A comprehensive targeted drug complex for treating tumors, its preparation and use

Abstract

This invention provides a drug complex comprising a pharmaceutical composition DBDx and a second active ingredient, wherein the pharmaceutical composition DBDx is composed of dipyridamole, ubenmelim, and dexamethasone; and the second active ingredient is selected from cetuximab, trastuzumab, rituximab, or bevacizumab. This invention provides the application of the above-mentioned drug complex in the preparation of antitumor drugs, particularly for pancreatic cancer, gastric cancer, esophageal cancer, squamous cell carcinoma, melanoma, lung cancer, liver cancer, or lymphoma.

Description

Technical Field

[0001] The present invention relates to a drug complex, in particular to a drug complex that targets tumor cells and simultaneously regulates the tumor microenvironment, and also to the preparation and application of the complex. Background Art

[0002] At present, the strategies for developing new anti-tumor drugs include two aspects: 1. Drugs that act on tumor cells: They mainly work by inhibiting tumor cell proliferation, inducing tumor cell apoptosis, and inducing tumor cell differentiation. 2. Drugs that regulate the tumor microenvironment: They mainly work through the following aspects: (1) inhibiting tumor angiogenesis or interfering with the tumor vascular network; (2) regulating immune cells and related cytokines infiltrating the tumor; (3) regulating growth factor secretion and growth factor receptor expression; (4) inhibiting the secretion of specific enzymes and regulating corresponding inhibitory factors; (5) interfering with the transport, uptake and excretion of substances inside and outside tumor cells. The toxicity of anti-tumor drugs currently used in clinical practice is a prominent problem that plagues tumor chemotherapy. Finding drugs with low toxicity that act on specific links or molecular targets in the tumor microenvironment to improve the anti-tumor effect or reduce its toxicity has become a new direction in the research of anti-tumor drugs and is also an urgent need for clinical treatment of tumors.

[0003] Dipyridamole (DPM) and its pharmaceutically acceptable derivatives or analogs such as mopidamole, BIBW22BS, RA25 or pharmaceutically acceptable salts thereof are non-nitrate coronary vasodilators that have the effects of dilating coronary vessels and promoting the formation of collateral circulation. Dipyridamole also has the effects of inhibiting platelet aggregation and preventing thrombosis.

[0004] The chemical name of dipyridamole is 2,2',2",2"'-[(4,8-dipiperidinylpyrimido[5,4,-d]pyrimidine-2,6-diyl)bis(nitrogen)-tetraethanol, and its molecular formula is C 24 H 40 N8O4 is an effective nucleoside transport inhibitor that inhibits nucleoside transport by blocking the equilibrative nucleoside transporters hENT1 (NatMed, 1997, 3: 89-93) and hENT2 (Biochem.J, 1997, 328: 739-43). As a nucleoside transport inhibitor, dipyridamole can enhance the anti-metabolite acivicin's inhibitory effect on tumor cell proliferation. In tumor treatment, dipyridamole can enhance the cytotoxic activity of a variety of anti-tumor drugs such as 5-fluorouracil, methotrexate, doxorubicin, etoposide, vinblastine, cisplatin, etc.

[0005] Ubenimex (BEN) and its pharmaceutically acceptable derivatives or analogs include AHPA-Val, Bestatin Hydrochloride, etc. The chemical name of Ubenimex is N-[(2S, 3R)-4-phenyl-3-amino-2-hydroxybutyryl]-L-leucine, and its molecular formula is C 16 H 24 N2O4 shows multiple immune activities, which can not only enhance the function of lymphocytes, but also activate mononuclear macrophages and enhance the killing activity of NK cells. Ubenimex is commonly used in tumor chemotherapy, radiotherapy and adjuvant therapy after surgery. It can be used in combination with chemotherapy, radiotherapy and combined with chemotherapy for the treatment of leukemia, multiple myeloma, lung cancer, breast cancer and other solid tumors. Ubenimex can also exert anti-tumor activity by directly acting on tumor tissue.

