CN113209302B - A pharmaceutical composition with anti-tumor effect - Google Patents
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Abstract
The invention discloses a pharmaceutical composition with anti-tumor effect, which contains a) an activator of NKT cells and b) a drug for controlling the activity or proliferation of tumor-associated fibroblasts. The pharmaceutical composition for treating the tumor combines the NKT cell activator and the drug for controlling the activity or proliferation of the tumor-related fibroblasts, improves the infiltration of immune cells in the solid tumor by removing the tumor-related fibroblasts, and simultaneously can increase the distribution and penetration of the NKT cell activator in the solid tumor.
Description
Technical Field
The invention particularly relates to a pharmaceutical composition with an anti-tumor effect.
Background
Natural killer T cells (NKT cells) are T lymphocytes that play an important bridge between innate and adaptive immunity in the body. Activation of NKT cells can both elicit an innate immune response mediated by NK cells to overcome tumor heterogeneity. Meanwhile, the method can also cause adaptive immune response mediated by effector T cells, thereby realizing effective control of tumors.
The immunotherapy of activating NKT cells has better anti-tumor effect in hemangioma, and can remarkably prolong the survival time of hemangioma patients. However, these immunotherapies did not show good therapeutic effects in the clinical treatment of solid tumors. The low responsiveness of solid tumors to immunotherapy is mainly due to two reasons: one is the inability of immune cells to enter the microenvironment of the tumor, and the other is the inhibition of immune cell activation and function entering the microenvironment.
Generally, solid tumors have their own unique matrix microenvironment, which can prevent drugs, immune cells and the like from entering the tumor microenvironment, promote the growth and metastasis of tumors, and realize the immune escape of the tumors to organisms. On one hand, the tumor-associated fibroblasts form a physical barrier by secreting a large amount of collagen and collagen fibers, thereby preventing small-molecule drugs and immune cells from entering a tumor part. On the other hand, tumor-associated fibroblasts form a chemical barrier by secreting chemokines and cytokines, and discharge immune cells while suppressing the occurrence of immune responses.
Disclosure of Invention
To solve the above problems, the present invention provides a pharmaceutical composition having an antitumor effect, which comprises a) an activator of NKT cells, and b) an agent for controlling the activity or proliferation of tumor-associated fibroblasts.
Further, the mass ratio of the NKT cell activator to the drug for controlling the activity or proliferation of the tumor-associated fibroblasts is 1 to 3:20 to 50, preferably: 1.25:25.
furthermore, the preparation is prepared by taking an NKT cell activator and a medicament for controlling the activity or proliferation of tumor-related fibroblasts as active ingredients and adding pharmaceutically acceptable auxiliary materials.
Further, the activator of NKT cells is α -GalCer, iGb3, and/or a pharmaceutically acceptable salt or hydrate thereof.
Further, the activator of NKT cells is α -GalCer, and/or a pharmaceutically acceptable salt or hydrate thereof.
Further, the drug for controlling the activity or proliferation of tumor-associated fibroblasts is TGF, HGF, PDGF, VEGF, IGF, MMP, FGF, uPA, cathepsin, a protein of NOX4, an SDF-1 inhibitor, an inhibitor of cell activity or proliferation, an inducer of apoptosis; and/or siRNA, ribozyme, antisense nucleic acid, DNA/RNA chimeric polynucleotide and a vector for expressing the siRNA, the ribozyme, the antisense nucleic acid, the DNA/RNA chimeric polynucleotide, and the vector, wherein the siRNA, the ribozyme, the antisense nucleic acid, the DNA/RNA chimeric polynucleotide are targeted by extracellular matrix-constituting molecules generated by tumor-associated fibroblasts or by 1 or more than 1 of molecules involved in the generation or secretion of the extracellular matrix-constituting molecules.
Further, the apoptosis inducer is ABT263, rg2, rg3, pirfenidone, nintedanib, tripterine, dihydromyricetin, and/or pharmaceutically acceptable salts or hydrates thereof.
