CN111437399B - Gene and chemical small molecule co-delivery system and application thereof in tumor treatment - Google Patents
Gene and chemical small molecule co-delivery system and application thereof in tumor treatment Download PDFInfo
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- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/52—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
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- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
- A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
- A61K48/0033—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being non-polymeric
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Abstract
The invention particularly relates to a gene and chemical small molecule co-delivery system and application thereof in tumor treatment. The drug co-delivery system is characterized in that small interfering RNA (ribonucleic acid) taking indoleamine 2, 3-dioxygenase-1 as a target spot is firstly combined with gemcitabine and is contained in a 2-methylimidazol zinc metal organic framework nano cage, so that immunosuppression related to regulatory T cells and myeloid-derived suppressor cells is relieved. Then mineralize on the surface of the nano-carrier to generate mineralized matter of oxygen so as to relieve the immunosuppression of M2 macrophage. After the mineralized shell surface is modified with the therapeutic ICB antibody, a multifunctional nano regulator is constructed. The multifunctional nano-regulator integrates multiple effects, excites a 'hot' tumor microenvironment, and greatly enhances the ICB treatment of the 'cold' malignant tumors.
Description
Technical Field
The invention belongs to the technical field of antitumor drug delivery, and particularly relates to a co-delivered gene and chemical small molecule metal organic nano-composite and application thereof in preparation of antitumor drugs.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Currently, chemotherapy remains the basis for modern cancer treatment. Specialized chemotherapy, such as Oxaliplatin (OXA), can induce true Immunogenic Cell Death (ICD) in cancer cells. ICD-induced immunogenicity can promote inter-tumor infiltration of Cytotoxic T Lymphocytes (CTLs) and accelerate tumor regression. However, in colon cancer and glioma, the tumor has immunosuppressive tumor microenvironment, has the characteristics of low tumor mutation load, less invasion of killer immune cells, lower immune response intensity and limited response to immunotherapy, and is called immune 'cold' tumor. Thus, the immune "cold" nature of malignant tumors such as colon cancer, alternating current and direct current, leads to an inevitable limitation in the effectiveness of chemotherapy-induced ICDs.
The advent of cancer immunotherapy, particularly immune checkpoint suppression (ICB), as one of the most attractive strategies to overcome the immunosuppressive tumor microenvironment and to stimulate cytotoxic T cells has changed current cancer treatment approaches. Bioinformatics colon cancer is a typical "cold" cancer that was found to overexpress CD47, but did not respond clinically satisfactorily to its corresponding Immune Checkpoint Blockade (ICB). Various tumor immunosuppressive factors including myeloid-derived suppressor cells (MDSCs), regulatory T cells (tregs) and M2 tumor-associated macrophages (M2-TAMs), as well as insufficient infiltration of tumor T cells, are major factors leading to Immune Checkpoint Blockade (ICBs) immunotherapy tolerance.
Indoleamine 2, 3-dioxygenase-1 (IDO-1) is an endogenous immunosuppressive mediator that promotes the recruitment of Tregs that suppress proliferation and induce apoptosis in effector T cells. In addition to IDO-mediated immunosuppression of tregs, recent preclinical and clinical studies have shown that myeloid suppressor cells (MDSCs), also interfere with the anti-tumor immune function of effector T cells.
Gemcitabine (GEM) is a nucleoside analogue that has been used clinically to treat various types of cancer, and recent studies have shown that GEM not only consumes MDSCs, but also induces immunogenic death (ICD) of tumor cells.
Disclosure of Invention
Based on the disclosure of the above background art, the present invention aims to provide an administration mode for activating immunity, inducing immunogenic death of tumor cells and relieving immune 'cold' property of certain malignant tumors. Based on the technical purpose, the invention provides a multi-drug delivery system based on metal-organic nano-composite, which overcomes the immune tolerance of tumors to ICBs (acute bacterial hepatitis B Virus) through multiple immune regulation effects, is used for resisting immunosuppressive factors point to point, simultaneously promotes tumor T cell infiltration, and strengthens the ICB treatment of cold malignant tumors
Based on the technical purpose, the invention provides the following technical scheme:
in a first aspect of the invention, a multi-drug co-delivery system is provided, the co-delivery system uses a nano material as a carrier, and the carrier is used for encapsulating drugs; the surface of the carrier is provided with a metal oxide mineralized layer, and the surface of the mineralized layer is also provided with therapeutic antibody modification.
