CN112891548B - Metal organic framework drug-loaded nano system based on small molecule drug - Google Patents

Metal organic framework drug-loaded nano system based on small molecule drug Download PDF

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CN112891548B
CN112891548B CN202110076551.6A CN202110076551A CN112891548B CN 112891548 B CN112891548 B CN 112891548B CN 202110076551 A CN202110076551 A CN 202110076551A CN 112891548 B CN112891548 B CN 112891548B
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栾玉霞
周诗瑶
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Abstract

The invention provides a preparation method and application of a metal organic framework drug-loaded nano system based on a small molecular drug, MIT and HYD are jointly loaded in pores of a metal organic framework ZIF-8 through a simple, convenient and rapid method to prepare nanoparticles, and active targeted HA modification of tumor cells is realized. Not only solves the problems of poor stability of MIT and HYD and co-delivery of MIT and HYD, but also enhances the immunopotency of chemotherapeutic drugs. The intravenous injection preparation of (M + H) @ ZIF/HA HAs low toxicity, good safety, stronger tumor cell toxicity and obvious effect of inhibiting solid tumor.

Description

Metal organic framework drug-loaded nano system based on small molecule drug
Technical Field
The invention relates to the technical field of medicines, in particular to a metal organic framework medicine carrying nano system based on small molecular medicines and a preparation method and application thereof.
Background
The information disclosed 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.
In recent years, over 1000 million new cancer cases are diagnosed each year, and in 2018, about 960 ten thousand patients die from the disease. This figure is expected to increase by about 70% in the next two decades. Tumor immunotherapy is a new therapeutic approach developed on the basis of tumor immunology, and is characterized by exerting an anti-tumor effect by regulating the immune defense mechanism of the body. Currently, tumor immunotherapy has evolved as the fourth largest leg following surgery, radiation therapy, chemotherapy.
Chemo-immune combination therapy of tumors is a very promising approach to improve the anti-tumor efficacy. Chemotherapeutic drugs can activate anti-tumor immune responses by enhancing tumor cell immunogenicity.
Apoptosis (Pyroptosis), also known as inflammatory necrosis, is a programmed cell death that is characterized by a constant swelling of cells until the cell membrane is ruptured, resulting in the release of cellular contents that in turn activate a strong inflammatory response. The research shows that chemotherapy can cause cell apoptosis, wherein the key protein GSDME obtains an active GSDME-N-terminal structural domain through the cutting action of caspase-3 under the action of chemotherapeutic drugs. GSDME-N oligomerizes on the cell membrane and forms pores through the membrane, eventually leading to cytolytic death, inducing a strong inflammatory response, thereby more fully activating lymphocytes, resulting in stronger anti-tumor immunity. However, the inventors have found that in most tumour cells, GSDME expression tends to be silent due to DNA methylation in the promoter region.
Disclosure of Invention
In order to solve the problem that expression silencing of GSDME is caused by DNA methylation of a promoter region in the prior art, the invention provides a metal organic framework drug-loaded nano system based on a small molecule drug, and a preparation method and application thereof. The chemotherapeutic drug and the DNA methylation inhibitor are jointly loaded in the metal organic framework nano system, so that on one hand, the expression of the GSDME protein in the tumor cells is up-regulated through the DNA methylation inhibitor; on the other hand, the cleavage of GSDME protein by caspase-3 is caused by chemotherapeutic drugs to generate GSDME-N end structural domain, thereby causing the cell apoptosis of tumor cells, inducing strong inflammatory reaction, promoting the formation of antitumor immune response and realizing the chemotherapy-immune combined antitumor therapy.
Specifically, the invention is realized by the following technical scheme:
in a first aspect of the present invention, a metal organic framework drug-loaded nano-system based on small molecule drugs is provided, which comprises: the active medicine is loaded in pores of the metal organic framework material, and the surface of the metal organic framework material is modified with the targeting functional material.
In the second aspect of the invention, a preparation method of a metal organic framework drug-loaded nano system based on small molecule drugs is provided, active drugs are added into a metal salt solution, the metal salt solution and a ligand solution are mixed and react, metal ions and ligands form a metal organic framework material, the active drugs are loaded into pores of the metal organic framework material to form a drug-loaded precursor material in the process of forming the metal organic framework material, the drug-loaded precursor material is dispersed into a targeting functional material solution and uniformly mixed, and the solid obtained through separation is the metal organic framework drug-loaded nano system based on the small molecule drugs.