Still further, the apoptosis-inducing agent is ABT263, rg2, pirfenidone, nintedanib, and/or a pharmaceutically acceptable salt or hydrate thereof.
Still further, the apoptosis-inducing agent is ABT263 and/or a pharmaceutically acceptable salt or hydrate thereof.
Further, the activator of NKT cells and the drug controlling the activity or proliferation of tumor-associated fibroblasts are in the same pharmaceutically acceptable formulation.
Further, the activator of NKT cells and the agent controlling the activity or proliferation of tumor-associated fibroblasts are in separate pharmaceutically acceptable formulations.
Further, the preparation is intravenous injection preparation, intraperitoneal injection preparation or oral administration preparation.
Furthermore, the intravenous injection preparation is micelle suspension, fat emulsion, liposome suspension or freeze-dried powder injection thereof.
Furthermore, the intravenous injection preparation is fat emulsion, or micelle suspension prepared by auxiliary materials HS15 and/or PEG-DSPE and freeze-dried powder injection thereof.
The invention also provides a preparation method of the medicinal preparation, which comprises the following steps:
1) Weighing the components in a mass-volume ratio of 1.25mg:25mg:0.5g:50ml of alpha-GalCer, ABT263, tween-20 and physiological saline;
2) Dissolving alpha-GalCer, ABT263 and tween-20 in chloroform, evaporating to remove chloroform, and adding physiological saline for redissolution to obtain injection;
or:
1) Weighing the components in a mass-volume ratio of 1.25mg:25mg:0.5g:50ml of alpha-GalCer, ABT263, HS15 and physiological saline;
2) Dissolving alpha-GalCer, ABT263 and HS15 in chloroform, evaporating to remove chloroform, and adding physiological saline to redissolve to obtain injection micelle;
or:
1) Weighing the components in a mass-volume ratio of 1.25mg:25mg:7.5g:7.5g:0.6g:1.125g:50ml of α -GalCer, ABT263, soybean oil: medium chain triglycerides: lecithin: glycerol and water for injection;
2) Mixing soybean oil and medium chain triglyceride, heating to 60 deg.C, adding lecithin, alpha-GalCer and ABT263, and stirring at 5000r/min to obtain oil phase; adding glycerol into water for injection, dissolving at 60 deg.C, and mixing to obtain water phase; mixing the water phase and the oil phase, stirring at 10000r/min for 5min, homogenizing at 800bar for 8 times, and adjusting pH to 6.5 with sodium hydroxide solution to obtain injection emulsion;
or:
1) Weighing the components in a mass-volume ratio of 1.25mg:25mg:340g:110mg:110mg:50ml of alpha-GalCer, ABT263, soybean lecithin S100, cholesterol, PEG2000-DSPE and physiological saline;
2) Dissolving alpha-GalCer, ABT263, soybean phospholipid S100, cholesterol and PEG2000-DSPE in chloroform, evaporating to remove chloroform, adding physiological saline to hydrate and remove membrane, and homogenizing at 10000psi for 10 times to obtain injectable liposome.
The invention also provides a combined medicine with anti-tumor effect, which contains an NKT cell activator, a medicine for controlling the activity or proliferation of tumor-associated fibroblasts and a pharmaceutically acceptable carrier, wherein the NKT cell activator and the medicine are used for simultaneous or separate administration; the ratio of the NKT cell activator to the tumor-associated fibroblast activity or proliferation controlling drug is (1-3): 20 to 30, preferably: 1.25:25.
the invention preferably provides the application of the pharmaceutical composition or the combined medicine in preparing anti-tumor medicines.
