Application of novel nanometer preparation containing zingiberenone A in preparation of antitumor drugs

Abstract

The invention discloses an application of a novel nano preparation containing zingiberenone A in preparation of antitumor drugs. The nano preparation comprises aminated dendritic mesoporous silica and zingiberenone A loaded on the aminated dendritic mesoporous silica. According to the invention, aminated dendritic mesoporous silica is adopted to load zingiberenone A, and a novel nano preparation which has high drug loading capacity, high encapsulation efficiency and high biocompatibility and contains zingiberenone A. The preparation has relatively low cytotoxicity, can be rapidly taken by tumor cells, remarkably enhances the capability of zingiberenone A in removing tumor cells, and can be used for preparing the nano preparation. The pharmaceutical composition can effectively inhibit proliferation of tumors in vivo, has a better treatment effect than that of a clinically common anti-tumor drug darafenib, and has a wide application prospect.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and more specifically to application of a novel nano preparation containing gingerol A in the preparation of anti-tumor drugs. Background Art

[0002] The existing treatment methods for tumors mainly use surgical resection, chemotherapy and radiotherapy, but they all have limitations such as strong toxic side effects and easy recurrence. Therefore, screening new, safe and effective anti-tumor drugs has very important clinical significance.

[0003] Gingerenone A (GA) is a natural phytochemical extracted from ginger, which has a wide range of medicinal values, including anti-tumor, anti-oxidation, anti-aging, anti-inflammatory, anti-viral, and blood sugar control. Studies have shown that GA can promote the anti-proliferation and senescence of breast cancer cells induced by oxidative stress (Gingerenone A InducesAntiproliferation and Senescence of Breast Cancer Cells.Antioxidants.;Tzu-Jung Yu.;et al.). At the same time, GA selectively kills cancer cells by dual inhibition of JAK2 and S6K1 (Identification of a Dual Inhibitor of Janus Kinase 2(JAK2)and p70 RibosomalS6 Kinase1(S6K1)Pathways.;Sanguine Byun.;et al.), and is an effective anti-tumor active ingredient.

[0004] However, due to the poor solubility, permeability, stability and absorbability of gingerolone A, it is difficult to reach an effective therapeutic concentration and achieve the expected effect after use, which greatly limits its scope of application. Summary of the invention

[0005] The purpose of the present invention is to overcome the above-mentioned defects of the prior art and provide an application of a novel nano preparation containing gingerol A in the preparation of anti-tumor drugs. The novel nano preparation containing gingerol A is prepared by loading gingerol A with amino-modified dendritic mesoporous silica. The novel nano preparation has high drug loading, high encapsulation rate and high biocompatibility. The preparation has low cytotoxicity, can be quickly taken up by tumor cells, significantly enhances the ability of gingerol A to eliminate tumor cells, and effectively inhibits the proliferation of tumors in the body. The therapeutic effect is better than that of the commonly used clinical anti-tumor drug dabrafenib, and the novel nano preparation has broad application prospects.

[0006] To achieve the above object, the technical solution of the present invention is as follows:

[0007] The invention discloses an application of a novel nano preparation containing gingerol A in the preparation of an anti-tumor drug. The nano preparation comprises amino-modified dendritic mesoporous silica and gingerol A loaded on the amino-modified dendritic mesoporous silica.

[0008] Optionally, the tumor includes one or more of melanoma, lymphohematopoietic system tumors, endocrine tumors, lung and mediastinal tumors, breast tumors, digestive system tumors, urinary and male reproductive system tumors, female reproductive system tumors, head and neck tumors, central nervous system tumors, skin tumors, and bone and soft tissue tumors.

[0009] Optionally, the dosage form of the drug includes tablets, capsules, pills, injections, sustained-release preparations or controlled-release preparations.

[0010] Optionally, the administration route of the anti-tumor drug includes intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration 、 One or more of rectal administration, skin mucosal administration and inhalation administration.

