Metal-quercetin nano polymer material as well as preparation method and application thereof

Abstract

The invention discloses a metal-quercetin nano polymer material which is formed by crosslinking metal ions Zn < 2 + > and quercetin, and every two molecules of quercetin are complexed with five Zn < 2 + >. The invention also discloses a preparation method and application thereof. The metal-quercetin nano polymer material, which is synthesized by the preparation method disclosed by the invention, is good in stability, controllable in size and good in biocompatibility. The synthesized QU-Zn has better dispersity and stability in an aqueous solution, the low water solubility of the quercetin is improved, and the bioavailability of the quercetin is improved. The metal-quercetin polymer material or pharmaceutical composition has strong superiority in the aspects of treating psoriasis, relieving skin injury and the like, and a new thought is provided for the design of multifunctional biological materials based on natural active products.

Description

Technical Field

[0001] The invention relates to a metal-quercetin nano polymer material and a preparation method and application thereof, belonging to the technical field of biomedical materials. Background Art

[0002] Psoriasis is an immune-related inflammatory skin disease characterized by chronic, recurrent erythematous plaques, white scales, and itching, which puts a great burden on the patient's body and mind and seriously affects their quality of life. The pathological characteristics of psoriasis are excessive proliferation of keratinocytes, neovascularization, and infiltration of inflammatory cells. The pathogenesis of psoriasis is complex, among which the inflammatory response induced by the IL-17 / 23 axis plays a more central role in its occurrence and development. Traditional treatments for psoriasis mainly include topical hormones, systemic immunosuppressants, retinoids, and physical therapy, but long-term use has obvious side effects and is expensive. Therefore, there is an urgent need to develop new, safe, effective, and low-cost treatment methods.

[0003] Metal-Phenolic Nanocomplexes (MPNs) are functional materials formed by coordination with metal ions as nodes and polyphenol compounds as organic ligands. MPNs are generally amorphous or sticky particles. By adjusting the reaction conditions, the size of the material can be controlled at the nanoscale, an ordered morphology can be created, and the specific surface area can be increased. They are widely used in disease treatment, drug delivery, and bioimaging. Compared with traditional nanomaterials, nanoscale MPNs have their own unique advantages, such as simple and diverse synthesis methods. The methods that can be selected include solvothermal, microwave, ultrasonic, and mechanochemical methods, which are suitable for large-scale industrial production. At the same time, metal-polyphenol nanocomplexes can improve the hydrophobicity of poorly soluble ligands and solve problems such as their low bioavailability.

[0004] Quercetin (QU) is a natural flavonoid compound widely found in many Chinese herbal medicines and daily diets. It has multiple pharmacological effects such as anti-inflammatory, antiviral, hypoglycemic, anti-tumor, and cardiovascular and cerebrovascular protection. However, the shortcomings of QU, such as poor water solubility, rapid metabolism, and easy degradation by enzymes, limit its clinical application. How to better increase the bioavailability of quercetin and improve its pharmacokinetics is a biomedical problem that needs to be solved urgently. In addition, the results of many studies have shown that the trace element Zn is closely related to psoriasis, and the zinc content in psoriasis patients is significantly lower than that in normal people. Therefore, the metal-polyphenol nanopolymer material construction technology is used to use quercetin as an organic molecular bridge, and the metal Zn 2+The coordination combination of quercetin and Zn ions forms a nanoscale polymer material, which can significantly improve the water solubility of quercetin, increase its bioavailability, exert its anti-inflammatory and other pharmacological effects, and combine with Zn ions for the treatment of psoriasis, providing a new strategy for the treatment of psoriasis and a new idea for the construction of other new multifunctional MPN materials. Summary of the invention

[0005] The object of the present invention is to provide a metal-quercetin nanopolymer material with a simple preparation method and low cost, which has good water solubility, low toxicity and can effectively treat psoriasis.

[0006] The technical solution adopted by the present invention is:

[0007] A metal-quercetin nanopolymer material, comprising metal ion Zn 2+ Cross-linked with quercetin, 5 Zn complexes per 2 molecules of quercetin 2+ .

