CN112915106A - Preparation and application of tumor immune microenvironment regulator - Google Patents
Preparation and application of tumor immune microenvironment regulator Download PDFInfo
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- CN112915106A CN112915106A CN202110164891.4A CN202110164891A CN112915106A CN 112915106 A CN112915106 A CN 112915106A CN 202110164891 A CN202110164891 A CN 202110164891A CN 112915106 A CN112915106 A CN 112915106A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/62—Leeches; Worms, e.g. cestodes, tapeworms, nematodes, roundworms, earth worms, ascarids, filarias, hookworms, trichinella or taenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/46—Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
A tumor immune microenvironment regulator comprises the following components: protectant, pulverized Poecilobdella manillensis; the protective agent comprises the following components: skim milk powder, cane sugar, vitamin C, propolis and glycerol. Further, the protective agent comprises the following raw materials in percentage by mass and volume with physiological saline: 5% of skim milk powder, 3% of cane sugar, 0.5% of vitamin C, 0.1% of propolis and 8% of glycerol. The invention can drive positive immunity by regulating and controlling a Tumor immune microenvironment, namely, increase infiltration proportion of CD8 positive T lymphocytes (CD8+ T) and natural killer cells (NK) in the Tumor microenvironment, and inhibit M1 type Tumor Associated Macrophages (TAM), so that the invention can sensitize an Immune Checkpoint Inhibitor (ICI) such as anti-Tumor effect of drugs such as Pabolizumab and nivolumab, and improve the Overall Response Rate (ORR) of the ICI in solid Tumor treatment.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to preparation and application of a tumor immune microenvironment regulator.
Background
In recent years, the application and research of Immune Checkpoint Inhibitors (ICI) in the treatment of solid tumors is well-established, and FAD has been approved successively for the treatment of a plurality of solid tumors from foreign drugs, such as pambolizumab (trade name KEYTRUDA), Nivolumab (trade name opdivvo), and the like, and the treatment and clinical trials of a plurality of solid tumors, such as epithelial urinary tract cancer, non-small cell lung cancer, and the like, such as dabigatran (injection), telepril (terepril), and the like, have been conducted domestically, however, the effective rate in each tumor species is substantially below 30% in the case of no biomarker screening (e.g., biomarkers such as TMB, PD-L1, dMMR/MSI-H, and the like), ICI monotherapy solid tumors, and even if the effective rate is improved, but a small proportion of response patients can be screened, for example, in colorectal cancer, such patients with dMMR/MSI-H, although potentially benefitting from ICI, account for less than 10% of all colorectal cancer patients, i.e., most patients with solid tumors still have difficulty benefitting from ICI treatment. Therefore, the exploration and application of various combination treatment schemes in different tumor species are increasingly important, and certain effects are achieved, such as ICI combined with anti-angiogenesis drugs and ICI combined with chemotherapy. The mechanism of such combination therapy is partly due to the superposition of the respective anticancer effects of two or three antitumor drugs, and in addition, the combination drug should exert a certain degree of immune regulation, so that the original tumor immune microenvironment pattern of the patient is changed, and the patient who originally does not respond to the ICI is converted into an ICI responder (responder). However, such combination therapy increases the risk of side effects on the one hand and increases the cost of administration for patients on the other hand, so that the invention prepares a novel adjuvant capable of regulating and controlling tumor immune microenvironment for sensitizing ICI to pan-solid tumor, so that more patients with solid tumor benefit from ICI treatment.
Disclosure of Invention
The invention aims to provide a preparation method of a tumor immune microenvironment regulator taking poecilobdella manillensis living freeze-dried powder as a main component;
the second purpose of the invention is to provide the tumor immune microenvironment regulator prepared by the method of the invention, which has good immune regulation and control effects and can achieve the effects of tumor immune microenvironment remodeling and pathogen elimination and body resistance strengthening on the immune level.
The third purpose of the invention is to provide the effect of the tumor immune microenvironment regulator on the sensitization ICI treatment of the solid tumor.