[0011] Optionally, the dosage of the nano preparation in the anti-tumor drug is 100 mg / kg to 400 mg / kg.

[0012] Optionally, the anti-tumor drug is a drug that inhibits tumor growth or inhibits tumor cell proliferation.

[0013] Optionally, the anti-tumor drug is a drug that promotes or induces apoptosis of tumor cells.

[0014] Optionally, the anti-tumor drug is a drug that inhibits the growth of transplanted tumors.

[0015] Optionally, the anti-tumor drug further contains a pharmaceutically acceptable carrier, excipient and / or auxiliary material.

[0016] Optionally, the loading amount of gingerol A in the nanoformulation is 15% to 30%.

[0017] Optionally, the encapsulation rate of gingerol A in the nanoformulation is 11% to 35%.

[0018] Optionally, the particle size of the nano preparation is 50nm to 200nm.

[0019] Optionally, the specific surface area of ​​the nanoparticle preparation is 800 m 2 / g~1000m 2 / g.

[0020] Optionally, the particle size of the amino-modified dendritic mesoporous silica is 50 nm to 200 nm.

[0021] Optionally, the pore size of the amino-modified dendritic mesoporous silica is 2 nm to 10 nm.

[0022] Optionally, the specific surface area of ​​the amino-modified dendritic mesoporous silica is 300 m 2 / g~1000m 2 / g.

[0023] Optionally, the method for preparing the nanoformulation comprises:

[0024] The gingerol A is dissolved in a solvent to obtain a gingerol A solution, and the gingerol A solution and the amino-modified dendritic mesoporous silica are added into a buffer solution for reaction, so that the gingerol A is loaded on the amino-modified dendritic mesoporous silica to obtain the nano-preparation.

[0025] The mass ratio of gingerolone A to amino-modified dendritic mesoporous silica in the gingerolone A solution is (1-5):1.

[0026] The buffer solution includes one or more of phosphate buffer, borate buffer, citrate buffer, phosphate and trimethylolmethane, acetate buffer, imidazole buffer, and carbonate buffer.

[0027] The pH of the buffer solution is 5.0-7.4.

[0028] The concentration of the gingerolone A in the gingerolone A solution is 2 mg / mL to 6 mg / mL.

[0029] The solvent includes any one of acetone, acetonitrile, ethanol, methanol and dimethyl sulfoxide.

[0030] The reaction temperature is 25°C to 80°C; the reaction time is 6h to 36h.

[0031] The invention also discloses an anti-tumor drug, the effective component of which is a novel nano preparation containing gingerol A; the nano preparation is the nano preparation in the above application.

[0032] Implementing the embodiments of the present invention will have the following beneficial effects:

[0033] (1) The present invention uses amino-modified dendritic mesoporous silica to load gingerolone A to prepare a novel nanoformulation containing gingerolone A with high drug loading, high encapsulation rate and high biocompatibility. The preparation has low cytotoxicity, can be quickly taken up by tumor cells, significantly enhances the ability of gingerolone A to eliminate tumor cells, and effectively inhibits the proliferation of tumors in vivo. Its therapeutic effect is better than that of the commonly used clinical anti-tumor drug dabrafenib, and can be used in anti-cancer drugs, with broad application prospects.

[0034] (2) The present invention selects amino-modified dendritic mesoporous silica as a drug carrier, and loads gingerol A thereon through non-covalent forces, so that the nanoformulation is highly enriched in the tumor site, thereby achieving the effect of targeting the tumor and improving the bioavailability of gingerol A.

