-polyphenol nanomaterial, which serves as a carrier for loading functional substances. The desired drug molecules can be directly dispersed in dimethyl sulfoxide, achieving direct and efficient loading of drug molecules during the preparation process.

[0019] Furthermore, the functional substance is a drug molecule, an imaging molecule, or an ultrasmall nanoparticle, wherein the drug molecule is doxorubicin hydrochloride, docetaxel, or cisplatin, the imaging molecule is indocyanine green, IR1048, or rhodamine B, and the ultrasmall nanoparticle is upconversion nanocrystal, iron oxide nanocrystal, or quantum dot nanocrystal.

[0020] Furthermore, when single micelle metal-polyphenol nanomaterials are loaded with functional substances, the loaded functional substances are released in a solution with pH=5.

[0021] This invention utilizes multiple substances to form single-micelle metal-polyphenol nanomaterials through interfacial diffusion self-assembly: Tannic acid has high solubility in dimethyl sulfoxide (DMSO) but low solubility in water, and it coordinates with metal ions in water to form a metal-polyphenol network. When DMSO is added to water, it becomes miscible with the water, causing tannic acid to precipitate at the DMSO-water interface and coordinate with metal ions to form a metal-polyphenol network, which then solidifies into nanoparticles. Surfactants control the size of the dynamic DMSO-water interface, thereby adjusting the particle size of the single-micelle metal-polyphenol nanomaterials. The amount of tannic acid and metal ions also affects the particle size; more tannic acid results in larger particle sizes, while more metal ions result in smaller particle sizes.

[0022] Compared with existing technologies, this invention can load a variety of functional substances with a high loading rate and can rapidly degrade to release the loaded substances. The method for preparing single-micelle metal-polyphenol nanomaterials provided by this invention is simple, and the particle size of the nanodots can be controlled by adjusting the concentration of each material. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of the synthesis process of single micelle metal-polyphenol nanodots in Example 1.

[0024] Figure 2A This is a large-area transmission electron microscope image of the single micelle metal-polyphenol nanodots prepared according to the present invention.

[0025] Figure 2B High-magnification transmission electron microscopy image of the single micelle metal-polyphenol nanodots prepared in this invention.

[0026] Figure 2C An optical photograph of an aqueous solution of single micelle metal-polyphenol nanodots prepared according to the present invention.

[0027] Figure 2D This is a statistical analysis of the stability of the single micelle metal-polyphenol nanodots prepared in this invention dispersed in different solutions.

[0028] Figure 3A Transmission electron microscopy image of 8nm single micelle metal-polyphenol nanodots prepared for this invention.

[0029] Figure 3B Transmission electron microscopy image of 50 nm single micelle metal-polyphenol nanodots prepared for this invention.

[0030] Figure 3C Transmission electron microscopy image of 200 nm single micelle metal-polyphenol nanodots prepared for this invention.

[0031] Figure 3D The particle size distribution statistics of single micelle metal-polyphenol nanodots with different particle sizes prepared in this invention are presented.

[0032] Figure 4A Optical photograph of single micelle metal-polyphenol nanodots prepared using zinc chloride instead of ferric chloride.

[0033] Figure 4B Optical photograph of single micelle metal-polyphenol nanodots prepared using copper chloride instead of ferric chloride.

[0034] Figure 4C Optical photograph of single micelle metal-polyphenol nanodots prepared using tricresylbenzene as a substitute for tannic acid.

[0035] Figure 5 Scanning electron microscope (SEM) image of the product obtained by directly mixing all raw materials in an aqueous solution.

[0036] Figure 6 An optical photograph of a single-micelle metal-polyphenol nanodot solution loaded with cisplatin, doxorubicin, and paclitaxel. Detailed Implementation

[0037] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments.

[0038] In the following embodiments, unless otherwise specified, the raw materials or processing techniques are conventional commercially available raw materials or conventional processing techniques in the art.

[0039] Example 1

[0040] See Figure 1 As shown, this embodiment provides a method for preparing single micelle metal-polyphenol nanoparticles:

[0041] (1) Disperse tannic acid and F127 in dimethyl sulfoxide solution and stir until a clear solution is obtained;

[0042] (2) Dissolve ferric chloride in an aqueous solution and stir until completely dissolved;

[0043] (3) Under stirring, the clear solution in step (1) is added dropwise to the ferric chloride solution in step (2), wherein the concentration of tannic acid is 10 mg / mL, the concentration of F127 is 1 g / mL, and the concentration of ferric chloride is 50 mg / mL.

[0044] (4) Dialyze the mixed solution obtained in step (3), and freeze-dry the product after dialysis to obtain the single micelle metal-polyphenol nanomaterial mentioned in this invention.

[0045] like Figure 3A As shown, the particle size of the prepared single micelle metal-polyphenol nanodots is 8 nm.

[0046] Figure 2A The image shows a large-area transmission electron microscope image of the prepared single micelle metal-polyphenol nanodots, which shows that they are well dispersed and have uniform size.

[0047] Figure 2B The image shows a high-magnification transmission electron microscope image of the prepared single micelle metal-polyphenol nanodots, which can be seen to have a particle size of less than 10 nanometers, which is an ultra-small size.