[0008] The molecular formula of quercetin is C 15 H 10 O7, the chemical structure is shown in formula (I):

[0009]

[0010] Preferably, the metal-quercetin nanopolymer material is stably dispersed in an aqueous solution, and the hydrated particle size is 110-170 nm, wherein the main particle size is 136 nm, and QU-Zn under the SEM field of view appears as sticky particles.

[0011] Preferably, the mass ratio of metal Zn in the metal-quercetin nanopolymer material is 37.2%.

[0012] Preferably, the metal ion Zn 2+ It forms coordination bonds with the phenolic hydroxyl and carbonyl groups in the quercetin structure.

[0013] The present invention also discloses a method for preparing the above-mentioned metal-quercetin nanopolymer material, which is characterized in that the steps include:

[0014] (1) preparing a quercetin N,N-dimethylformamide solution and a Zn(CH2COOH)2·2(H2O) N,N-dimethylformamide solution respectively;

[0015] (2) mixing the two and heating them for reaction;

[0016] (3) collecting the precipitate by centrifugation;

[0017] (4) After washing the precipitate, it is redispersed in water to obtain an aqueous solution of the metal-quercetin nanopolymer material QU-Zn.

[0018] Preferably, in step (1), the concentration of the quercetin N,N-dimethylformamide solution is 5 mg / mL, and the concentration of the Zn(CH2COOH)2·2(H2O) N,N-dimethylformamide solution is 7.25 mg / mL.

[0019] Preferably, in step (2), the reaction of quercetin and Zn 2+ The molar ratio of addition was 1:2, the reaction temperature was 60°C, and the reaction time was 4h.

[0020] Preferably, in step (3), the centrifugal speed is 20000 rpm and the centrifugal time is 10 min.

[0021] Preferably, the washing in step (4) means that the precipitate is washed once with N,N-dimethylformamide and then washed three times with ultrapure water.

[0022] The invention also discloses the application of the metal-quercetin nano polymer material in preparing a medicine for treating psoriasis.

[0023] The polymer material of the present invention can be used alone or in the form of a pharmaceutical composition for the treatment of psoriasis. The mode of administration can be determined according to the specific situation, and can be prepared into dosage forms suitable for different modes of administration according to conventional methods in the field of pharmacy, such as solutions, liniments, ointments, gels, sprays, creams, and patches.

[0024] The synthesized metal-quercetin nano polymer material QU-Zn of the present invention has good stability, controllable size and good biocompatibility. The synthesized QU-Zn has good dispersibility and stability in aqueous solution, improves the low water solubility of quercetin, and increases the bioavailability of quercetin. The metal-quercetin polymer material or drug combination has strong advantages in treating psoriasis, reducing skin damage, etc., and provides new ideas for the design of multifunctional biomaterials based on natural active products.

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

[0026] (1) The present invention uses quercetin as an organic ligand and Zn 2+ Stable coordination, one-step synthesis of metal-quercetin nanopolymer material QU-Zn, the design method is simple and easy to operate, can efficiently synthesize nanopolymer materials, and the flavonoid mass ratio can be as high as 62.8%, with a high loading rate.

[0027] (2) The QU-Zn synthesized in the present invention has controllable size and good stability. It can be conjugated or mixed with other small molecules, polypeptides, polysaccharides, nucleic acids, proteins, medical isotopes, etc. to construct a multimodal drug delivery system, which has potential application prospects.

[0028] (3) The metal-quercetin nanopolymer material or drug combination synthesized by the present invention shows significant therapeutic effect on psoriasis, is low-cost, and has broad clinical application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 Schematic diagram of the structure of QU-Zn.

[0030] Figure 2 It is the ultraviolet absorption spectrum of QU-Zn of the present invention measured by ultraviolet spectrophotometer (UV).

[0031] Figure 3 It is the infrared spectrum of QU-Zn of the present invention measured by Fourier transform infrared spectrometer (FTIR).

[0032] Figure 4 It is the hydrated particle size of QU-Zn of the present invention measured by dynamic light scattering (DLS).