[0035] (3) The experimental results of the present invention show that the nanoformulation containing gingerol A can significantly inhibit the proliferation of A431 human epidermal cancer cells, A375 human malignant melanoma cells, Caco2 human colon adenocarcinoma cells, SW579 human thyroid squamous cell carcinoma cells, HCT-116 human colorectal cancer cells, and HepG2 human liver cancer cells, and has a wide range of anti-tumor effects, especially significant effects on melanoma; and shows a good effect of inhibiting tumor growth in a mouse transplanted tumor model, and has no obvious toxic and side effects, and has good application prospects and high application value in the preparation of anticancer drugs, and the preparation method of the drug preparation is simple, low cost, and good economic benefits of the drug. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is a graph showing the effects of different concentrations of GA@AMSN and GA on the proliferation of A431 human epidermal cancer cells in Example 2 of the present invention.

[0037] Figure 2 This is a graph showing the effects of different concentrations of GA@AMSN and GA on the proliferation of A375 human malignant melanoma cells in Example 2 of the present invention.

[0038] Figure 3 This is a graph showing the effects of different concentrations of GA@AMSN and GA on the proliferation of Caco2 human colon adenocarcinoma cells in Example 2 of the present invention.

[0039] Figure 4 This is a graph showing the effects of different concentrations of GA@AMSN and GA on the proliferation of SW579 human thyroid squamous cell carcinoma cells in Example 2 of the present invention.

[0040] Figure 5 This is a graph showing the effects of different concentrations of GA@AMSN and GA on the proliferation of HCT-116 human colorectal cancer cells in Example 2 of the present invention.

[0041] Figure 6 This is a graph showing the effects of different concentrations of GA@AMSN and GA on the proliferation of HepG2 human liver cancer cells in Example 2 of the present invention.

[0042] Figure 7 The pharmacodynamic evaluation of the test drug of Example 2 of the present invention on the A375 cell subcutaneous transplanted tumor model in mice (A, tumor growth curve; B, tumor weight; C, tumor picture).

[0043] Figure 8 This is the pharmacodynamic evaluation of the test drug of Example 2 of the present invention on the A375 cell subcutaneous transplanted tumor model in mice (A, weight change curve of tumor-bearing mice; B, relative weight change curve of tumor-bearing mice).

[0044] Fig. 9 This is the result of H&E staining of the liver after treatment with the test drug (GA@AMSN) in Example 2 of the present invention. DETAILED DESCRIPTION

[0045] The present invention is further described below in conjunction with specific embodiments, but the present invention is not limited in any way.

[0046] The invention discloses application of a novel nano preparation containing gingerol A in preparing an anti-tumor drug. The nano preparation comprises amino-modified dendritic mesoporous silica and gingerol A loaded on the amino-modified dendritic mesoporous silica.

[0047] In a specific embodiment, the tumor includes one or more of melanoma, lymphohematopoietic system tumors, endocrine tumors, lung and mediastinal tumors, breast tumors, digestive system tumors, urinary and male reproductive system tumors, female reproductive system tumors, head and neck tumors, central nervous system tumors, skin tumors, and bone and soft tissue tumors.

[0048] In a specific embodiment, the dosage form of the drug includes tablets, capsules, pills, injections, sustained-release preparations or controlled-release preparations.

[0049] In a specific embodiment, the administration route of the anti-tumor drug includes intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration 、 One or more of rectal administration, skin mucosal administration and inhalation administration.

[0050] In a specific embodiment, the dosage of the nanoformulation in the anticancer drug is 100 mg / kg to 400 mg / kg.

[0051] In one embodiment, the anti-tumor drug is a drug that inhibits tumor growth or inhibits tumor cell proliferation.

[0052] In one embodiment, the anti-tumor drug is a drug that promotes or induces apoptosis of tumor cells.

[0053] In one embodiment, the anti-tumor drug is a drug that inhibits the growth of transplanted tumors.

[0054] In a specific embodiment, the anti-tumor drug further contains a pharmaceutically acceptable carrier, excipient and / or auxiliary material.

[0055] In a specific embodiment, the loading amount of gingerol A in the nanoformulation is 15% to 30%.

[0056] In a specific embodiment, the encapsulation efficiency of gingerol A in the nanoformulation is 11% to 35%.