In a third aspect of the invention, an immune enhancing drug or an anti-tumor drug is provided, which comprises a metal organic framework drug-loaded nano-system based on a small molecule drug.
The invention provides an application of a metal organic framework drug-loaded nano system based on small molecule drugs in preparation of drugs for enhancing immunity or anti-tumor drugs.
One or more embodiments of the present invention have the following advantageous effects:
(1) the metal organic framework drug-loaded nano system based on the small molecule drug not only solves the problem of low stability of the small molecule drug, but also solves the problem of simultaneous delivery of the small molecule drug when the small molecule drug exerts synergistic effect.
(2) According to the invention, through targeted modification, the metal organic framework drug-loaded nano system based on small molecule drugs can realize specific active targeting to a target site.
(3) The metal organic framework drug-loaded nano system based on the micromolecular drug provided by the invention has stronger cytotoxicity and high targeting property to tumor cells, and provides possibility for enhancing in-vivo anti-tumor selectivity.
(4) The metal organic framework drug-loaded nano system based on the small molecular drugs provided by the invention utilizes chemotherapy and immunotherapy combined treatment, enhances the immune effect of chemotherapeutic drugs, and shows good anti-tumor effect.
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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. Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a TEM photograph of (M + H) @ ZIF/HA in example 2 of the present invention;
FIG. 2 is a graph showing the experimental characterization of (M + H) @ ZIF/HA in vitro cytotoxicity in example 3 of the present invention;
FIG. 3 is a graph showing the in vivo anti-tumor effect of (M + H) @ ZIF/HA in example 4 of the present invention.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
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 example embodiments according to the present disclosure. 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.
The research shows that chemotherapy can cause cell apoptosis, wherein the key protein GSDME obtains an active GSDME-N-terminal structural domain through the cutting action of caspase-3 under the action of chemotherapeutic drugs. GSDME-N oligomerizes on the cell membrane and forms pores through the membrane, eventually leading to cytolytic death, inducing a strong inflammatory response, thereby more fully activating lymphocytes, resulting in stronger anti-tumor immunity. However, the inventors have found that in most tumour cells, GSDME expression tends to be silent due to DNA methylation in the promoter region.
In view of the fact that a chemotherapeutic agent and a DNA methylation inhibitor need to be delivered synchronously to play a synergistic effect, the invention provides a metal organic framework drug-loaded nano-system based on a small-molecule drug, and a preparation method and application thereof.
In a first aspect of the present invention, a metal organic framework drug-loaded nano-system based on small molecule drugs is provided, which comprises: the active medicine is loaded in pores of the metal organic framework material, and the surface of the metal organic framework material is modified with the targeting functional material.
The mass ratio of the targeting functional material to the metal organic framework material to the active medicament is 0.5-1.5: 15-30: 3-5, preferably 1:20: 4.
The active drug is selected from chemotherapeutic agents and DNA methylation inhibitors;
the mass ratio of the chemotherapeutic agent to the DNA methylation inhibitor is 2-6:1, preferably 3-4:1, and more preferably 4: 1.
In one or more embodiments of the invention, the chemotherapeutic agent is mitoxantrone and the DNA methylation inhibitor is hydralazine;
the mass ratio of mitoxantrone to hydralazine is 2-6:1, preferably 3-4:1, and more preferably 4: 1.
In one or more embodiments of the invention, the targeting functional material is Hyaluronic Acid (HA);
in one or more embodiments of the present invention, the metal organic framework material is ZIF-8.
Metal-Organic Frameworks (MOFs), which are Organic-inorganic hybrid materials with intramolecular pores formed by self-assembly of Organic ligands and Metal ions through coordination bonds. Due to the controllable pore size, functional groups and good biocompatibility, the prepared nano MOFs material can be used for drug slow release in living cells, and has important significance in the field of biomedicine. However, due to the specificity of different drug molecular structures, the number of currently known classes of drugs that can be loaded by MOF materials is very limited.
Hyaluronic acid is a natural macromolecular polymer, can be specifically combined with CD44 receptor over-expressed on the surface of tumor cells, and is used for modifying a drug carrier to realize active targeted drug delivery of tumors.
According to the metal organic framework drug-loaded nano system based on the small molecular drugs, the MOFs are used as drug carriers, active drugs are loaded in pores of a metal organic framework material at the same time, and the co-delivery of the active drugs is realized, so that a synergistic effect is achieved.
In addition, loading the active drug in the pores of the MOFs can also increase the stability of the active drug, thereby enhancing the therapeutic effect of the active drug.
