Application of a novel nano-preparation containing zingiberone A in preparation of an antitumor drug

Abstract

The application discloses application of a novel nano preparation containing zingerone A in preparation of an antitumor drug, and the nano preparation comprises aminated dendritic mesoporous silica and zingerone A loaded on the aminated dendritic mesoporous silica. The application adopts the aminated dendritic mesoporous silica to load the zingerone A, and a novel nano preparation containing zingerone A with high drug loading, high encapsulation rate and high biocompatibility is prepared. The preparation has low cytotoxicity, can be quickly taken up by tumor cells, significantly enhances the ability of the zingerone A to remove tumor cells, effectively inhibits the proliferation of tumors in vivo, and has a treatment effect superior to that of a commonly used clinical antitumor drug, namely, dabrafenib, and has a wide application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medicine, more particularly to application of a novel nano preparation containing gingerenone A in preparation of an antitumor drug. BACKGROUND

[0002] The existing tumor treatment methods mainly adopt surgical resection, chemotherapy and radiotherapy, but all have limitations such as strong toxic and side effects and easy recurrence. Therefore, screening of a new and safe and effective antitumor drug has very important clinical significance.

[0003] Gingerenone A (GA) is a natural phytochemical extracted from ginger, which has broad medicinal value, including antitumor, antioxidant, anti-aging, anti-inflammatory, antiviral, blood glucose control, etc. Studies have shown that GA can promote the antiproliferation and senescence of breast cancer cells induced by oxidative stress (Gingerenone A Induces Antiproliferation 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 Ribosomal S6 Kinase1 (S6K1) Pathways.;Sanguine Byun.;et al.), which is an effective antitumor active ingredient.

[0004] However, due to the poor solubility, permeability, stability and absorbability of gingerenone A, it is difficult to achieve the expected effect after use at an effective treatment concentration, which greatly limits its application range. SUMMARY

[0005] The present application aims to overcome the above-mentioned defects in the prior art, and provides application of a novel nano preparation containing gingerenone A in preparation of an antitumor drug. The gingerenone A is loaded on aminated dendritic mesoporous silica to prepare a novel nano preparation containing gingerenone A, which has high drug loading capacity, high encapsulation efficiency, high biocompatibility, low cytotoxicity, can be quickly taken up by tumor cells, significantly enhances the ability of gingerenone A to remove tumor cells, effectively inhibits the proliferation of tumors in vivo, and has a treatment effect superior to that of the clinically commonly used antitumor drug dabrafenib, and has a broad application prospect.

[0006] To achieve the above-mentioned purpose, the technical scheme of the present application is as follows:

[0007] The application of a novel nano-preparation containing zingiberenone A in the preparation of an anti-tumor drug, wherein the nano-preparation comprises aminated dendritic mesoporous silica and zingiberenone A loaded on the aminated dendritic mesoporous silica.

[0008] Optionally, the tumor comprises one or more than two of melanoma, lymphoid and hematopoietic system tumor, endocrine tumor, lung and mediastinum tumor, breast tumor, digestive system tumor, urinary and male reproductive system tumor, female reproductive system tumor, head and neck tumor, central nervous system tumor, skin tumor, and bone and soft tissue tumor.

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

[0010] Optionally, the administration route of the anti-tumor drug comprises one or more than two of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration 、 , rectal administration, skin mucosa administration and inhalation administration.

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

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

[0013] Optionally, the anti-tumor drug is a drug for promoting or inducing tumor cell apoptosis.

[0014] Optionally, the anti-tumor drug is a drug for inhibiting the growth of a transplanted tumor.

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

[0016] Optionally, the loading amount of zingiberenone A in the nano-preparation is 15%-30%.

[0017] Optionally, the encapsulation efficiency of zingiberenone A in the nano-preparation is 11%-35%.

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

[0019] Optionally, the specific surface area of the nano-preparation is 800 m 2 / g-1000 m 2 / g.

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

[0021] Optionally, the amino-functionalized dendritic mesoporous silica has a pore size of 2-10 nm.

[0022] Optionally, the amino-functionalized dendritic mesoporous silica has a specific surface area of 300-1000 m 2 / g. 2 / g.

[0023] Optionally, the preparation method of the nano-preparation comprises:

[0024] Dissolving zingerone A in a solvent to obtain a zingerone A solution, adding the zingerone A solution and the amino-functionalized dendritic mesoporous silica into a buffer solution to react, so as to load the zingerone A on the amino-functionalized dendritic mesoporous silica, and obtaining the nano-preparation.