[0057] In a specific embodiment, the particle size of the nanoparticle preparation is 50nm to 200nm.

[0058] In a specific embodiment, the specific surface area of ​​the nanoformulation is 800 m2 / g to 1000 m2 / g.

[0059] In a specific embodiment, the particle size of the amino-modified dendritic mesoporous silica is 50 nm to 200 nm.

[0060] In a specific embodiment, the pore size of the amino-modified dendritic mesoporous silica is 2 nm to 10 nm.

[0061] In one embodiment, the specific surface area of ​​the amino-modified dendritic mesoporous silica is 300 m 2 / g~1000m 2 / g.

[0062] In one specific embodiment, the method for preparing the nanoformulation comprises:

[0063] (1) Add the template and the catalyst into water and mix them to form an aqueous phase.

[0064] (2) Mixing the silicon source and the solvent to form an oil phase.

[0065] (3) The oil phase and the water phase are subjected to a homogeneous reaction, and after the reaction is completed, the reaction is centrifuged, dried, and then calcined to obtain dendritic mesoporous silica.

[0066] (4) Adding dendritic mesoporous silica and an ammonia source to an acetonitrile solution for amino modification to achieve amino modification and obtain amino-modified dendritic mesoporous silica.

[0067] (5) dissolving gingerol A in a solvent to obtain a gingerol A solution, adding the gingerol A solution and amino-modified dendritic mesoporous silica into a buffer solution for reaction, so as to load gingerol A on the amino-modified dendritic mesoporous silica to obtain a nanoformulation.

[0068] Specifically, the present invention first prepares a dendritic mesoporous silica having a unique central radial pore structure in a water / oil two-phase system, and then modifies the surface of the silica with amino groups. Compared with traditional mesoporous silica, the present invention selects a dendritic mesoporous silica with higher pore permeability, larger pore volume, multiple surface functions and good biocompatibility as a drug carrier, and further modifies the drug with amino groups. The amino-modified dendritic mesoporous silica is used as a carrier to achieve high loading of gingerol A through non-covalent forces. The obtained nano-preparation has uniform particle size and has the characteristics of high drug loading, high encapsulation rate, high biocompatibility and low toxicity.

[0069] Furthermore, the present invention rationally optimizes the preparation conditions to regulate the structure of the mesoporous silica nanomaterial, including the particle size, pore size, specific surface area, etc., which is conducive to forming a mesoporous structure with a relatively good pore size distribution rate.

[0070] In a specific embodiment, the mass ratio of gingerolone A to amino-modified dendritic mesoporous silica in the gingerolone A solution is (1-5):1.

[0071] In a specific embodiment, the buffer solution includes one or more of phosphate buffer, borate buffer, citrate buffer, phosphate and tris(hydroxymethyl)methane, acetate buffer, imidazole buffer, and carbonate buffer.

[0072] In one embodiment, the pH of the buffer solution is 5.0-7.4.

[0073] In a specific embodiment, the concentration of gingerol A in the gingerol A solution is 2 mg / mL to 6 mg / mL.

[0074] In a specific embodiment, the solvent in step (5) includes any one of acetone, acetonitrile, ethanol, methanol, and dimethyl sulfoxide.

[0075] In a specific embodiment, the temperature of the homogeneous reaction is 25° C. to 80° C.; and the time of the homogeneous reaction is 6 h to 36 h.

[0076] In a specific embodiment, the template agent includes one or two of hexadecyltrimethylammonium chloride, octadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, hexadecyltrimethylammonium bromide chloride, hexadecylpyridinium chloride, and dodecyltrimethylammonium bromide. Preferably, the template agent is hexadecyltrimethylammonium chloride.

[0077] In a specific embodiment, the catalyst includes one or more of triethanolamine, tripropanolamine, diethanolamine, ethanolamine, and ammonia. Preferably, the catalyst is triethanolamine.