[0006] Glucocorticoids, such as dexamethasone (DEX) and its pharmaceutically acceptable derivatives or analogs, such as dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone sodium palmitate, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, triamcinolone, betamethasone, etc., have pharmacological effects such as anti-inflammatory, immunosuppressive, anti-toxin, and anti-shock. Dexamethasone is widely used in the treatment of various diseases, such as autoimmune diseases, allergies, inflammation, asthma, and dermatological and ophthalmic diseases. Tumors are closely related to inflammation, and the occurrence of inflammation promotes the occurrence and development of tumors. Dexamethasone controls inflammatory reactions through multiple pathways and inhibits the development of tumors. In tumor treatment, dexamethasone can reduce certain side effects of chemotherapy in cancer patients and reduce nausea and vomiting symptoms after chemotherapy. Dexamethasone is also commonly used in the treatment of some malignant blood diseases. In the treatment of brain tumors, dexamethasone is often used to reduce the permeability of tumor-related blood vessels to reduce the development of edema.

[0007] Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2). It blocks the attachment of human epidermal growth factor to HER2 by binding to HER2, thereby blocking the growth of tumor cells. Trastuzumab can also stimulate the body's own immune cells to destroy tumor cells. It is mainly used clinically for metastatic breast cancer with overexpression of HER2.

[0008] Cetuximab is an IgG1 monoclonal antibody targeting EGF receptors, which can specifically bind to EGF receptors expressed on the surface of normal cells and various tumor cells. After the two specifically bind, it blocks the intracellular signal transduction pathway by inhibiting the tyrosine kinase (TK) bound to the EGF receptor, thereby inhibiting the proliferation of tumor cells, inducing tumor cell apoptosis, and reducing the production of matrix metalloproteinases and vascular endothelial growth factor.

[0009] Bevacizumab (trade name Avastin) is a monoclonal antibody that can inhibit vascular endothelial growth factor, reduce tumor angiogenesis, and inhibit tumor growth. It is used to treat various types of metastatic tumors and is often used to treat patients with advanced metastatic colon cancer. In addition, for advanced metastatic or recurrent non-small cell lung cancer, bevacizumab can be combined with carboplatin and paclitaxel for the first-line treatment of advanced metastatic non-squamous non-small cell lung cancer, with good clinical efficacy.

[0010] Rituximab is a chimeric mouse / human monoclonal antibody that specifically binds to the CD20 antigen that runs through the cell membrane. This antigen is present in pre-B and mature B lymphocytes, but not in hematopoietic stem cells, post-B cells, normal plasma cells or other normal tissues. It is suitable for the treatment of relapsed or resistant follicular central lymphoma, mainly for the treatment of non-Hodgkin's lymphoma. Summary of the invention

[0011] The purpose of the present invention is to provide a drug complex that targets tumor cells and simultaneously regulates the tumor microenvironment. The idea of ​​the present invention is to examine the combined action index of the drug composition DBDx and a variety of monoclonal antibody tumor drugs and the effects on the growth inhibition of a variety of tumor cells, and to provide a new comprehensive targeted drug complex with significant synergistic effects.

[0012] Based on this, the present invention provides a drug complex, which includes a drug composition DBDx and a second active ingredient, wherein the drug composition DBDx is composed of component A, component B and component C.

[0013] The component A is dipyridamole, a pharmaceutically acceptable derivative of dipyridamole, a pharmaceutically acceptable analog of dipyridamole, or a pharmaceutically acceptable salt thereof;

[0014] The component B is ubenimex, a pharmaceutically acceptable derivative of ubenimex, a pharmaceutically acceptable analog of ubenimex, or a pharmaceutically acceptable salt thereof;

[0015] The component C is dexamethasone, a pharmaceutically acceptable derivative of dexamethasone, a pharmaceutically acceptable analog of dexamethasone or a pharmaceutically acceptable salt thereof;

[0016] The second active ingredient is selected from cetuximab, trastuzumab, rituximab or bevacizumab.

[0017] The pharmaceutical composition DBDx of the present invention can refer to the records of Chinese invention patents CN 201010133844.5 and CN201010133858.7, or refer to Xiujun Liu et al., A multifunctional drug combination shows highly potent therapeutic efficacy against human cancer xenografts inathymic mice. PLoS One. 2014 Dec 22; 9(12): e115790.doi:10.1371 / journal.pone.0115790.

[0018] As a particularly preferred embodiment, the mass ratio of component A, component B and component C is 100:20:1 based on the mass ratio of dipyridamole, ubenimex and dexamethasone.