Further, the tumor is a sarcoma, lung cancer, bronchial cancer, pleuropulmonary blastoma, prostate cancer, breast cancer, pancreatic cancer, islet cell cancer, stomach cancer, intestinal cancer, thyroid cancer, parathyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, extrahepatic bile duct cancer, gallbladder cancer, kidney cancer, renal pelvis cancer, bladder cancer, adrenal cancer, glioma, endometrial cancer, corpus uteri cancer, cervical cancer, vaginal cancer, multiple myeloma, esophageal cancer, lip and oral and pharynx cancer, laryngeal cancer, melanoma, villous colon adenoma, germ cell tumor, gestational trophoblastic tumor, ovarian epithelial cancer, ovarian germ cell tumor, pituitary tumor, transitional cell cancer of ureter, retinoblastoma, salivary gland carcinoma, melanoma, non-melanoma skin cancer, merkel cell skin cancer, testicular cancer, and/or squamous thymoma.
Furthermore, the tumor is breast cancer, pancreatic cancer, lung cancer, gastric cancer, intestinal cancer, prostatic cancer and melanoma.
Furthermore, the tumor is breast cancer, prostatic cancer, lung cancer, gastric cancer and intestinal cancer.
Further, the tumor is breast cancer or prostate cancer.
The pharmaceutical composition with the anti-tumor effect combines the NKT cell activator and the drug for controlling the activity or proliferation of the tumor-related fibroblasts, improves the infiltration of immune cells in solid tumors by removing the tumor-related fibroblasts, and simultaneously increases the distribution and penetration of the NKT cell activator in the solid tumors, thereby playing a role in synergy.
It will be apparent that various other modifications, substitutions and alterations can be made in the present invention without departing from the basic technical concept of the invention as described above, according to the common technical knowledge and common practice in the field.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
Example 1 injection A1 of the pharmaceutical composition for treating tumor of the present invention
Weighing alpha-GC1.25mg, ABT263 25mg and tween-20.5 g, dissolving the alpha-GC1.25mg, ABT263 25mg and tween-20.5g by using chloroform, removing the chloroform by a rotary evaporator, and adding 50mL of physiological saline for demoulding and dissolving to obtain the compound.
Example 2. Injection micelle A2 of pharmaceutical composition for treating tumor according to the present invention
Weighing alpha-GC1.25mg, ABT263 25mg and HS15.5g, dissolving the alpha-GC1.25mg, ABT263 25mg and HS15.5g by chloroform, removing the chloroform by a rotary evaporator, and adding 50mL of physiological saline for demoulding and dissolving to obtain the compound.
Example 3 injectable emulsion of pharmaceutical composition for treating tumors according to the invention A3
Weighing 7.5g of soybean oil and 7.5g of medium-chain triglyceride in a beaker, uniformly mixing by stirring, heating to 60 ℃, adding 0.6g of lecithin 1.25mg of alpha-GC 15mg, ABT263 25mg and 5000r/min, and stirring at high speed to obtain an oil phase; adding 1.125g of glycerol into 50mL of water for injection, and heating to 60 ℃ to dissolve to obtain a water phase; adding the water phase and oil phase into a stirrer at the same time, stirring at 10000r/min for 5min, stirring to obtain primary emulsion, homogenizing the primary emulsion under high pressure (800bar, 8 times), and adjusting pH to 6.5 with sodium hydroxide solution.
Example 4 injection of the pharmaceutical composition for treating tumor of the present invention liposome A4
Weighing alpha-GC1.25mg, ABT263 25mg, soybean lecithin S100 g, cholesterol 110mg and PEG2000-DSPE 110mg, dissolving with chloroform, removing chloroform by rotary evaporator, adding 50mL physiological saline for hydration and demoulding, and treating with high pressure homogenizer (10000 psi, cycle 10 times) to obtain the final product.
The advantageous effects of the present invention will be described below by way of test examples.
Test example 1 antitumor Effect of the pharmaceutical composition of the present invention
1. Experimental materials:
medicine preparation: injections A1 to A4 obtained in examples 1 to 4; α -GC injection (home-made, dissolved in physiological saline containing 1% tween-20), ABT263 injection (home-made, dissolved in physiological saline containing 1% tween-20);
tumor strain: 4T1 breast cancer cells and RM-1 prostate cancer cells;
animals: male Balb/c mice, 18-22g.