[0078] In a specific embodiment, the silicon source includes one or more of ethyl orthosilicate, methyl orthosilicate, tetra(2-methoxy-1-methylethyl) silicate, tetraisopropyl orthosilicate, tetrabutyl silicate, and tetraisopropyl orthosilicate. Preferably, the silicon source is ethyl orthosilicate.

[0079] In a specific embodiment, the ammonia source includes one or more of 3-aminopropyltriethoxysilane, 3-aminopropyltrimethoxysilane, N-(2-aminoethyl)-3-aminopropyltriethoxysilane, and γ-aminopropyldiethoxymethylsilane. Preferably, the ammonia source is 3-aminopropyltriethoxysilane.

[0080] In a specific embodiment, the solvent in step (2) includes one or more of chlorobenzene, cyclohexane, chloroform, dichloromethane, and water.

[0081] In a specific embodiment, the preparation method of aminated dendritic mesoporous silica specifically includes: adding a template and a catalyst to water, mixing them at 40°C to 60°C for 10min to 30min to form an aqueous phase, and adding a chlorobenzene solution containing a silicon source, wherein the mass ratio of the template, the catalyst and the silicon source is (20-30): (0.5-1.2): (6-12), mixing at 40°C to 60°C for 12h to 36h, centrifuging and drying, and calcining at 300°C to 600°C for 4h to 8h to obtain dendritic mesoporous silica; adding the dendritic mesoporous silica and the ammonia source in a mass ratio of (0.08-0.1): (50-100) to an acetonitrile solution, and reacting at 60°C to 85°C for 8h to 16h to achieve amination modification to obtain aminated dendritic mesoporous silica.

[0082] In a specific embodiment, the present invention has no particular limitation on the mixing method, as long as the raw materials can be mixed evenly.

[0083] The invention also discloses an anti-tumor drug, the active ingredient of which is a novel nano preparation containing gingerol A.

[0084] The following are specific embodiments

[0085] Example 1 Preparation of a novel nanoformulation containing gingerol A (GA@AMSN)

[0086] Preparation of MSN: 30g N-hexadecyltrimethylammonium chloride (CTAC) was dissolved in a 500mL round-bottom flask using 300mL ultrapure water, and then 1.0g triethanolamine was added to the dissolved CTAC solution and stirred to form an upper aqueous phase. Then, 12mL tetraethyl silicate and 100mL solvent (60mL cyclohexane + 40mL chlorobenzene) were mixed in a beaker and used as the oil phase. The oil phase was transferred to a flask to form a two-phase reaction system. The reaction was maintained at a stirring speed of 300rpm / min at 60°C for 12h. The milky white liquid was taken out and centrifuged (10000r / min, 15min) to finally obtain a white solid product, which was washed three times with ethanol to remove the solvent and then dried in air to obtain a white powder. The white powder was placed in a muffle furnace and calcined at 550 °C for 6 h to remove CTAC. The obtained product was washed with deionized water and ethanol once each and then dried in vacuum to obtain MSN with a specific surface area of ​​926.3128 m 2 / g, pore diameter is 8.5612nm, pore volume is 3.374020cm 3 / g.

[0087] Preparation of AMSN: 200 mg of MSN was added to 40 mL of acetonitrile for ultrasonic dispersion, 200 μl of 3-aminopropyltriethoxysilane (APTE) was added to the above reaction system, and the reaction was stirred at 600 rpm at 80°C for 12 h. After the reaction, the liquid was centrifuged, and the obtained sample was washed twice with water and ethanol respectively to obtain AMSN.

[0088] Preparation of GA@AMSN: 40 mg AMSN was added to 5 mL of GA in acetonitrile solution (5 mg / mL, 10 mg / mL, 15 mg / mL). Ultrasonic dispersion was performed and the mixture was stirred and incubated at room temperature for 8 h. Then, centrifugation was performed and the supernatant was removed. The product was collected, washed three times with deionized water and vacuum dried to obtain GA@AMSN.