In the multi-drug co-delivery system provided by the invention, the metal organic framework material is used as a carrier, and the metal organic framework material has abundant pore structures, so that abundant attachment sites can be provided, and a plurality of anti-tumor drugs can be simultaneously entrapped. In addition, the metal organic framework material also has pH sensitivity, and based on the pH difference between the tumor microenvironment and the internal environment, the delivery system can realize the targeted release at the tumor tissue.
Based on the aim of activating an immune system, the invention designs that a nano-carrier is used for encapsulating drugs, and the drugs are used for inducing the recruitment of Tregs and eliminating the anti-tumor immune function of myeloid suppressor cells on T cells. The encapsulation effect of the drug is enhanced by adding the mineralized layer on the surface of the nano carrier, and on the other hand, the appropriate mineralized layer material is selected, so that H can be consumed in a tumor microenvironment2O2Generating O2Thereby relieving the immunosuppression of M2 macrophage, and realizing the purpose of activating immune system by multiple ways in cooperation with therapeutic ICB antibody.
Based on the research of the invention, a most preferable antitumor drug co-delivery system is provided, and is a gene and chemical small molecule co-delivery system, wherein the co-delivery system adopts a 2-methylimidazolium zinc (ZIF-8) metal organic framework as a carrier, and simultaneously encapsulates gemcitabine and indoleamine 2, 3-dioxygenase-1 (IDO-1); the surface of the carrier is provided with MnO2Mineralized layer and therapeutic monoclonal antibody (aCD-47) electrostatic modification.
The small interfering RNA with indoleamine 2, 3-dioxygenase-1 as a target spot is firstly combined with gemcitabine to be applied to a ZIF-8-based nanocage to relieve immunosuppression related to regulatory T cells and myeloid-derived suppressor cells. Then mineralize on the surface of the nano-carrier to generate mineralized matter of oxygen so as to relieve the immunosuppression of M2 macrophage. After the mineralized shell surface is modified with the therapeutic ICB antibody, a multifunctional nano regulator is constructed. The multifunctional nano-regulator integrates multiple effects, excites a 'hot' tumor microenvironment, and greatly enhances the ICB treatment of the 'cold' malignant tumors.
In a second aspect of the present invention, there is provided a use of the multiple drug co-delivery system of the first aspect in the preparation of an anti-tumor drug.
In a third aspect, the present invention provides an anti-tumor drug, which comprises the co-delivery system of the multiple drugs of the first aspect and pharmaceutically necessary excipients.
The beneficial effects of one or more technical schemes are as follows:
1. the present invention provides a metal-organic nanocomposite co-delivering small chemical molecules (GEMs) and genes (siIDO) for point-to-point anti-immunosuppressive factor while promoting tumor T cell infiltration, the composite comprising a chemotherapeutic GEM that silences indoleamine 2, 3-dioxygenase-1 (IDO-1), reduces recruitment of Tregs that inhibit proliferation and induce apoptosis of effector T cells, consumes MDSCs, and induces immunogenic death (ICD) of tumor cells.
2. In order to enhance the homing capability of tumors and reduce non-specific side effects, the invention adopts a 2-methylimidazolium zinc (ZIF-8) metal organic framework as a nano carrier, and co-delivers the siIDO and GEM with negative charges.
3. In order to protect siRNA from being degraded by enzyme, prevent GEM leakage and simultaneously relieve the hypoxia-enhanced M2-TAM immunosuppression effect, MnO is added2Mineralized to further tattoo on the surface of ZIF-8-based GEM and siIDO co-loaded nanocage (GSZ).
4. The present invention synthesizes for the first time metal-organic nanocomposites that co-deliver small chemical molecules (GEMs) and genes (siIDO), which modulators stimulate a "hot" immune tumor environment, restoring the therapeutic efficacy against ICB in these so-called "cold" malignancies.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
Figure 1 is a TEM image of GSZMA nanoplates described in example 1;
figure 2 is the GSZMA nanoplate particle size distribution plot described in example 1;
FIG. 3 is a graph showing the results of cytotoxicity analysis of the nano-formulation described in example 2;
FIG. 4 is a BLI analysis of different treatment groups of animals described in example 3;
FIG. 5 is an H & E staining image of tumor sections of the animal model described in example 3.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
As introduced in the background art, aiming at the defects in the prior art, the invention provides a drug co-delivery system and application thereof in preparing anti-tumor drugs in order to solve the technical problems.