2. The method and the result are as follows:
inhibition of 4T1 breast cancer: 4T1 cells grown logarithmically were injected into the mouse axilla (1X 10) 6 One cell/one), 10 days later, random groups were divided and administration was started, and A1, A2, A3, A4, α -GC solutions, ABT263 solutions were administered by tail vein injection once every other day at 5mg/kg ABT263 and 5 μ g/one (0.25 mg/kg) α -GC at 4 times. The control group was injected intravenously with sterile normal saline. The mice were sacrificed 48h after drug withdrawal, weighed and the subcutaneous tumor mass was removed, the tumor was weighed, and the tumor inhibition rate was calculated. The results are shown in Table 1.
Inhibition of RM-1 prostate cancer: number of pairs of studentsLong RM-1 cells injected in mice axilla (1X 10) 6 One cell/one), 10 days later, the administration was randomly grouped and started, and A1, A2, A3, A4, α -GC solutions, ABT263 solutions were administered by tail vein injection once every two days at doses of 5mg/kg ABT263 and 5 (0.25 mg/kg) μ g/α -GC, 4 times. The control group was injected intravenously with sterile normal saline. The mice were sacrificed 1 week after drug withdrawal, weighed and the subcutaneous tumor mass was stripped off, weighed, and the tumor inhibition rate was calculated. The results are shown in Table 2.
Tumor inhibition (%) = (1- (treatment group average tumor weight/control group average tumor weight)) × 100%
TABLE 1 inhibitory Effect of the compositions of the present invention on 4T1 Breast cancer
| Group of | Mouse number (only) (beginning/end) | Tumor weight (g) | Tumor inhibition rate |
| Physiological saline | 10/10 | 1.52 Earth 0.45 | |
| alpha-GC injection | 10/10 | 1.27 Earth 0.37 | 16.45％ |
| ABT263 injection | 10/10 | 1.02 Earth 0.26 | 32.89％ |
| Drug Al (prepared in example 1) | 10/10 | 0.58 soil 0.19# # # | 61.84％ |
| Medicine A2 (prepared in example 2) | 10/10 | 0.32 soil 0.24# # #& | 78.95％ |
| Medicine A3 (prepared in example 3) | 10/10 | 0.35 soil 0.26# # #& | 76.97％ |
| Medicine A4 (prepared in example 4) | 10/10 | 0.29 shi 0.27# # #& | 80.92％ |
TABLE 2 inhibitory Effect of the compositions of the present invention on RM-1 prostate cancer
Note: # P <0.05, # P <0.01 compared to the alpha-GC injection group; * P <0.05, P <0.01 compared to ABT263 injection group; & P <0.05, & P <0.01 compared to drug A1.
As can be seen from tables 1 and 2, the pharmaceutical composition (Al, A2, A3, A4) of the invention has significantly better tumor inhibition effect compared with the alpha-GC injection or ABT263 injection. In addition, after the composition is prepared into a nano preparation, the tumor inhibition effect of the composition is better than that of a solution of the composition.
And (4) conclusion: the experimental results show that under the same drug dosage, the anti-tumor effect of the drug combination is better than that of the drug combination used alone, the synergistic effect is achieved, and the feasibility and the necessity of the combination of the nkt activator and the tumor-related fibroblast inhibitor are proved; in addition, the composition of the invention has better tumor inhibition effect in different solid tumors, which indicates that the pharmaceutical composition of the invention can be widely used for treating the solid tumors.
Test example 2. The effect of the pharmaceutical composition of the present invention on the number and activity of immune cells in solid 4T1 breast cancer tumors.
The administration was carried out according to test example 1. After the last 48 hours of administration, tumor tissues of each group of animals were taken, digested with collagenase to prepare single cell suspensions, and then total NKT cells (CD 45) were measured by flow cytometry + CD3 + NK1.1 + ) And activating NKT cells (CD 3) + CD1d tetramer + INF-γ + ) The number of the cells. The results are shown in Table 3.