Carboxyl and hydroxyl on hyaluronic acid are coordinated and combined with uncoordinated metal coordination sites, and hyaluronic acid is modified on the surface through electrostatic adsorption of hyaluronic acid and positively charged MOFs materials, so that the active drug and the targeting functional material are combined together, and tumor targeting efficient delivery of the active drug is realized.
In this series of examples, the chemotherapeutic agent is Mitoxantrone (MIT) and the DNA methylation inhibitor is Hydralazine (HYD). Experiments prove that the MIT and HYD loaded metal organic framework nano drug delivery system provided by the invention not only overcomes the defect of poor stability of MIT and HYD in vivo, but also can exert a synergistic effect by co-delivering MIT and HYD to cause tumor cells to generate cell apoptosis, enhance anti-tumor immune response and realize chemotherapy-immune combined treatment.
In the second aspect of the invention, a preparation method of a metal organic framework drug-loaded nano system based on small molecule drugs is provided, active drugs are added into a metal salt solution, the metal salt solution and a ligand solution are mixed and react, metal ions and ligands form a metal organic framework material, the active drugs are loaded into pores of the metal organic framework material to form a drug-loaded precursor material in the process of forming the metal organic framework material, the drug-loaded precursor material is dispersed into a targeting functional material solution and uniformly mixed, and the solid obtained through separation is the metal organic framework drug-loaded nano system based on the small molecule drugs.
The concentration of metal ions in the metal salt solution is 150-250mg/mL, preferably 200 mg/mL;
the total concentration of the active medicine is 30-70mg/mL, preferably 40 mg/mL;
the concentration of the ligand solution is 0.5-4g/mL, preferably 2 g/mL;
adding the active drug into metal salt solution, and reacting at room temperature for 3-10min, preferably 5 min;
mixing the metal salt solution and the ligand solution for reaction, and reacting at room temperature for 10-20min, preferably 15 min;
the concentration of the targeting functional material solution is 5-20mg/mL, preferably 10 mg/mL.
Dispersing the administration precursor material into the targeting functional material solution, uniformly mixing, stirring at room temperature for 30-48h, preferably 36 h.
The concentration of the drug precursor material is 0.5-3mg/mL, preferably 2mg/mL when the drug precursor material is dispersed into the target function material solution.
In one or more embodiments of the invention, the active agent is a chemotherapeutic agent, a DNA methylation inhibitor, and the targeting functional material is hyaluronic acid.
In one or more embodiments of the invention, the metal salt is a zinc salt;
preferably, the ligand is 2-methylimidazole (2-MIM).
In one or more embodiments of the present invention, a chemotherapeutic agent, a DNA methylation inhibitor, is used as an active agent, comprising the steps of:
adding the water solution of the chemotherapeutic agent and the DNA methylation inhibitor into the water solution of the metal salt to obtain a mixed solution, dropwise adding the mixed solution into the ligand water solution under the stirring condition to form a suspension, centrifugally separating, washing with water, drying to obtain a solid, uniformly dispersing the solid into the hyaluronic acid water solution to form a suspension, centrifugally separating, washing with water, and drying.
In one or more embodiments of the invention, the chemotherapeutic agent is mitoxantrone and the DNA methylation inhibitor is hydralazine.
In one or more embodiments of the present invention, taking MIT, HYD, ZIF-8 metal organic framework as an example, the preparation method includes: dissolving MIT and HYD in water, and adding dropwise to zinc nitrate hexahydrate (ZnNO) under stirring 3 ·6H 2 O) water solution, dropwise adding the mixed solution into the 2-MIM water solution under the condition of stirring; centrifuging the suspension, washing with water, and drying to obtain blue solid (M + H) @ ZIF-8;
uniformly dispersing (M + H) @ ZIF-8 in an HA aqueous solution, stirring at room temperature, centrifuging the formed suspension, washing with water, and drying to obtain a blue solid, namely, a MIT and HYD-based metal organic framework drug delivery system (M + H) @ ZIF/HA with an active tumor targeting function.
In a third aspect of the invention, a medicine for enhancing immunity or an anti-tumor medicine is provided, which comprises a metal organic framework medicine carrying nano system based on a small molecule medicine.
In one or more embodiments of the invention, the drug is an intravenous injection.
The invention provides an application of a metal organic framework drug-loaded nano system based on small molecule drugs in preparation of drugs for enhancing immunity or anti-tumor drugs.
In one or more embodiments of the invention, the tumor is selected from the group consisting of malignant melanoma, skin cancer, breast cancer, ovarian cancer, lung cancer, colon cancer.