In order to achieve the purpose, the invention adopts the technical scheme that:
a tumor immune microenvironment regulator comprises the following components: protectant, pulverized Poecilobdella manillensis;
the protective agent comprises the following components: skim milk powder, cane sugar, vitamin C, propolis and glycerol.
Further, the protective agent comprises the following raw materials in percentage by mass (mass to volume ratio with physiological saline): 5% of skim milk powder, 3% of cane sugar, 0.5% of vitamin C, 0.1% of propolis and 8% of glycerol.
Further, the propolis replacement is gelatin.
Further, the preparation method of the tumor immune microenvironment regulator comprises the following steps:
s1, protective agent preparation: dissolving skimmed milk powder, sucrose, vitamin C, propolis and glycerol in physiological saline, stirring, and pre-cooling at 4 deg.C;
s2, preparing a poecilobdella manillensis crushed material: soaking fresh Poecilobdella manillensis in clear water for 8-12 hours to drain dirt; soaking in chlorine dioxide water solution for 2-3 min for sterilization, draining water, pre-cooling in a refrigerator at 0-4 deg.C for 4-6 hr, taking out from the low-temperature storage tank at 0-4 deg.C, and pulping to obtain pulverized slurry of Poecilobdella manillensis;
s3, stirring and uniformly mixing the protective agent solution in the equal volume of S1 and the smashed slurry of Poecilobdella manillensis in the volume of S2, putting the mixture into an ultralow-temperature storage box for 2 hours, and freezing to obtain a freeze-dried sample; placing the freeze-dried sample in a freezing frame for vacuum freeze drying, and crushing the freeze-dried sample by a crusher with a 100-mesh sieve to obtain the freeze-dried regulator powder; the regulator freeze-dried powder is the tumor immune microenvironment regulator.
Further, the ultra-low-temperature storage tank temperature was set to-45 ℃.
Further, the concentration of the chlorine dioxide aqueous solution is 50 ppm.
Further, in the preparation method, the propolis is replaced by gelatin.
Further, the tumor immune microenvironment regulator is powder existing alone or tablet existing alone or additive existing in a compound way.
Further, the tumor immune microenvironment regulator is used by the method comprising the following steps: in combination with an immune checkpoint inhibitor.
Compared with the prior art, the invention has at least the following beneficial effects:
the invention can drive positive immunity by regulating and controlling a Tumor immune microenvironment, namely, increase infiltration proportion of CD8 positive T lymphocytes (CD8+ T) and natural killer cells (NK) in the Tumor microenvironment, and inhibit M2 type Tumor Associated Macrophages (TAM), so that the invention can sensitize an Immune Checkpoint Inhibitor (ICI) such as anti-Tumor effect of drugs such as Pabolizumab and nivolumab, and improve the Overall Response Rate (ORR) of the ICI in solid Tumor treatment.
Drawings
FIG. 1 is a representation of multiple immunofluorescence labeled tumor tissue and immune cells therein;
FIG. 2 is a diagram of the results of animal experiments (tumor-bearing mice) using the inventive substance as a tumor immune microenvironment regulator.
FIG. 3 is a diagram of the results of animal experiments (tumor-bearing mice) on the anti-tumor effect of ICI with sensitization by the inventive drug as tumor immune microenvironment regulator.
Detailed Description
The principles and features of this invention are described below in conjunction with the following drawings, which are set forth by way of illustration only and are not intended to limit the scope of the invention.
As shown in the figure:
example 1:
a tumor immune microenvironment regulator comprises the following components: protectant, pulverized Poecilobdella manillensis; the protective agent comprises the following components: skim milk powder, cane sugar, vitamin C, propolis and glycerol.
Example 2:
on the basis of the example 1, the proportion of the raw materials in the protective agent (mass-volume ratio to normal saline) is as follows: 5% of skim milk powder, 3% of cane sugar, 0.5% of vitamin C, 0.1% of propolis and 8% of glycerol.
Example 3:
on the basis of examples 1-2, the propolis replacement set is gelatin.