[0033] Figure 5 The material morphology of QU-Zn of the present invention is measured by scanning electron microscopy (SEM).

[0034] Figure 6 This is the X-ray photoelectron spectroscopy (XPS) spectrum of QU-Zn of the present invention.

[0035] Figure 7 The QU-Zn of the present invention is determined by using the Zn peak in X-ray photoelectron spectroscopy (XPS).

[0036] Figure 8 This is a stability study of the QU-Zn of the present invention: A is the hydrated particle size of QU-Zn from different batches; B is the hydrated particle size of the same batch of QU-Zn after being placed for different time periods.

[0037] Fig. 9 The figure shows the solubility comparison of QU-Zn of the present invention and quercetin of the same dose in water.

[0038] Fig.10 The figure shows the effect of QU-Zn of the present invention on the PASI score of imiquimod-induced psoriasis mice.

[0039] Fig.11 The figure shows the effect of QU-Zn of the present invention on skin lesions of psoriasis mice induced by imiquimod. Specific implementation methods

[0041] The present invention is further described below in conjunction with embodiments, but the description of the embodiments does not impose any limitation on the protection scope of the present invention.

[0042] Unless otherwise defined, all technical terms and scientific terms used herein have the same meaning as those generally understood by those skilled in the art of the present invention, and the terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention. In addition, although demonstrations of parameters including specific values ​​may be provided herein, it should be understood that the parameters do not need to be exactly equal to the corresponding values, but may be approximated to the corresponding values ​​within an acceptable error tolerance or design constraint.

[0043] Unless otherwise specified, the materials and instruments used in the following examples can be obtained from conventional commercial channels.

[0044] Example 1 Preparation and Characterization of QU-Zn

[0045] A solution of quercetin in N,N-dimethylformamide (5 mg / mL) and a solution of Zn(CH2COOH)2·2(H2O) in N,N-dimethylformamide (7.25 mg / mL) were prepared respectively. 2+ The two were mixed evenly in a molar ratio of 1:2 and reacted at 60°C for 4 hours. After the reaction, the precipitate was collected by centrifugation at 20,000×g, washed once with N,N-dimethylformamide, washed three times with ultrapure water, and resuspended in ultrapure water to obtain a QU-Zn aqueous solution. The structure of the product QU-Zn is shown below: Figure 1 As shown, it is composed of quercetin and Zn 2+ The spatial network material formed by coordination. The UV absorption spectrum of QU-Zn was measured by UV spectrophotometer ( Figure 2 ), compared with QU, the absorbance of QU-Zn increased overall, and the two characteristic absorption peaks red-shifted overall, proving that its structure changed; Fourier transform infrared spectrometer measured its infrared spectrum ( Figure 3 ), as shown in the figure, 1014cm -1 Ortho-hydroxyl CO absorption peak, 1169 cm -1 C-OH absorption peak, 1319.4 cm -1 o-dihydroxy peak, 1382 cm -1 C-OH absorption and 1663 cm -1 The C=O stretching vibration peak and other absorption peaks changed, and a new structure was formed; the particle size analyzer measured its hydrated particle size ( Figure 4 ) and SEM to determine its size and morphology ( Figure 5 ), the results showed that QU-Zn was stably dispersed in aqueous solution, and the hydrated particle size was 110-170nm; X-ray photoelectron spectroscopy determined that its element distribution was C, O, Zn ( Figure 6 ), and is Zn 2+ ( Figure 7 ).

[0046] Example 2 Stability Study of QU-Zn

[0047] The synthesized QU-Zn was placed in the dark at 4℃ for 1d, 7d and 14d and its hydrated particle size was measured to investigate the material stability ( Figure 8 A); The hydrated particle sizes of three batches of QU-Zn synthesized at different times were measured to investigate the stability of the synthetic process of the material ( Figure 8 B). The results show that QU-Zn has good stability and the synthesis method is highly reproducible.