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

[0026] The buffer solution comprises one or two or more of a phosphate buffer solution, a borate buffer solution, a citrate buffer solution, a phosphate and a tris buffer solution, an acetate buffer solution, an imidazole salt buffer solution, and a carbonate buffer solution.

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

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

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

[0030] The temperature of the reaction is 25-80℃, and the reaction time is 6-36 h.

[0031] The application further discloses an anti-tumor drug, and the functional component is a novel nano-preparation containing zingerone A; the nano-preparation is the nano-preparation in the application.

[0032] The application has the following beneficial effects:

[0033] (1) The application uses the amino-functionalized dendritic mesoporous silica to load zingerone A, so as to prepare a novel nano-preparation containing zingerone A, which has high drug loading capacity, high encapsulation efficiency, and high biocompatibility, has low cytotoxicity, can be quickly taken up by tumor cells, significantly enhances the ability of zingerone A to remove tumor cells, effectively inhibits the proliferation of tumors in vivo, and has a treatment effect superior to that of a clinically commonly used anti-tumor drug, darafin, and can be applied to the field of anti-cancer drugs, and has a wide application prospect.

[0034] (2) The present application selects the amino-modified dendritic mesoporous silica as a drug carrier, and loads zingerone A on the drug carrier through non-covalent force, so that the nano-preparation is highly enriched in the tumor site, thereby achieving the effect of targeting tumor and improving the bioavailability of zingerone A.

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

[0036] Figure 1 The figure is the result of the influence of different concentrations of GA@AMSN and GA of the embodiment 2 of the present application on the proliferation of A431 human epidermal carcinoma cells.

[0037] Figure 2 The figure is the result of the influence of different concentrations of GA@AMSN and GA of the embodiment 2 of the present application on the proliferation of A375 human malignant melanoma cells.

[0038] Figure 3 The figure is the result of the influence of different concentrations of GA@AMSN and GA of the embodiment 2 of the present application on the proliferation of Caco2 human colon adenocarcinoma cells.

[0039] Figure 4 The figure is the result of the influence of different concentrations of GA@AMSN and GA of the embodiment 2 of the present application on the proliferation of SW579 human thyroid squamous carcinoma cells.

[0040] Figure 5 The figure is the result of the influence of different concentrations of GA@AMSN and GA of the embodiment 2 of the present application on the proliferation of HCT-116 human colorectal cancer cells.

[0041] Figure 6 The figure is the result of the influence of different concentrations of GA@AMSN and GA of the embodiment 2 of the present application on the proliferation of HepG2 human hepatoma cells.

[0042] Figure 7 The figure is the pharmacodynamic evaluation of the test drug of the embodiment 2 of the present application on the A375 cell mouse subcutaneous transplanted tumor model (A, tumor growth curve; B, tumor weight; C, tumor picture).

[0043] Figure 8 Pharmacodynamic evaluation of the test drug of the present embodiment 2 on a mouse subcutaneous transplantation tumor model of A375 cells (A, weight change curve of tumor-bearing mice; B, relative weight change curve of tumor-bearing mice).

[0044] Figure 9 The liver H&E staining result graph after treatment of the test drug (GA@AMSN) in the present embodiment 2. DETAILED DESCRIPTION

[0045] The present application is further described below in conjunction with specific embodiments, but in no way limits the present application.

[0046] The application discloses application of a novel nano preparation containing zingerone A in preparation of an antitumor drug, wherein the nano preparation comprises aminated dendritic mesoporous silica and zingerone A loaded on the aminated dendritic mesoporous silica.

[0047] In an embodiment, the tumor comprises one or more than two of melanoma, lymphoid and hematopoietic system tumor, endocrine tumor, lung and mediastinum tumor, breast tumor, digestive system tumor, urinary and male reproductive system tumor, female reproductive system tumor, head and neck tumor, central nervous system tumor, skin tumor and bone and soft tissue tumor.

[0048] In an embodiment, the dosage form of the drug comprises a tablet, a capsule, a pill, an injection, a sustained-release preparation or a controlled-release preparation.

[0049] In an embodiment, the administration route of the antitumor drug comprises one or more than two of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration 、 rectal administration, skin mucosa administration and inhalation administration.

[0050] In an embodiment, the dosage of the nano preparation in the anticancer drug is 100 mg / kg-400 mg / kg.

[0051] In an embodiment, the antitumor drug is a drug for inhibiting tumor growth or inhibiting tumor cell proliferation.

[0052] In an embodiment, the antitumor drug is a drug for promoting or inducing tumor cell apoptosis.

[0053] In an embodiment, the antitumor drug is a drug for inhibiting growth of a transplantation tumor.

[0054] In an embodiment, the antitumor drug further comprises a pharmaceutically acceptable carrier, excipient and / or adjuvant.