Example 4:
on the basis of embodiments 1-3, the preparation method of the tumor immune microenvironment regulator is characterized by comprising the following steps:
s1, protective agent preparation: dissolving skimmed milk powder, sucrose, vitamin C, propolis and glycerol in physiological saline, stirring, and pre-cooling at 4 deg.C;
s2, preparing a poecilobdella manillensis crushed material: soaking fresh Poecilobdella manillensis in clear water for 8-12 hours to drain dirt; soaking in chlorine dioxide water solution for 2-3 min for sterilization, draining water, pre-cooling in a refrigerator at 0-4 deg.C for 4-6 hr, taking out from the low-temperature storage tank at 0-4 deg.C, and pulping to obtain pulverized slurry of Poecilobdella manillensis;
s3, stirring and uniformly mixing the protective agent solution in the equal volume of S1 and the smashed slurry of Poecilobdella manillensis in the volume of S2, putting the mixture into an ultralow-temperature storage box for 2 hours, and freezing to obtain a freeze-dried sample; and (3) placing the freeze-dried sample in a freezing frame for vacuum freeze drying, and crushing the freeze-dried sample by a crusher with a 100-mesh sieve to obtain the freeze-dried regulator powder. The regulator freeze-dried powder is the tumor immune microenvironment regulator.
Example 5:
on the basis of examples 1 to 4, the temperature of the ultra-low-temperature storage tank was set to-45 ℃.
Example 6:
based on examples 1-5, the chlorine dioxide aqueous solution has a concentration of 50 ppm.
Example 7:
on the basis of examples 1-6, the propolis replacement set in the preparation method is gelatin.
Example 8:
based on examples 1-7, the tumor immune microenvironment regulator is a powder existing alone or a tablet existing alone or an additive existing in a compound way.
Example 9:
based on examples 1-10, the tumor immune microenvironment regulator is used by the following methods: in combination with an immune checkpoint inhibitor.
Example 10:
a preparation method of tumor immune microenvironment regulation powder comprises the following steps:
s1, protective agent preparation: dissolving skimmed milk powder, sucrose, vitamin C, propolis and glycerol in physiological saline, stirring, and pre-cooling at 4 deg.C; the protective agent comprises the following raw materials in percentage by mass (in volume ratio to normal saline): 5% of skim milk powder, 3% of cane sugar, 0.5% of vitamin C, 0.1% of propolis and 8% of glycerol.
S2, preparing a poecilobdella manillensis crushed material: soaking fresh Poecilobdella manillensis in clear water for 12 hours to drain dirt; soaking in chlorine dioxide aqueous solution for 3 min for sterilization, draining off water from the filter paper, pre-cooling in a refrigerator at 0 deg.C for 5 hr, taking out from the low-temperature storage box at 0 deg.C, and pulping to obtain Poecilobdella manillensis pulverized slurry;
s3, stirring and uniformly mixing the protective agent solution in the equal volume of S1 and the smashed slurry of Poecilobdella manillensis in the volume of S2, putting the mixture into an ultralow-temperature storage box for 2 hours, and freezing to obtain a freeze-dried sample; and (3) placing the freeze-dried sample in a freezing frame for vacuum freeze drying, and crushing the freeze-dried sample by a crusher with a 100-mesh sieve to obtain the freeze-dried regulator powder.
And (3) verification experiment:
experimental mice are subcutaneously planted with a tumor cell line T24 and are divided into four groups, each group comprises 10 mice, the first group is used for drinking purified water, the second group is used for ICI medicament tail vein intervention at the same time, the third group is used for drinking purified water dissolved with the freeze-dried powder, the fourth group is used for drinking purified water dissolved with the freeze-dried powder, the ICI medicament tail vein intervention is performed at the same time, tumor measurement and evaluation are carried out at different times of subcutaneous tumor growth and comparison between groups are carried out, and simultaneously, different groups of tumors are taken and analyzed for infiltration proportion and quantity of immune cells of different tumor tissues through multiple immunofluorescence staining (40 samples in each group are obtained in four times of repeated experiments).