In a first aspect of the invention, a multi-drug co-delivery system is provided, the co-delivery system uses a nano material as a carrier, and the carrier is used for encapsulating drugs; the surface of the carrier is provided with a metal oxide mineralized layer, and the surface of the mineralized layer is also provided with therapeutic antibody modification.
Preferably, in the multi-drug co-delivery system, the drugs include, but are not limited to, chemotherapeutic drugs, nucleic acid therapeutic drugs, small molecule peptides, sterols, and the like; the co-delivery system simultaneously entraps two or more drugs, of the same or different types.
Further preferably, in the multi-drug co-delivery system, the drug includes any one of the following cases:
(1) at least two chemotherapeutic agents; (2) at least two nucleic acid therapeutic agents; (3) at least one chemotherapeutic agent and a nucleic acid therapeutic agent.
In some preferred embodiments of the above technical solutions, the nucleic acid therapeutic agent includes, but is not limited to, small interfering ribonucleic acid (siRNA), micro rna (mirna), antisense oligonucleotide (AS ODN), or a combination thereof.
In some preferred embodiments of the above embodiments, the multiple drug co-delivery system is used for co-delivering a nucleoside-derived drug and a small interfering RNA agent.
In a more specific embodiment, the nucleoside derivative drug is gemcitabine or cytarabine.
In a more specific embodiment, the small interfering RNA species is an immunosuppressant, specifically, indoleamine 2, 3-dioxygenase-1 (IDO-1).
Preferably, the nano material is a metal organic framework material. The nano material needs to meet high load capacity, the metal organic framework material has high porosity and large specific surface area so as to provide abundant drug load sites, and the 2-methylimidazolium zinc (ZIF-8) metal organic framework material has good effect of meeting high specific surface area and degradation capacity of pH response as a carrier in the co-delivery system.
More preferably, the metal organic framework material is 2-methylimidazolium zinc (ZIF-8).
Preferably, the metal oxide mineralized layer is bound to the support surface by physical adsorption.
The metal oxide mineralized layer is attached to the surface of the carrier through a physical adsorption effect, and firstly, the metal oxide mineralized layer plays a role in encapsulating the medicine in the carrier, so that the degradation of the medicine before reaching a focus is reduced. Secondly, through the choice of metal oxide materials, it is also possible to release beneficial therapeutic ingredients in certain disease microenvironments.
In some embodiments, the invention provides a co-delivery system for antineoplastic drugs using MnO2A mineralized layer of metal oxide is prepared that, in the tumor microenvironment, can release oxygen to mitigate immunosuppression of M2 macrophages.
The therapeutic antibody is selected according to the intended use of the co-delivery system, preferably the therapeutic antibody has the same or a synergistic effect as the drug.
In one embodiment of the above preferred embodiment, there is provided a co-delivery system for antitumor drugs, which employs a 2-methylimidazolium zinc (ZIF-8) metal organic framework as a carrier, and simultaneously encapsulates gemcitabine and indoleamine 2, 3-dioxygenase-1 (IDO-1); the surface of the carrier is provided with MnO2Mineralized layer and therapeutic monoclonal antibody (aCD-47) electrostatic modification.
In addition, the invention also provides a preparation method of the co-delivery system of the anti-tumor drugs, which comprises the following steps: preparing ZIF-8-based GEM and siIDO co-loaded nanocage (GSZ) in water phase by one-pot method, adding KMnO into GSZ solution4And uniformly stirring to obtain a GSZM solution, and adding the aCD-47 into the GSZM solution to uniformly stir to obtain the GSZMA nanoparticles.
In a typical embodiment of the present invention, a specific preparation method is provided, which comprises the following steps:
(1) zinc nitrate was dissolved in ultrapure water and then added to the GEM and siIDO solutions with stirring. Subsequently, the mixed solution was added dropwise to the 2-methylimidazole solution by stirring; stirring for 10 minutes at room temperature under the dark condition, then centrifugally separating GSZ, and washing for three times by ultrapure water; the final product was finally collected by vacuum drying.