TABLE 3 Effect of the compositions of the invention on the number of NKT cells and their activation in 4T breast cancer tumors
Note: # P <0.05, # P <0.01 compared to the alpha-GC injection group; * P <0.05, P <0.01 compared to ABT263 injection group; & P <0.05, & P <0.01 compared to drug A1.
Compared with the alpha-GC injection or ABT263 injection, the NKT cells entering the tumor are obviously more than those in the solution group, and the activated NKT cells are also more in proportion.
And (4) conclusion: the experimental results show that under the same drug dosage, the drug can obviously increase the infiltration of NKT cells in the tumor, has the synergistic effect and simultaneously has more NKT cells capable of being activated in situ in the tumor. In addition, after the composition is prepared into a nano preparation, the capability of increasing tumor infiltration and in-situ activation of NKT cells is also obviously better than that of a composition solution.
Claims (12)
1. A pharmaceutical composition with anti-tumor effect is characterized in that: it contains a) an activator of NKT cells, and b) an agent that controls the activity or proliferation of tumor-associated fibroblasts; the activator of NKT cells is alpha-GalCer, and/or a pharmaceutically acceptable salt or hydrate thereof; the medicament for controlling the activity or proliferation of the tumor-associated fibroblasts is ABT263 and/or a pharmaceutically acceptable salt or hydrate thereof.
2. The pharmaceutical composition of claim 1, wherein: the mass ratio of the NKT cell activator to the medicine for controlling the activity or proliferation of the tumor-related fibroblasts is 1 to 3:20 to 50.
3. The pharmaceutical composition of claim 2, wherein: the mass ratio of the NKT cell activator to the tumor-associated fibroblast activity or proliferation control drug is 1.25:25.
4. the pharmaceutical composition of claim 1, wherein: the preparation is prepared by taking an NKT cell activator and a medicament for controlling the activity or proliferation of tumor-related fibroblasts as active ingredients and adding pharmaceutically acceptable auxiliary materials.
5. The pharmaceutical composition of claim 4, wherein: the NKT cell activator and the drug for controlling the activity or proliferation of tumor-associated fibroblasts are in the same pharmaceutically acceptable formulation.
6. The pharmaceutical composition of claim 4, wherein: the activator of NKT cells and the agent that controls the activity or proliferation of tumor-associated fibroblasts are in separate pharmaceutically acceptable formulations.
7. The pharmaceutical composition of claim 4, wherein: the preparation is intravenous injection preparation, intraperitoneal injection preparation or oral administration preparation.
8. The pharmaceutical composition of claim 7, wherein: the intravenous injection preparation is micellar suspension, fat emulsion, liposome suspension or their lyophilized powder injection.
9. The pharmaceutical composition of claim 8, wherein: the intravenous injection preparation is fat emulsion, or micelle suspension prepared by auxiliary materials HS15 and/or PEG-DSPE and freeze-dried powder thereof.
10. A combined medicine with an anti-tumor effect is characterized in that: it contains an activator of NKT cells, a drug controlling the activity or proliferation of tumor-associated fibroblasts, and a pharmaceutically acceptable carrier for simultaneous or separate administration; the mass ratio of the NKT cell activator to the medicine for controlling the activity or proliferation of the tumor-related fibroblasts is 1 to 3:20 to 50; the activator of NKT cells is alpha-GalCer, and/or a pharmaceutically acceptable salt or hydrate thereof; the medicament for controlling the activity or proliferation of the tumor-associated fibroblasts is ABT263 and/or a pharmaceutically acceptable salt or hydrate thereof.
11. The combination of claim 10 wherein: the mass ratio of the NKT cell activator to the tumor-associated fibroblast activity or proliferation control drug is 1.25:25.
12. use of a pharmaceutical composition according to any one of claims 1 to 9 or a pharmaceutical combination according to any one of claims 10 to 11 for the preparation of an anti-tumor medicament; the tumor is prostate cancer or breast cancer.
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