[0089] Example 2 GA@AMSN in vitro tumor cell activity experiment

[0090] 1. Experimental cells

[0091] A431 human epidermal carcinoma cells, A375 human malignant melanoma cells, Caco2 human colon adenocarcinoma cells, SW579 human thyroid squamous cell carcinoma cells, HCT-116 human colorectal cancer cells, and HepG2 human hepatoma cells were purchased from the Cell Bank of Type Culture Collection Committee of the Chinese Academy of Sciences.

[0092] 2. Experimental methods

[0093] The MTT experiment was used to analyze the effect of GA@AMSN prepared in Example 1 on cell proliferation. 4 Cells were plated in each well. After the cells adhered to the wall, 100 μL of culture medium containing GA@AMSN and GA at the corresponding drug concentration (5 μM to 25 μM) was added. Six replicate wells were set for each concentration, and the error of the results in each well did not exceed 5%. After 24 hours of drug action, the culture supernatant in the well was discarded. 100 μL of 5 mg / ml MTT solution was added to each well. After incubation for 3 hours, the culture was terminated and the culture supernatant in the well was carefully discarded. 100 μL of DMSO was added to each well to dissolve the crystals. The light absorption value of each well was measured at a wavelength of 490 nm using an enzyme-linked immunosorbent assay to calculate the IC50 value.

[0094] The results are as follows Figure 1-Figure 6 As shown, the GA@AMSN of the present invention has a good synergistic inhibitory effect. After 24 hours of action, it can dose-dependently inhibit the proliferation of A431 human epidermal cancer cells, A375 human malignant melanoma cells, Caco2 human colon adenocarcinoma cells, SW579 human thyroid squamous cell carcinoma cells, HCT-116 human colorectal cancer cells and HepG2 human liver cancer cells.

[0095] Example 3 Experimental results of GA@AMSN mouse tumor model

[0096] According to the experimental results of Example 2, this example compares the effects of GA@AMSN and positive drugs on A375 melanoma as follows:

[0097] 1. Experimental animals:

[0098] NU / NU mice, female, 6-8 weeks, 18-22g, were purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd. All experimental mice were housed in Shanghai Lidi SPF animal room and adapted to the environment for at least 3 days in advance. All experimental mice were housed in the SPF animal room IVC constant temperature and pressure system, where the temperature was 20-26°C, the humidity was 40-70%, and the light cycle was 12 hours light and 12 hours dark. No more than 6 mice were kept in each cage, the size of the cage was 325mm×210mm×180mm, and the bedding used in the cage was autoclaved corn cobs, which were changed twice a week. Throughout the experiment, all experimental mice were free to eat, the feed was sterilized by Co60 irradiation, and the drinking water was autoclaved. Feed and drinking water were kept in sufficient supply.

[0099] 2. Experimental design

[0100] 2.1. Cultivation of A375 Tumor Cells

[0101] A375 cells were cultured in 90% DMEM + 10% inactivated FBS at 37°C and 5% CO 2 The cells in the logarithmic growth phase will be used to establish an in vivo transplant tumor model.

[0102] 2.2. A375 tumor cell inoculation

[0103] Take A375 cells in the logarithmic growth phase, add appropriate amount of HBSS, resuspend, count, and adjust the cell density to 4×10 7 cells / mL and placed on ice for later use. 0.1 mL of tumor cell suspension was subcutaneously inoculated on the right side of each NU / NU mouse, i.e., 4×10 6 cells / mouse. The average tumor volume was 109.65 (84.69-136.81) mm 3 Fifteen mice were randomly divided into three groups, each with five mice. The three groups were given PBS, gingerol A nanoformulation (GA@AMSN), and positive control drug Dabrafenib, respectively. The detailed administration method, dosage, and route of administration are shown in Table 1. The day of group administration was day 0.