[0048] Example 3 Comparison of the solubility of QU-Zn and quercetin

[0049] The material QU-Zn obtained in Example 1 was determined by ICP. 2+ The mass proportion is 37.2%, and the calculated mass proportion of QU is 62.8%. QU-Zn (0.5 mg / mL) and the equivalent amount of QU aqueous solution (0.3 mg / mL) contained in QU-Zn were prepared, and the solubility difference between the two in water was compared ( Fig. 9 ),like Fig. 9 As shown, the aqueous solution of QU-Zn is clear and transparent with good water solubility, while QU is insoluble in water.

[0050] Example 4: The therapeutic effect of QU-Zn on psoriasis

[0051] The material QU-Zn was prepared according to the steps of Example 1, and added to 20% poloxamer 407 to prepare a 0.5 mg / mL gel to investigate its therapeutic effect on psoriasis.

[0052] One day before drug treatment, the hair on the back of Balb / c mice was removed with a mild depilatory cream, and the mice were randomly divided into 3 groups and raised normally. The specific treatment methods are as follows:

[0053] Normal control group: 62.5 mg / mouse / day of vaseline ointment was applied to the back skin of mice for 6 days.

[0054] Model group: 5% imiquimod cream (62.5 mg / mouse / day) was applied to the back skin of mice for 6 days.

[0055] Treatment group: 5% imiquimod cream (62.5 mg / mouse / day) was applied to the back skin of mice, and 100 mL of QU-Zn gel (0.5 mg / mL) was applied 6 hours later for 6 days.

[0056] The skin manifestations of mice in each group were observed every day and scored according to the PASI scoring table ( Fig.10 ) and take photos for comparison ( Fig.11). The results showed that the QU-Zn prepared by the present invention and its drug composition showed significant therapeutic effects on imiquimod-induced psoriasis mice.

[0057] The above embodiments are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with this technology to understand the contents of the present invention and implement them accordingly. They cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims

1. A metal-quercetin nanopolymer material, characterized in that: From metal ion Zn 2+ Cross-linked with quercetin, 5 Zn complexes per 2 molecules of quercetin 2+ .

2. The metal-quercetin nanopolymer material according to claim 1, characterized in that: The metal-quercetin nano polymer material is stably dispersed in an aqueous solution, and the hydrated particle size is 110-170 nm.

3. The metal-quercetin nanopolymer material according to claim 2, characterized in that: The mass ratio of metal Zn in the metal-quercetin nanopolymer material is 37.2%.

4. The metal-quercetin nanopolymer material according to any one of claims 1 to 3, characterized in that: Metal ion Zn 2+ It forms coordination bonds with the phenolic hydroxyl and carbonyl groups in the quercetin structure.

5. The method for preparing the metal-quercetin nanopolymer material according to any one of claims 1 to 4, characterized in that: The steps include: (1) preparing a quercetin N,N-dimethylformamide solution and a Zn(CH2COOH)2·2(H2O) N,N-dimethylformamide solution respectively; (2) mixing the two and heating them for reaction; (3) collecting the precipitate by centrifugation; (4) After washing the precipitate, it is redispersed in water to obtain an aqueous solution of the metal-quercetin nanopolymer material QU-Zn.

6. The preparation method according to claim 5, characterized in that: In step (1), the concentration of the quercetin N,N-dimethylformamide solution is 5 mg / mL, and the concentration of the Zn(CH2COOH)2·2(H2O) N,N-dimethylformamide solution is 7.25 mg / mL.

7. The preparation method according to claim 6, characterized in that: In step (2), control the quercetin and Zn 2+ The molar ratio of addition was 1:2, the reaction temperature was 60°C, and the reaction time was 4h.

8. The preparation method according to claim 7, characterized in that: In step (3), the centrifugal speed is 20000 rpm and the centrifugal time is 10 min.

9. The preparation method according to claim 8, characterized in that: The washing in step (4) refers to washing the precipitate once with N,N-dimethylformamide and then washing three times with ultrapure water.

10. Use of the metal-quercetin nanopolymer material according to any one of claims 1 to 4 in the preparation of a drug for treating psoriasis.

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