[0055] In an embodiment, the loading amount of zingerone A in the nano preparation is 15%-30%.

[0056] In a specific embodiment, the nano-preparation has an encapsulation efficiency of 11% to 35% for zingerone A.

[0057] In a specific embodiment, the nano-preparation has a particle size of 50 nm to 200 nm.

[0058] In a specific embodiment, the nano-preparation has a specific surface area of 800 m2 / g to 1000 m2 / g.

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

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

[0061] In a specific embodiment, the amino-functionalized dendritic mesoporous silica has a specific surface area of 300 m 2 / g to 1000 m 2 / g.

[0062] In a specific embodiment, the method for preparing the nano-preparation comprises:

[0063] (1) mixing a template agent and a catalyst in water to form an aqueous phase.

[0064] (2) mixing a silicon source with a solvent to form an oil phase.

[0065] (3) performing a homogeneous reaction of the oil phase and the aqueous phase, and after the reaction, centrifuging, drying, and calcining to obtain dendritic mesoporous silica.

[0066] (4) adding the dendritic mesoporous silica and an ammonia source in an acetonitrile solution to perform amino-functionalization modification to obtain amino-functionalized dendritic mesoporous silica.

[0067] (5) dissolving zingerone A in a solvent to obtain a zingerone A solution, and adding the zingerone A solution and the amino-functionalized dendritic mesoporous silica into a buffer solution to perform a reaction to load the zingerone A on the amino-functionalized dendritic mesoporous silica, thereby obtaining the nano-preparation.

[0068] Specifically, the present application firstly prepares dendritic mesoporous silica with a unique central radial hole structure in a water / oil two-phase system, then modifies the amino group on the surface, and selects dendritic mesoporous silica with higher pore permeability, larger pore volume, multiple surface functions and good biocompatibility as a drug carrier, and further modifies the amino group, so as to realize high loading of zingerone A by non-covalent force with the amino-modified dendritic mesoporous silica as a carrier. The obtained nano-preparation has uniform particle size, high drug loading, high encapsulation rate, high biocompatibility and low toxicity.

[0069] Further, the preparation conditions are reasonably optimized to regulate the structure of the mesoporous silica nanomaterial, including particle size, pore size, specific surface area and the like, which is beneficial to form a mesoporous structure with a good pore size distribution rate.

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

[0071] In a specific embodiment, the buffer solution includes one or two or more of a phosphate buffer, a borate buffer solution, a citrate buffer solution, a phosphate and a tris buffer, an acetate buffer, an imidazole salt buffer solution, and a carbonate buffer solution.

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

[0073] In a specific embodiment, the concentration of zingerone A in the zingerone A solution is 2 mg / mL-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℃-80℃, and the time of the homogeneous reaction is 6h-36h.

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

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

[0078] In an embodiment, the silicon source comprises one or more of tetraethyl orthosilicate, tetramethyl orthosilicate, tetra(2-methoxy-1-methylethyl) orthosilicate, tetraisopropyl orthosilicate, tetrabutyl orthosilicate, tetraisopropyl orthosilicate. Preferably, the silicon source is tetraethyl orthosilicate.

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

[0080] In an embodiment, the solvent in step (2) comprises one or more of chlorobenzene, cyclohexane, chloroform, dichloromethane, water.

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

[0082] In an embodiment, the present application is not particularly limited in mixing mode, and the raw materials can be uniformly mixed.

[0083] The present application also discloses an antitumor drug, and the active ingredient is a novel nano preparation containing zingiberene A.

[0084] The following are specific embodiments

[0085] Example 1: Preparation of a novel nano preparation containing zingiberene A (GA@AMSN)

[0086] Preparation of MSNs: 30 g of N-hexadecyltrimethylammonium chloride (CTAC) was dissolved in 300 mL of ultrapure water in a 500 mL round-bottom flask. 1.0 g of triethanolamine was then added to the dissolved CTAC solution and stirred thoroughly to form an upper aqueous phase. Next, 12 mL of tetraethyl silicate and 100 mL of solvent (60 mL of cyclohexane + 40 mL of chlorobenzene) were thoroughly mixed in a beaker to form the oil phase. The oil phase was transferred to the flask to form a two-phase reaction system. The reaction was stirred at 60°C for 12 h at a speed of 300 rpm. The resulting milky white liquid was removed and centrifuged (10,000 rpm for 15 min) to obtain a white solid product. This solid was washed three times with ethanol to remove the solvent and then air-dried 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 once with deionized water and ethanol, 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 and ultrasonically dispersed. 200 μl of 3-aminopropyltriethoxysilane (APTE) was added to the reaction system, and the mixture was stirred at 600 rpm and 80°C for 12 hours. After the reaction, the liquid was centrifuged and the resulting sample was washed twice with water and then twice with ethanol to obtain AMSN.