[0019] In the present invention, the mass ratio of the pharmaceutical composition DBDx to the second active ingredient is 121:(30-50).

[0020] The present invention also provides the use of the drug complex in preparing drugs for treating pancreatic cancer, gastric cancer, esophageal cancer, squamous cell carcinoma, melanoma, lung cancer, liver cancer, lymphoma and the like.

[0021] The tumors include, but are not limited to, pancreatic cancer, gastric cancer, esophageal cancer, squamous cell carcinoma, melanoma, lung cancer, liver cancer, lymphoma, etc.

[0022] The drug complex comprises a therapeutically effective amount of the anti-tumor drug and a medically acceptable carrier.

[0023] Preferably, in the drug complex, the weight content of the anti-tumor drug is 0.5-99.9%.

[0024] The medically acceptable carrier refers to conventional drug carriers in the pharmaceutical field, such as diluents, excipients such as water, fillers such as starch, sucrose, binders such as cellulose derivatives gelatin, polyvinyl pyrrolidone, lubricants such as talc, etc.

[0025] The drug complex of the present invention can be prepared by conventional methods in the pharmaceutical field.

[0026] The advantages and positive effects of the present invention are: the anti-tumor comprehensive targeted drug complex involved in the present invention achieves the purpose of effectively treating tumors mainly by acting on tumor cells while regulating the tumor microenvironment, and the toxic side effects caused by cytotoxic drugs are expected to be alleviated.

[0027] The present invention verifies that the drug complex has significant synergistic effects and can be used in combination to treat pancreatic cancer, gastric cancer, esophageal cancer, squamous cell carcinoma, melanoma, lung cancer, liver cancer, and lymphoma, effectively improving the therapeutic effect on tumors and reducing the occurrence and development of complications in patients. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The effect of the drug complex on the tumor volume of human pancreatic cancer AsPC-1 cells in the in vivo anti-tumor activity study of Example 2;

[0029] Figure 2 This is the effect of the drug complex on the body weight of experimental mice in the in vivo anti-tumor activity study of Example 2;

[0030] Figure 3 This is a photo of human pancreatic cancer AsPC-1 cells in the in vivo anti-tumor activity study of Example 2;

[0031] Figure 4 The effect of the drug complex on the tumor volume of human gastric cancer BCG823 cells in the in vivo anti-tumor activity study of Example 2;

[0032] Figure 5 This is the effect of the drug complex on the body weight of experimental mice in the in vivo anti-tumor activity study of Example 2;

[0033] Figure 6 This is a photo of human gastric cancer BCG823 cells in the in vivo anti-tumor activity study of Example 2;

[0034] Figure 7 The effect of the drug complex on the tumor volume of human squamous cell carcinoma A431 cells in the in vivo anti-tumor activity study of Example 2;

[0035] Figure 8 This is the effect of the drug complex on the body weight of experimental mice in the in vivo anti-tumor activity study of Example 2;

[0036] Fig. 9 This is a photo of human squamous cell carcinoma A431 cells in the in vivo anti-tumor activity study of Example 2;

[0037] Fig.10 This is the effect of the drug complex on the tumor volume of human esophageal cancer KYSE150 cells in the in vivo anti-tumor activity study of Example 2;

[0038] Fig.11 This is the effect of the drug complex on the body weight of experimental mice in the in vivo anti-tumor activity study of Example 2;

[0039] Fig.12 This is a photograph of human esophageal cancer KYSE150 cells in the in vivo anti-tumor activity study of Example 2. DETAILED DESCRIPTION

[0040] The following examples are used to explain the technical solutions of the present invention in a non-limiting manner.

[0041] In the present invention, unless otherwise specified, "%" used to explain concentrations refers to mass percentage, and ":" refers to mass ratio.

[0042] The present invention relates to the following medicines and reagents:

[0043] Dipyridamole and dexamethasone: standard products, purchased from the National Institute for the Control of Pharmaceutical and Biological Products; ubenimex: raw material, Zhejiang Proconyu Pharmaceutical Co., Ltd.; dipyridamole tablets, Yabao Pharmaceutical Group Co., Ltd.; dexamethasone tablets, Shanxi Tongda Pharmaceutical Co., Ltd.; ubenimex capsules, Zhejiang Proconyu Pharmaceutical Co., Ltd.; trastuzumab: trastuzumab for injection (Herceptin), Roche Pharmaceuticals; cetuximab: cetuximab injection (Erbitux), Merck Pharmaceuticals; rituximab: rituximab injection (MabThera), Roche Pharmaceuticals; bevacizumab: bevacizumab injection (Avastin), Roche Pharmaceuticals.