In this embodiment, 47.4mg of zinc nitrate was added in a volume of 5mL of ultrapure water.
This implementationIn this manner, the amount of GEM solution was 2mL, 40mg mL-1The amount of siIDO solution was 10. mu.L, 50. mu.M.
The amount of the 2-methylimidazole solution in this embodiment was 5mL, 65.7mg mL-1。
In the series of embodiments, the room temperature refers to indoor environment temperature, and is generally 15-30 ℃.
(2) Mixing KMnO4Dropwise adding the solution into the GSZ solution, stirring for 10min, collecting the nanoparticles by using a centrifugal machine, and washing with ultrapure water for three times; aCD-47 (50. mu.L, 5mg mL)-1) GSZM solution (1mL, 2mg mL) was slowly added dropwise-1) And stirring for 5min to obtain GSZMA nanometer particles, centrifuging, and re-dispersing in PBS buffer solution.
KMnO in this embodiment4The amount of the solution was 5mL, 0.2mg mL-1The amount of GSZ solution is 3mL, 1mg mL-1。
The amount of aCD-47 solution in this embodiment is 50. mu.L, 5mg mL-1The amount of the GSZM solution was slowly dropped to 1mL, 2mg m L-1。
The pH of the phosphoric acid buffer solution in this series of examples was 7-7.5.
In a second aspect of the present invention, there is provided a use of the multiple drug co-delivery system of the first aspect in the preparation of an anti-tumor drug.
In a third aspect, the present invention provides an anti-tumor drug, which comprises the co-delivery system of the multiple drugs of the first aspect and pharmaceutically necessary excipients.
Preferably, the anti-tumor drug is an injection; further preferred, a co-delivery system comprising the multi-drug of the first aspect together with an injection adjuvant; in other preferred embodiments, other agents having an anti-tumor effect or an adjunctive anti-tumor effect, such as angiogenesis inhibitors, are also included.
Preferably, the anti-tumor drug is a drug for inhibiting tumor metastasis; further preferably, the compound is an anti-tumor medicament for inhibiting tumor cell lung metastasis.
Preferably, the anti-tumor drug is a drug with an immunosuppressive effect; further preferably, the anti-tumor drug is used for inducing long-term adoptive immune memory effect.
In order to make the technical solution of the present invention more clearly understood by those skilled in the art, the technical solution of the present invention will be described in detail with reference to specific examples, wherein the reagents described in the following examples are all commercially available products.
Example 1
(1) 47.4mg of zinc nitrate was dissolved in 5mL of ultrapure water, and then GEM (2mL, 40mg mL) was added with stirring-1) And siIDO (10. mu.L, 50. mu.M) solution. Subsequently, the mixed solution was added dropwise to a 2-methylimidazole solution (5mL, 65.7mg mL) by stirring-1) In (1). After stirring for 10 minutes at room temperature in the dark, GSZ was prepared and then centrifuged, washed three times with ultrapure water and the final product was collected by vacuum drying.
(2) Mixing KMnO4Solution (5mL, 0.2 mgml)-1) Adding dropwise to GSZ (3mL, 1 mgml)-1) The solution was stirred for 10min, then the nanoparticles were collected with a centrifuge and washed three times with ultrapure water. aCD-47 (50. mu.L, 5mg mL)-1) GSZM solution (1mL, 2mg mL) was slowly added dropwise-1) And stirring for 5min to obtain GSZMA nanometer particles, centrifuging, and re-dispersing in PBS buffer solution.
The GSZMA nanosheets prepared in this example were subjected to morphology characterization, TEM spectra results are shown in fig. 1, and particle size distribution is shown in fig. 2.