The effect of the immunity enhancing medicine or the antitumor medicine is to enhance the immune effect of the chemotherapeutic medicine, enhance the tumor cell toxicity or improve the antitumor efficacy.
The present invention is described in further detail below with reference to specific examples, which are intended to be illustrative of the invention and not limiting.
Example 1: a metal organic framework drug delivery system with tumor active targeting function based on Mitoxantrone (MIT) and Hydralazine (HYD) is prepared as an intravenous preparation.
Accurately weighing MIT 30mg and HYD 10mg by an analytical balance, dissolving in 2mL of water, and dripping 200mg/mL ZnNO under stirring 3 ·6H 2 And (2) adding the suspension into an O aqueous solution, dropwise adding the suspension into a 2-MIM aqueous solution of 2g/mL under the condition of stirring, carrying a medicine, namely ZIF nanoparticles, spontaneously forming, centrifuging the suspension, washing with water, removing a supernatant, and drying in vacuum to obtain a blue solid (M + H) @ ZIF-8.
Uniformly dispersing (M + H) @ ZIF-8 with the concentration of 2mg/mL in 10mg/mL hyaluronic acid aqueous solution, and stirring for 36H at room temperature; and centrifuging the formed suspension, washing with water, drying to obtain a blue solid, and uniformly dispersing the blue solid in water by ultrasonic treatment to obtain an intravenous injection preparation which is recorded as (M + H) @ ZIF/HA nano-aggregate. The zeta potential of (M + H) @ ZIF-8 is 27.1. + -. 0.7mV, and the zeta potential of (M + H) @ ZIF/HA is-23.8. + -. 0.4 mV.
Example 2: (M + H) @ ZIF/HA nano-aggregate morphology observation.
Absorbing 20 μ L (M + H) @ ZIF/HA nano-aggregate suspension, dripping on a carbon film copper net, absorbing excessive liquid by using filter paper, drying at room temperature, and observing the form of the (M + H) @ ZIF/HA nano-aggregate under a transmission electron microscope. The electron micrograph is as shown in figure 1, and the result shows that (M + H) @ ZIF/HA can be dispersed in water to form a relatively round nanoparticle structure with the diameter of about 100-200 nm, the shape is uniform, the dispersibility is good, the nanoparticle size is suitable for intravenous injection administration, and the requirement of Enhanced Permeation and Retention (EPR) effect on the particle size is met. The preparation process of the nanoparticles does not need to add organic solvent and surfactant, does not need to heat, and has simpler and quicker reaction.
Example 3: (M + H) @ ZIF/HA in vitro cytotoxicity assay.
1. Culture of cells
4T1 cells were selected as the study. The frozen cells were harvested and cultured at 37 ℃ in 5% CO 2 Culturing under the condition, carrying out passage when the cells grow to high density, proportionally transferring the cells into a culture flask for continuous culture and counting the cells.
2. Cytotoxicity test
4T1 cells were collected in logarithmic growth phase and compared for cytotoxicity of free drug versus nanoparticles. After trypsinizing the cells in logarithmic growth phase and making them into single cell suspensions, they were seeded into 96-well plates at 6000 cells per well for overnight culture. After the cells adhere to the wall, a series of different concentrations of HYD, MIT, (M + H) @ ZIF/HA of 200 μ L are added, each concentration is provided with 3 multiple holes, each plate is provided with a blank control group without cells and a positive control group without drugs, and the plates are placed in an incubator for incubation for 72H. After the incubation time was reached, 20. mu.L of MTT solution was added to each well, incubation was continued for 4h, and then the supernatant was aspirated, 100. mu.L of DMSO was added to each well, and the absorbance of each well was measured at a wavelength of 570nm in a microplate reader. The cell inhibition rate was calculated according to the following formula:
Figure BDA0002907722110000071
wherein A is Positive for Indicating absorbance of wells of cells not treated with drugDegree, A Sample (I) Indicates the absorbance of the wells of the cells treated with each sample, A Blank space Represents the absorbance of wells that were not seeded with cells and were not drug treated.