[0044] The anti-tumor drug composition DBDx: The ratio of the three components is always maintained at a mass ratio of 100:20:1 among dipyridamole, ubenimex and dexamethasone.

[0045] The present invention relates to the following tumor cells:

[0046] Human pancreatic cancer AsPC-1 cells, human gastric cancer BCG823 cells, human esophageal cancer KYSE150, KYSE520 cells, human squamous cell carcinoma A431 cells, mouse melanoma B16 cells, human non-small cell lung cancer A549 cells, human liver cancer HepG2 cells, human non-Hodgkin lymphoma Z-138 cells, human lymphoma Maver cells, human diffuse large B-cell lymphoma WSU-DLCL2 cells and human non-small cell lung cancer HCC827 cells were all purchased from the Cell Center of the Institute of Basic Medicine, Chinese Academy of Medical Sciences.

[0047] The present invention relates to the following experimental animals:

[0048] BALB / c female nude mice, 6-8 weeks old, weighing 18-22 g.

[0049] Example 1 Investigating the IC50 of the combined drug DBDx and the second active ingredient trastuzumab, cetuximab, rituximab, bevacizumab in the comprehensive targeted drug complex, and the in vitro combined action index of each combination

[0050] The concentration gradient of DBDx and the concentration gradient of trastuzumab, cetuximab, rituximab, and bevacizumab were set, and the IC50 was determined using the MTT method according to the prior art. At the same time, the cells were given the drug alone and in combination, and the drug combination index CDI value was calculated based on the cell survival rate. The results are shown in Tables 1-4.

[0051] Table 1 Inhibitory effects of the comprehensive targeted drug complex (DBDx and trastuzumab) on proliferation of human pancreatic cancer, human gastric cancer, human non-small cell lung cancer and human liver cancer cells

[0052]

[0053] Table 2 Inhibitory effect of the comprehensive targeted drug complex (DBDx and rituximab) on proliferation of human non-Hodgkin's lymphoma, human lymphoma, and human diffuse large B-cell lymphoma cells

[0054]

[0055] Table 3 Inhibitory effect of the comprehensive targeted drug complex (DBDx and cetuximab) on proliferation of human squamous cell carcinoma, human non-small cell lung cancer, human esophageal cancer, mouse melanoma, and human hepatoma cells

[0056]

[0057] Table 4 Inhibitory effect of the comprehensive targeted drug complex (DBDx and bevacizumab) on proliferation of human non-small cell lung cancer and human hepatocellular carcinoma cells

[0058]

[0059]

[0060] The above results show that in in vitro cell experiments, the CDI index of the combination of DBDx and trastuzumab for human pancreatic cancer, human gastric cancer, human non-small cell lung cancer and human liver cancer cells was less than 1, showing a synergistic effect. Among them, the CDI index for human pancreatic cancer AsPC-1 cells and human gastric cancer BCG823 cells was less than 0.8, achieving moderate synergistic effect.

[0061] The CDI index of DBDx combined with rituximab on human non-Hodgkin's lymphoma Z-138 cells and human diffuse large B-cell lymphoma WSU-DLCL2 cells was less than 1, showing a synergistic effect.

[0062] The combination of DBDx and cetuximab showed a CDI index of less than 1 for human squamous cell carcinoma A431 cells, human non-small cell lung cancer A549 cells, human esophageal cancer KYSE150, KYSE520 cells, mouse melanoma B16 cells and human liver cancer HepG2 cells, showing a synergistic effect. Among them, the CDI index for human squamous cell carcinoma A431 cells, human esophageal cancer KYSE520 cells and mouse melanoma B16 cells was less than 0.8, achieving a moderate synergistic effect.

[0063] The combination of DBDx and bevacizumab showed a CDI index of less than 1 for human non-small cell lung cancer A549 cells, human non-small cell lung cancer HCC827 cells and human liver cancer HepG2 cells, showing a synergistic effect.