Example 2 evaluation of cytotoxicity assay
MTT method for determining in vitro cytotoxicity of the drug-loaded preparation comprises the step of measuring the cytotoxicity of CT26 tumor cells at 5 x103The density of cells/well was seeded in 96-well plates and cultured until 80% confluence was reached. The cell culture medium was replaced with a series of media of different concentrations and different formulations for 48h, the medium was removed and 100. mu.L of MTT reagent (0.5mg mL) was added-1) And (3) incubating for 4h, taking off the MTT solution, adding 150 mu L DMSO to dissolve the metabolic activity cells, standing for 10min on a shake flask at 37 ℃, and measuring the absorbance at 490nm by using a microplate reader. The results are shown in FIG. 3, and the measured results show that GEM, GZ, GSZ, GSZM and GSZMP all have better killing effect on CT26 cells, but the GSZMA nano-composite has fine effect on CT26The cytocidal effect is stronger than that of free GEM, which shows that the composite material has better tumor treatment effect.
Example 3 evaluation of Long-term adoptive Immunomagnetic memory Effect induced by Nanoregulators
To establish an animal lung metastasis model, 1x10 was injected into the tail vein of each Balb/c mouse5 luc+CT26 cells. Thereafter, mice were randomly grouped, including PBS, GZ, SZ, GSZ, GSZM, GSZMA.
The doses of GEM, siIDO1, aCD-47 were 5mg kg-1、0.9mg kg-1And 50 μ g/mouse, 5 injections per 3 days via tail vein. Mice were then treated with different nanoparticles and the effect of the treatment was assessed at different times using an in vivo imaging apparatus (IVIS) spectroscopy system. Finally, the mice were sacrificed and tumor tissue was taken for H&And E, dyeing.
BLI results are shown in fig. 4, with the lowest fluorescence intensity of GSZMA-pretreated mice compared to the PBS group, which was further confirmed by H & E staining analysis (fig. 5). The results show that the nano-regulator prepared in example 1 can effectively and directly resist tumor growth.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (14)
1. A co-delivery system of multiple drugs, which is characterized in that the co-delivery system takes nano materials as carriers, and the carriers are used for encapsulating drugs; the surface of the carrier is provided with a metal oxide mineralized layer, and the surface of the mineralized layer is also provided with therapeutic antibody modification;
the multi-drug co-delivery system is an anti-tumor drug co-delivery system, and the co-delivery system adopts a 2-methylimidazolium zinc metal organic framework as a carrier and simultaneously carries gemcitabine and an indoleamine 2, 3-dioxygenase-1 inhibitor; the surface of the carrier is provided with MnO2Mineralized layer and therapeutic sheetThe cloned antibody is electrostatically modified.
2. The co-delivery system according to claim 1, wherein the metal oxide mineralized layer is bound to the carrier surface by physical adsorption.
3. The co-delivery system of claim 1, wherein the therapeutic antibody has the same or synergistic effect as the drug.
4. The co-delivery system for multiple drugs according to claim 1, wherein the preparation method of the co-delivery system for anti-tumor drugs comprises the steps of: preparing a ZIF-8-based GEM and siIDO encapsulated co-supported nanocage in an aqueous phase by a one-pot method, and adding KMnO into the nanocage solution4And uniformly stirring to obtain a mixed solution, and adding the aCD-47 into the mixed solution to uniformly stir to obtain the nano-particles.
5. Use of a multiple drug co-delivery system according to any one of claims 1 to 4 for the preparation of an anti-tumor drug.
6. An antitumor agent comprising the co-delivery system of the multiple drugs according to any one of claims 1 to 4 and pharmaceutically necessary excipients.
7. The antitumor agent according to claim 6, wherein said antitumor agent is an injection.
8. The antitumor agent according to claim 6, wherein said antitumor agent comprises a co-delivery system of multiple drugs according to any one of claims 1 to 4 together with an injection adjuvant.
9. The antitumor agent according to claim 8, further comprising other agents having an antitumor effect or an auxiliary antitumor effect.
10. The antitumor agent according to claim 9, wherein said antitumor agent is an angiogenesis inhibitor.
11. The antitumor agent according to claim 9, wherein said antitumor agent is an agent for inhibiting tumor metastasis.
12. The antitumor agent according to claim 11, wherein said antitumor agent is an antitumor agent that inhibits lung metastasis of tumor cells.
13. The antitumor agent according to claim 9, wherein said antitumor agent is a drug having an immunosuppressive action.
14. The antineoplastic drug of claim 13, wherein said antineoplastic drug is used to induce long-term adoptive immune memory effects.
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