[0088] Preparation of GA@AMSN: 40 mg of AMSN was added to 5 mL of GA in acetonitrile (5 mg / mL, 10 mg / mL, and 15 mg / mL). Ultrasonic dispersion was performed, and the mixture was incubated with stirring at room temperature for 8 h. The supernatant was then removed by centrifugation, 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 hepatocarcinoma cells were purchased from the Cell Bank of the Committee of Type Culture Collection of the Chinese Academy of Sciences.

[0092] 2. Experimental methods

[0093] The tumor cell proliferation experiment was carried out by MTT experiment, and the influence of GA@AMSN prepared in Example 1 on cell proliferation was analyzed. Cells were plated in a 96-well plate at 1x10 4 cells per well, and after the cells adhered, 100 μL of culture medium containing the corresponding drug concentration (5 μM-25 μM) was added to GA@AMSN and GA, respectively, 6 replicates were set for each concentration, and the error of each well was not more than 5%. After 24 h of drug action, the culture supernatant in the well was aspirated, 100 μl of 5 mg / ml MTT solution was added to each well, and the culture was continued for 3 h, then the culture was terminated, and the culture supernatant in the well was carefully aspirated. 100 μl of DMSO was added to each well to dissolve the crystals. The light absorption value of each well was determined at 490 nm wavelength by enzyme-linked immunoassay instrument, and the IC50 value was calculated.

[0094] The results are shown in Figures 1-6 As shown, the GA@AMSN of the application has good synergistic inhibition effect, and can inhibit the proliferation of A431 human epidermal carcinoma cells, A375 human malignant melanoma cells, Caco2 human colon adenocarcinoma cells, SW579 human thyroid squamous carcinoma cells, HCT-116 human colorectal cancer cells and HepG2 human hepatoma cells in a dose-dependent manner after 24 h of action.

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

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

[0097] 1. Experimental animals:

[0098] NU / NU mice, female, 6-8 weeks, 18-22 g, purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd. All experimental mice were raised in Shanghai Lidi SPF animal room, and were adapted to the environment for at least 3 days in advance. All experimental mice were raised in SPF animal room IVC constant temperature and pressure system, with temperature of 20-26℃, humidity of 40-70%, and light cycle of 12 hours light and 12 hours dark. No more than 6 mice were raised in each cage, and the cage size was 325mmx210mmx180mm. The bedding used in the cage was high-pressure sterilized corn cob, which was replaced twice a week. During the entire experiment, all experimental mice could freely eat and drink, and the feed was sterilized by Co60 irradiation, and the drinking water was high-pressure sterilized, and the feed and drinking water were kept in sufficient supply.

[0099] 2. Experimental design

[0100] 2.1. Culture of A375 tumor cells

[0101] A375 cells, culture conditions for 90% DMEM + 10% inactivated FBS, placed in 37℃, 5% CO2 incubator culture. Logarithmic growth phase of cells will be used to establish the establishment of in vivo tumor xenograft model.

[0102] 2.2, A375 tumor cells inoculation

[0103] Take the logarithmic growth phase of A375 cells, add an appropriate amount of HBSS resuspended, count, adjust the cell density to 4×10 7 cells / mL, placed on ice for standby. In each NU / NU mice right subcutaneous inoculation of 0.1 mL tumor cell suspension, that is, 4×10 6 cells per. Select the average tumor volume in 109.65 (84.69-136.81) mm 3 of 15 mice for pharmacodynamic grouping, randomly divided into 3 groups, 5 in each group. 3 groups were given PBS, gingerone A nano preparation (GA@AMSN), positive control drug Dabrafenib. The detailed administration method, administration dose and administration route are shown in Table 1, and the grouping administration day is day 0.

[0104] Table 1. Grouping and administration

[0105]

[0106] The volume of administration: according to the weight of tumor-bearing mice to adjust the volume of administration (10 μL / g)

[0107] 3, evaluation index

[0108] Mainly to establish A375 cell line subcutaneous tumor and evaluate the anti-tumor activity of the test drug on the model.

[0109] 3.1 Tumor volume: measured twice a week using a vernier caliper, and the tumor volume calculation formula is V = 0.5 × (a × b 2 ), where a and b represent the long diameter and short diameter of the tumor, respectively.

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

[0111] Where Ti is the average tumor volume after the compound group starts to administer, 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 administration starts.