[0104] Table 1. Grouping and dosing

[0105]

[0106] Dosage volume: Adjust the dosage volume according to the weight of tumor-bearing mice (10 μL / g)

[0107] 3. Evaluation Metrics

[0108] The main purpose is to establish subcutaneous transplanted tumors of A375 cell line and evaluate the anti-tumor activity of the test drugs in this model.

[0109] 3.1 Tumor volume: Tumor volume was measured twice a week using a vernier caliper. The tumor volume was calculated as V = 0.5 × (a × b 2 ), where a and b represent the long and short diameters of the tumor, respectively.

[0110] 3.2 Tumor growth inhibition rate TGI (%) = [1-(Ti-T0) / (Vi-V0)] × 100

[0111] Wherein, Ti is the average tumor volume of the compound group after the start of administration, T0 is the average tumor volume of the compound group at the first administration, V0 is the average tumor volume of the vehicle control group at the first administration, and Vi is the average tumor volume of the vehicle control group after the start of administration.

[0112] 3.3 Relative tumor proliferation rate T / C (%): The calculation formula is as follows: T / C% = TRTV / CRTV × 100% (TRTV: RTV of the treatment group; CRTV: RTV of the negative control group). The relative tumor volume (RTV) was calculated based on the results of tumor measurement. The calculation formula is RTV = Vt / V0, where V0 is the average tumor volume measured at the time of group administration (i.e., d0), Vt is the average tumor volume at a certain measurement, and TRTV and CRTV are taken from the same day.

[0113] 3.4 The body weight of all tumor-bearing mice was measured twice a week. At the same time, the weight gain change ratio of mice after drug administration was calculated: RCBW (%) = (BWi-BW0) / BW0×100, where BWi is the average body weight after the start of drug administration and BW0 is the average body weight at the first drug administration.

[0114] 4. Data Analysis

[0115] All data were analyzed by Graphpad and expressed as Mean ± SEM. The differences between the test drug group and the control group were compared by One-way ANOVALS D (L) test, and p < 0.05 was considered to be significantly different.

[0116] 5. Results

[0117] On the 21st day of group administration, the average tumor volume of the model control group (PBS) was 2075.28±384.4mm 3 The average tumor volumes of the GA@AMSN, 100 mg / kg group and the Dabrafenib, 100 mg / kg group were 1184.15±212.76 mm 3 、1211.51±130.65mm 3 Compared with the model control group, the tumor growth inhibition rate (TGI%) was 45.34% and 43.95%, respectively. All drug groups were able to inhibit the growth of subcutaneous transplanted tumors in A375 mice, but it did not show statistical significance (p>0.05). On the 25th day of group administration, the average tumor volume of the GA@AMSN, 100mg / kg administration group and the Dabrafenib, 100mg / kg administration group was 1900.7±384.05mm 3 、1985.26±230.72mm 3 , see Table 2 and Figure 7 .

[0118] On the 21st day of group administration, the average tumor volume of mice in the model control group exceeded 2000mm 3In view of the requirements of humane endpoints, they were euthanized directly on the same day. The entire experiment ended on the 25th day of administration. All mice in the GA@AMSN, 100 mg / kg administration group and the Dabrafenib, 100 mg / kg administration group were euthanized, and the tumors were removed, weighed, and photographed. The average weight of the tumor in the model control group was 2.11±0.36 g (day 21); the average weight of the tumor in the GA@AMSN, 100 mg / kg administration group and the Dabrafenib, 100 mg / kg administration group were 2.02±0.41 g (day 25), and 2.07±0.27 g (day 25), respectively. The results of tumor volume and tumor weight were basically consistent, see Tables 3 and Figure 7 .

[0119] In addition, in this experiment, all mice did not show continuous weight loss or other abnormal symptoms, indicating that the tumor-bearing mice were able to tolerate the drugs at the tested doses, as shown in Table 4 and Figure 8 .