FIG. 1 is a representation of multiple immunofluorescence labeled tumor tissue and immunocytes therein, wherein A is a positive control, B is a negative control, C is a sample stain, D is a CD8+ T cell stain, E is an NK cell stain, and F is a macrophage;
FIG. 2 shows the results of animal experiments (tumor-bearing mice) with the inventive substance as a tumor immune microenvironment regulator, and the number of immune cells counted by staining tumor tissues of all mice;
table 1 and fig. 3 show the results of animal experiments (tumor-bearing mice) on the anti-tumor effect of the present invention as a tumor immune microenvironment regulator, comparing the tumor areas of different groups of mice, and the contents of table one are as follows.
Table one: immune regulation data (tumor area mm)2) As a result:
in conclusion, the invention can regulate and control the infiltration quantity of CD8+ T cells and NK cells with killing capacity in tumors to be increased, and simultaneously shows the inhibition on the quantity of M2 macrophages promoting the growth of the tumors, so that the invention plays a role in regulating the tumor immune microenvironment, achieves the improvement of the tumor immune microenvironment and provides an applicable condition for ICI. The composition combines ICI, shows an anti-tumor effect superior to that of ICI single medicine, can be used as an immune microenvironment regulator, and plays a role in sensitizing ICI.
The preferred embodiments of the invention disclosed above are intended to be illustrative only. The preferred embodiments are not intended to be exhaustive or to limit the invention to the precise embodiments disclosed. Obviously, many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and the practical application, to thereby enable others skilled in the art to best utilize the invention. The invention is limited only by the claims and their full scope and equivalents.
Claims (9)
1. A tumor immune microenvironment regulator is characterized by comprising the following components: protectant, pulverized Poecilobdella manillensis;
the protective agent comprises the following components: skim milk powder, cane sugar, vitamin C, propolis and glycerol.
2. The tumor immune microenvironment regulating agent according to claim 1, wherein the ratio of the raw materials in the protective agent to the physiological saline by mass/volume is: 5% of skim milk powder, 3% of cane sugar, 0.5% of vitamin C, 0.1% of propolis and 8% of glycerol.
3. The tumor immune microenvironment modulator according to claim 1, wherein the propolis replacement is provided as gelatin.
4. A preparation method of a tumor immune microenvironment regulator is characterized by comprising the following steps:
s1, protective agent preparation: dissolving skimmed milk powder, sucrose, vitamin C, propolis and glycerol in physiological saline, stirring, and pre-cooling at 4 deg.C;
s2, preparing a poecilobdella manillensis crushed material: soaking fresh Poecilobdella manillensis in clear water for 8-12 hours to drain dirt; soaking in chlorine dioxide water solution for 2-3 min for sterilization, draining water, pre-cooling in a refrigerator at 0-4 deg.C for 4-6 hr, taking out from the low-temperature storage tank at 0-4 deg.C, and pulping to obtain pulverized slurry of Poecilobdella manillensis;
s3, stirring and uniformly mixing the protective agent solution in the equal volume of S1 and the smashed slurry of Poecilobdella manillensis in the volume of S2, putting the mixture into an ultralow-temperature storage box for 2 hours, and freezing to obtain a freeze-dried sample; placing the freeze-dried sample in a freezing frame for vacuum freeze drying, and crushing the freeze-dried sample by a crusher with a 100-mesh sieve to obtain the freeze-dried regulator powder;
the regulator freeze-dried powder is the tumor immune microenvironment regulator.
5. The method of claim 3, wherein the temperature of the cryopreservation chamber is set at-45 ℃.
6. The method of claim 3, wherein the concentration of the aqueous solution of chlorine dioxide is 50 ppm.
7. The method for preparing a tumor immune microenvironment modulator according to claim 3, wherein the propolis replacement is gelatin.
8. A method for using a tumor immune microenvironment modulator, which is the tumor immune microenvironment modulator of any one of claims 1 to 7, and the tumor immune microenvironment modulator is a powder existing alone or a tablet existing alone or an additive existing in combination.
9. A method of using a tumor immune microenvironment modulator according to any one of claims 1 to 7, comprising: in combination with an immune checkpoint inhibitor.
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