[0112] 3.3 Relative tumor proliferation rate T / C (%): The formula is as follows: T / C % = TRTV / CRTV x 100% (TRTV: RTV of treatment group; CRTV: RTV of negative control group). According to the results of tumor measurement, the relative tumor volume (RTV) was calculated according to the formula RTV = Vt / V0, wherein V0 is the average tumor volume measured at the time of grouping (i.e. d0), Vt is the average tumor volume at a certain time of measurement, and TRTV and CRTV are the data of the same day.

[0113] 3.4 The body weight of all tumor-bearing mice was measured twice a week. At the same time, the change rate of body weight increase of mice after administration was calculated: RCBW (%) = (BWi - BW0) / BW0 x 100, BWi is the average body weight after starting administration, and BW0 is the average body weight at the first 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 ANOVA L test, and p < 0.05 was considered to be a significant difference.

[0116] 5. Results

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

[0118] On the 21st day of grouping and administration, the average tumor volume of the model control group mice was more than 2000 mm 3, in view of the humane end point requirement, euthanasia was performed directly on the same day. At the end of 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, the tumors were stripped and weighed and photographed. The average weight of the tumors in the model control group was 2.11 ± 0.36 g (21st day); the average weight of the tumors in the GA@AMSN, 100 mg / kg administration group and the Dabrafenib, 100 mg / kg administration group was 2.02 ± 0.41 g (25th day) and 2.07 ± 0.27 g (25th day), respectively. The tumor volume and tumor weight results were basically consistent, see Table 3 and Figure 7 .

[0119] In addition, in this experiment, all mice did not show sustained weight loss and other abnormal symptoms, indicating that tumor-bearing mice can tolerate the tested dose of drugs, see Table 4 and Figure 8 .

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

[0121]

[0122] Note: Compared with the control group, *p <0.05 is considered to have significant difference.

[0123] Table 3. Mean 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 is considered to have significant difference

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

[0127]

[0128] According to the experimental results above, the nano preparation of zingerone A 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 nano preparation of zingerone A was 45.34%, which was better than that of the positive drug Dabrafenib, which was 43.95%. After 25 days of administration, the data of the nano preparation of zingerone A in terms of average tumor volume, average tumor weight, and body weight change rate were all better than those of the positive drug Dabrafenib, and the effect of inhibiting melanoma A375 was significant. The nano preparation GA@AMSN has great application potential in the field of anti-melanoma therapy.

[0129] Further, the liver of the GA@AMSN, 100 mg / kg administration group was collected for paraffin section, and the morphology of cells and tissues was evaluated by H&E staining analysis. The results of H&E staining experiment are shown in Figure 9 As shown, it was found that the liver tissue structure had no obvious abnormalities, no fibrous tissue hyperplasia and mononuclear inflammatory cell infiltration was found in the hepatic sinusoidal area, no clear point and focal necrosis and sheet necrosis was found in the liver parenchyma. No clear blood stasis and bile stasis was found in the liver sinusoid, and no clear histological manifestations of liver tissue damage was found.

[0130] The above-described embodiments only express several embodiments of the present application, and the description is more specific and detailed, but it cannot be understood as limiting the scope of the application. It should be noted that for ordinary skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of the present application. Therefore, the protection scope of the present application patent should be subject to the appended claims.

Claims

1. Application of a novel nanoformulation containing gingerol A in the preparation of anti-tumor drugs, characterized in that: The tumor is melanoma; The nanoformulation comprises amino-modified dendritic mesoporous silica and gingerol A loaded on the amino-modified dendritic mesoporous silica; The preparation method of the nano preparation comprises: (1) adding a template and a catalyst into water and mixing them to form an aqueous phase; the template is hexadecyltrimethylammonium chloride; (2) Mixing a silicon source with a solvent to form an oil phase; the silicon source is ethyl orthosilicate; (3) homogeneously reacting the oil phase with the water phase, centrifuging after the reaction, drying, and then calcining to obtain dendritic mesoporous silica; (4) Adding dendritic mesoporous silica and an ammonia source to an acetonitrile solution for amino modification to obtain amino-modified dendritic mesoporous silica; (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 the gingerol A on the amino-modified dendritic mesoporous silica to obtain the nanoformulation; the mass ratio of gingerol A to amino-modified dendritic mesoporous silica in the gingerol A solution is (1-5):

1.

2. 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 one or more of intravenous injection, intraperitoneal injection, intramuscular injection, subcutaneous injection, oral administration, rectal administration, skin and mucosal administration and inhalation administration.

3. 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.

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

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

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

7. The use according to any one of claims 1 to 6, characterized in that The anti-tumor drug further contains pharmaceutically acceptable carriers, excipients and / or auxiliary materials.

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