[0048] Figure 2C The image shows an optical photograph of the prepared single micelle metal-polyphenol nanodots in an aqueous solution, demonstrating that the obtained nanoparticles can be stably dispersed in the aqueous solution, indicating excellent dispersibility.

[0049] Figure 2D The stability of the prepared single-micelle metal-polyphenol nanodots in different solutions is statistically analyzed; it can be seen that the obtained nanoparticles can be stably dispersed in different solutions, indicating excellent dispersibility and biocompatibility.

[0050] Figure 5 The scanning electron microscope image shows the product obtained by directly mixing all the raw materials in Example 1 in an aqueous solution. It can be seen that controllable micro / nano structures cannot be prepared without the preparation strategy described in this invention.

[0051] Figure 6 The image shows an optical photograph of a single-micelle metal-polyphenol nanodot solution loaded with cisplatin, doxorubicin, and paclitaxel (i.e., the corresponding loaded drugs are directly dispersed together in the dimethyl sulfoxide solution in step (1), and the drug concentration can be between 0-100 mg / mL). It can be seen that the single-micelle metal-polyphenol nanodot solution does not change significantly after loading the corresponding drugs. Centrifugation of the loaded solution reveals that there is no corresponding fluorescence of the drug in the supernatant, which means that the drug is 100% loaded into the single-micelle metal-polyphenol nanodot.

[0052] Example 2

[0053] Same as Example 1, except that the concentration of ferric chloride in step (2) was reduced to 5 mg / mL to obtain the single micelle metal-polyphenol nanomaterials of the present invention. The particle size test results are shown in the figure below. Figure 3C As shown, the particle size is 200 nm. If the concentration of ferric chloride is reduced to 0, no nanoscale materials can be obtained.

[0054] Example 3

[0055] Same as Example 1, except that the concentration of F127 in step (1) was reduced to 0.1 g / mL to obtain the single micelle metal-polyphenol nanomaterials of the present invention. The particle size test results are shown in the figure below. Figure 3B As shown, the particle size is 50 nm. If the F127 concentration is reduced to 0, only irregular flocculent matter can be obtained, rather than size-controllable nanomaterials.

[0056] Example 4

[0057] Same as Example 1, except that tannic acid in step (1) is replaced with tricresyl benzene, such as Figure 4C As shown in the optical photograph, the single micelle metal-polyphenol nanomaterials described in this invention can still be prepared.

[0058] Example 5

[0059] Same as Example 1, except that ferric chloride in step (2) is replaced with zinc chloride, such as Figure 4A As shown in the optical photograph, the single micelle metal-polyphenol nanomaterials described in this invention can still be prepared.

[0060] Example 6

[0061] Same as Example 1, except that ferric chloride in step (2) is replaced with copper chloride, such as Figure 4B As shown in the optical photograph, the single micelle metal-polyphenol nanomaterials described in this invention can still be prepared.

[0062] 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 a unimolecular metal-polyphenol nanomaterial, characterized in that, The polybasic acid and the surfactant are dispersed in an organic solvent to obtain a clear solution, which is added dropwise to an aqueous soluble metal salt solution under stirring, the obtained mixed solution is dialyzed, and then freeze-dried to obtain the target product, i.e., a single-micelle metal-polyphenol nanomaterial; The polybasic acid is tannic acid, trimesic acid or terephthalic acid; The surfactant is F127, F108, F68 or P123; The organic solvent is dimethyl sulfoxide, or a mixture of dimethyl sulfoxide and a water-insoluble solvent, wherein the water-insoluble solvent is one or a mixture of both of mesitylene and cyclohexane.

2. The method for preparing a single-micelle metal-polyphenol nanomaterial according to claim 1, characterized in that, In the mixed solution, the concentration of the polybasic acid is 10-100 mg / mL, the concentration of the surfactant is 0.1-1 g / mL, and the concentration of the soluble metal salt is 5-50 mg / mL.

3. The method for preparing a single micelle metal-polyphenol nanomaterial according to claim 1, characterized in that, The metal ion in the soluble metal salt is iron ion, copper ion, zinc ion or magnesium ion, and the anion is chloride ion, sulfate ion, nitrate ion or acetate ion.

4. A single-micelle metal-polyphenol nanomaterial prepared by the preparation method of any one of claims 1-3.

5. The use of a unimicellar metal-polyphenol nanomaterial according to claim 4, characterized by the fact that it is used in the form of a food supplement. The nanomaterial is used as a carrier to load functional substances.

6. The use of a unigmsomal metal-polyphenol nanomaterial according to claim 5, characterized in that, The functional substances are drug molecules, imaging molecules or ultra-small nanoparticles, wherein the drug molecules are doxorubicin hydrochloride, docetaxel or cisplatin, the imaging molecules are indocyanine green, IR1048 or rhodamine B, and the ultra-small nanoparticles are upconversion nanocrystals, ferroferric oxide nanocrystals or quantum dot nanocrystals.

7. The use of a unigmsomal metal-polyphenol nanomaterial according to claim 5, characterized in that, When the single-micelle metal-polyphenol nanomaterial loads the functional substances, it can release the loaded functional substances in a solution with pH=5.

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