[0064] The calculation formula of drug combination index CDI value is as follows:

[0065]

[0066] Calculated based on the number of living cells, i.e. absorbance value, AB is the ratio of the two-drug combination group to the control group, and A and B are the ratios of each single-drug group to the control group. If CDI < 1, it proves that the combined action of the two drugs is synergistic, CDI = 1, it proves that the combined action of the two drugs is additive, and CDI > 1 proves that the combined action of the two drugs is antagonistic.

[0067] Example 2 Study on the in vivo anti-tumor activity of the comprehensive targeted drug complex (DBDx and trastuzumab)

[0068] Human pancreatic cancer AsPC-1 cells and human gastric cancer BCG823 cells cultured in vitro were inoculated into the subcutaneous tissue of one side of the armpit of BALB / c nu / nu nude mice. After 2-3 generations, the axillary tumors were obtained and cut into 1.5 mm 3 The tumor grew to 100-300 mm after 7 days of inoculation. 3 Then they were randomly divided into groups according to the tumor size, with 6 mice in each group, and drug administration began. In the human pancreatic cancer AsPC-1 nude mouse transplant tumor model, DBDx was administered 5 times a week, for a total of 10 times in 2 weeks. Trastuzumab was administered once a week, for a total of 2 times in 2 weeks. In the human gastric cancer BCG823 nude mouse transplant tumor model, DBDx was administered 5 times a week, for a total of 15 times in 3 weeks. Trastuzumab was administered once a week, for a total of 3 times in 3 weeks. The control group was given normal saline, and the remaining groups were given the drugs in the corresponding embodiments, and the administration method was as follows: DBDx was administered orally, and trastuzumab was administered by injection.

[0069] The long diameter a and short diameter b of the tumor were measured every day, and the weight of the animal was recorded. 2 / 2Calculate the tumor volume, draw the tumor growth curve, and calculate the tumor inhibition rate.

[0070] The results are shown in Table 5 and Figure 1-3 shown.

[0071] Table 5 Inhibitory effect of the combined targeted drug complex (DBDx and trastuzumab) on the growth of human pancreatic cancer AsPC-1 nude mouse transplanted tumors

[0072]

[0073] No animals in each group died from the time of inoculation to 17 days.

[0074] Compared with the control group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; compared with trastuzumab, ▲p<0.001; compared with DBDx, △p<0.01.

[0075] The experimental results show that the combination of DBDx and trastuzumab has a very significant inhibitory effect on the growth of human pancreatic cancer AsPC-1 tumors transplanted into nude mice, and shows an obvious dose-effect relationship. This effect is stronger than the combination and trastuzumab alone. Moreover, the effect is long-lasting and has no effect on the weight of experimental animals.

[0076] The calculation formula of drug combination index CDI value is as follows:

[0077]

[0078] According to the weight of tumor tissue obtained after the experiment, AB is the ratio of the tumor weight of the two-drug combination group to the control group, and A and B are the ratios of the tumor weight of each single-drug group to the control group. If CDI < 1, it proves that the combined action of the two drugs is synergistic, CDI = 1, it proves that the combined action of the two drugs is additive, and CDI > 1 proves that the combined action of the two drugs is antagonistic. The calculation method of the following embodiments is the same.

[0079] The drug combination index CDI value was 0.64, indicating significant synergy.

[0080] The same method was used to detect human gastric cancer BCG823 transplanted into nude mice. The results are shown in Tables 6 and Figure 4-6 .

[0081] Table 6 Inhibitory effect of the comprehensive targeted drug complex (DBDx and trastuzumab) on the growth of human gastric cancer BCG823 nude mouse transplanted tumors

[0082]

[0083]

[0084] Drug administration began 7 days after tumor inoculation, with DBDx administered 5 times a week for a total of 15 times, and trastuzumab administered once a week for a total of 3 times. N=6, and no animals in each group died on the 31st day of observation.

[0085] Compared with the control group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; compared with trastuzumab, ◇p<0.05; compared with DBDx, ◆p<0.01.

[0086] The experimental results show that the combination of the combination and trastuzumab has a very significant inhibitory effect on the growth of human gastric cancer BCG823 tumors transplanted into nude mice, and shows an obvious dose-effect relationship. This effect is stronger than the combination and trastuzumab alone. Moreover, the effect is long-lasting and has no effect on the weight of experimental animals.