[0120] Table 2. Average tumor volume of mice in each group (Mean±SEM)

[0121]

[0122] Note: Compared with the control group, *p<0.05 is considered to be significantly different.

[0123] Table 3. Average tumor weight of mice in each group (Mean±SEM)

[0124]

[0125] Note: Compared with the control group, ***p<0.001, ****p<0.0001, *p<0.05 were considered to be significantly different

[0126] Table 4. Body weight changes of mice in each group (Mean±SEM)

[0127]

[0128] According to the above experimental results, the gingerolone A nanoformulation has a strong inhibitory effect on the proliferation of melanoma A375, which may be related to its special recognition ability with cancer cells. After 21 days of administration, the tumor growth inhibition rate (TGI%) of the gingerolone A nanoformulation was 45.34%, which was better than the 43.95% of the positive drug dabrafenib. After 25 days of administration, the gingerolone A nanoformulation was better than the positive drug dabrafenib in terms of average tumor volume, average tumor weight, and weight change rate of mice. The effect of inhibiting melanoma A375 was significant. The nanoformulation GA@AMSN has great application potential in the field of anti-melanoma treatment.

[0129] Furthermore, the livers of the GA@AMSN, 100 mg / kg treatment group were collected for paraffin sectioning, and the morphology of cells and tissues was evaluated by H&E staining analysis. Fig. 9 As shown in the figure, no obvious abnormalities were found in the liver tissue structure, no fibrous tissue hyperplasia and mononuclear inflammatory cell infiltration were found in the portal area, and no clear focal necrosis and sheet necrosis were found in the liver parenchyma. No clear hepatic sinusoidal congestion and bile stasis were found, and there were no clear histological manifestations of liver tissue damage.

[0130] The above-mentioned embodiments only express several implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent application. It should be pointed out that, for a person of ordinary skill in the art, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. Application of a novel nano preparation containing gingerol A in the preparation of anti-tumor drugs, characterized in that: The nano preparation comprises aminated dendritic mesoporous silica and zingiberenone A loaded on the aminated dendritic mesoporous silica.

2. The use according to claim 1, characterized in that: The tumors include one or more of melanoma, lymphohematopoietic system tumors, endocrine tumors, lung and mediastinal tumors, breast tumors, digestive system tumors, urinary and male reproductive system tumors, female reproductive system tumors, head and neck tumors, central nervous system tumors, skin tumors, and bone and soft tissue tumors.

3. The use according to claim 1, characterized in that: The dosage form of the drug includes tablets, capsules, pills, injections, sustained-release preparations or controlled-release preparations; The administration routes of the anti-tumor drug include intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration 、 One or more of rectal administration, skin mucosal administration and inhalation administration.

4. The use according to claim 1, characterized in that: The dosage of the nano preparation in the anti-tumor drug is 100 mg / kg to 400 mg / kg.

5. The use according to claim 1, characterized in that: The anti-tumor drug is a drug that inhibits tumor growth or tumor cell proliferation.

6. The use according to claim 1, characterized in that: The anti-tumor drug is a drug that promotes or induces apoptosis of tumor cells.

7. The use according to claim 1, characterized in that: The anti-tumor drug is a drug that inhibits the growth of transplanted tumors.

8. The use according to any one of claims 1 to 7, characterized in that: The anti-tumor drug also contains pharmaceutically acceptable carriers, excipients and / or auxiliary materials.

9. The use according to claim 1, characterized in that: The preparation method of the nano preparation comprises: The gingerol A is dissolved in a solvent to obtain a gingerol A solution, and the gingerol A solution and the amino-modified dendritic mesoporous silica are added into a buffer solution for reaction, so that the gingerol A is loaded on the amino-modified dendritic mesoporous silica to obtain the nano-preparation.

10. An anti-tumor drug, characterized in that: The active ingredient is a new nano-preparation containing gingerol A; The nanoformulation is the nanoformulation used in any one of claims 1 to 9.

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