[0087] The drug combination index CDI value was 0.62, indicating significant synergy.

[0088] Example 3 In vivo antitumor activity of the comprehensive targeted drug complex (DBDx and cetuximab)

[0089] The experimental method is the same as that of Example 2, except that the experimental cells are human esophageal cancer KYSE150 cells and human squamous cell carcinoma A431 cells cultured in vitro.

[0090] Administration began 7 days after inoculation, with DBDx administered 5 times a week for 3 weeks, a total of 15 times, and cetuximab administered once a week for 3 weeks, a total of 3 times. 5 times a week for 2 weeks, and cetuximab administered once a week for 2 weeks. The control group was given normal saline, and the other groups were given the drugs in the corresponding examples, respectively, and the administration method was as follows: DBDx was administered orally, and cetuximab was administered by injection.

[0091] The results are shown in Table 7. Figure 7-9 .

[0092] Table 7 Inhibitory effect of the comprehensive targeted drug complex (DBDx and cetuximab) on the growth of human squamous cell carcinoma A431 xenografts in nude mice

[0093]

[0094] Drug administration started 7 days after tumor inoculation, N=6, and no animals in each group died on day 17. Compared with the control group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, compared with cetuximab, ★p<0.0001, compared with DBDx, ☆p<0.01.

[0095] The experimental results show that the combination of DBDx and cetuximab has a very significant inhibitory effect on the growth of human squamous cell carcinoma A431 transplanted in nude mice, and shows a clear dose-effect relationship. This effect is stronger than the combination and cetuximab alone. Moreover, the effect is long-lasting and has no effect on the weight of experimental animals.

[0096] The drug combination index CDI value was 0.76, showing a synergistic effect.

[0097] The same method was used to detect human esophageal cancer KYSE150 cells transplanted into nude mice. The results are shown in Table 8. Figure 10-12 Table 8 Inhibitory effect of the comprehensive targeted drug complex (DBDx and cetuximab) on the growth of human esophageal cancer KYSE150 nude mouse transplanted tumors

[0098]

[0099] Drug administration began 7 days after inoculation, with DBDx administered 5 times a week for 3 weeks and 15 times in total, and cetuximab administered once a week for 3 weeks and 3 times in total. N=6, no animals died in each group until 31 days of observation. Compared with the control group, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001, compared with cetuximab in the combination group, ●p<0.001, compared with DBDx, ○p<0.0001.

[0100] The experimental results show that DBDx and cetuximab have a very significant inhibitory effect on the growth of human esophageal cancer KYSE150 tumors transplanted into nude mice, and there is an obvious dose-effect relationship. This effect is stronger than the use of DBDx and cetuximab alone. Moreover, the effect is long-lasting and has no effect on the weight of experimental animals.

[0101] The drug combination index CDI value was 0.40, indicating significant synergy.

[0102] The above results show that the antibody drug and the combination drug DBDx in the comprehensive targeted drug complex have a very significant synergistic effect. Their combination can be used to treat pancreatic cancer, gastric cancer, esophageal cancer, squamous cell carcinoma, melanoma, lung cancer, liver cancer, and lymphoma, effectively improving the therapeutic effect on tumors and reducing the occurrence and development of complications in patients.

Claims

1. A comprehensive targeted drug complex, comprising a drug composition DBDx and a second active ingredient, wherein the drug composition DBDx is composed of component A, component B and component C, The component A is dipyridamole or a pharmaceutically acceptable salt thereof; The component B is ubenimex or a pharmaceutically acceptable salt thereof; The component C is dexamethasone or a pharmaceutically acceptable salt thereof; The second active ingredient is selected from cetuximab, trastuzumab, rituximab or bevacizumab.

2. The drug complex according to claim 1, characterized in that The mass ratio of component A, component B and component C is 100:20:1 based on dipyridamole, ubenimex and dexamethasone.

3. The drug complex according to claim 1, characterized in that The mass ratio of DBDx to the second active ingredient in the pharmaceutical composition is 121:(30-50).

4. Use of the drug complex according to any one of claims 1 to 3 in the preparation of an anti-tumor drug, wherein the tumor is pancreatic cancer, gastric cancer, esophageal cancer, squamous cell carcinoma, melanoma, lung cancer, liver cancer or lymphoma.

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