The results of the experiments on the inhibition rate of 4T1 cells in different concentrations of different samples are shown in FIG. 2. As can be seen from FIG. 2, the toxicity of bulk drugs MIT and (M + H) @ ZIF-8/HA on cells exhibited concentration dependence. Compared with bulk drug MIT, (M + H) @ ZIF/HA HAs stronger cell inhibition rate. This is because HA in (M + H) @ ZIF/HA can specifically bind to CD44 receptor overexpressed on the surface of 4T1, and therefore the intracellular capacity of (M + H) @ ZIF/HA is higher than that of bulk drug MIT, and the cell inhibition effect of (M + H) @ ZIF/HA is better than that of bulk drug MIT. Through the cell inhibition rate experiment, the conclusion can be drawn that: the (M + H) @ ZIF/HA HAs strong cytotoxicity, and can improve tumor treatment effect.
Example 4: (M + H) @ ZIF/HA in vivo antitumor assay.
Balb/c mice have axillary tumors (100 ten thousand cells of 4T1 each) which grow to 100mm 3 On the left and right, 4 groups were randomized, 5 per group, and saline (NS), HYD, MIT and (M + H) @ ZIF/HA were injected intravenously. Changes in tumor volume were recorded during treatment.
As can be seen from FIG. 3, the tumor volume growth of the mice of the (M + H) @ ZIF/HA group was slower than that of the MIT group due to the synergistic effect of tumor-targeted chemotherapy and immunotherapy. Because of the EPR effect of the preparation and the active targeting effect of hyaluronic acid, the drug accumulation at the tumor part is high, so the tumor inhibition effect of the (M + H) @ ZIF/HA preparation is obviously superior to that of MIT. The tumor targeted chemotherapy-immunotherapy is proved to greatly improve the anti-breast cancer effect.
According to the preparation method, MIT and HYD are loaded in pores of a metal organic framework ZIF-8 together through a simple, convenient and rapid method to prepare nanoparticles, and active targeted HA modification of tumor cells is realized. The problems of poor stability of MIT and HYD and co-delivery of MIT and HYD are solved. The preparation scheme is economical and environment-friendly, and can be used for mass production, and the solid is easy to store and transport, thereby providing possibility for industrial production. The intravenous injection preparation of (M + H) @ ZIF-8/HA HAs low toxicity, good safety, stronger tumor cell toxicity and obvious effect of inhibiting solid tumor.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the embodiments described above, or equivalents may be substituted for elements thereof. 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 (17)

1. A metal organic framework drug-loaded nano-system based on small molecule drugs is characterized by comprising: the active medicine is loaded in pores of the metal organic framework material, and the surface of the metal organic framework material is modified with the targeting functional material;
the active drug is selected from chemotherapeutic agents and DNA methylation inhibitors; the chemotherapeutic agent is mitoxantrone, and the DNA methylation inhibitor is hydralazine; the mass ratio of the chemotherapeutic agent to the DNA methylation inhibitor is 4: 1;
the targeting functional material is hyaluronic acid; the metal organic framework material is ZIF-8; the mass ratio of the targeting functional material to the metal organic framework material to the active medicament is 1:20: 4.
2. The preparation method of the metal organic framework drug-loaded nano system based on the small molecule drug as claimed in claim 1, is characterized in that the active drug is added into the metal salt solution, then the metal salt solution and the ligand solution are mixed to react, the metal ions and the ligand form the metal organic framework material, the active drug is loaded into the pores of the metal organic framework material to form the drug-loaded precursor material in the process of forming the metal organic framework material, the drug-loaded precursor material is dispersed into the targeting functional material solution and uniformly mixed, and the solid obtained by separation is the metal organic framework drug-loaded nano system based on the small molecule drug.
3. The preparation method of the metal organic framework drug-loaded nano-system based on small molecule drugs according to claim 2,
the concentration of metal ions in the metal salt solution is 150-250 mg/mL;
the total concentration of the active medicine is 30-70 mg/mL;
the concentration of the ligand solution is 0.5-4 g/mL;
adding the active drug into the metal salt solution, and reacting at room temperature for 3-10 min;
mixing the metal salt solution and the ligand solution for reaction, and reacting for 10-20min at room temperature;
the concentration of the targeting functional material solution is 5-20 mg/mL;
dispersing the administration precursor material into the targeting functional material solution, uniformly mixing, stirring at room temperature for 30-48 h;
the concentration of the drug precursor material is 0.5-3mg/mL when the drug precursor material is dispersed into the targeting functional material solution.
4. The method for preparing a metal-organic framework drug-loaded nanosystem based on small molecule drugs according to claim 2, wherein the metal ion concentration in the metal salt solution is 200 mg/mL.
5. The method of claim 2, wherein the total active drug concentration is 40 mg/mL.
6. The preparation method of the metal organic framework drug-loaded nanosystem based on the small molecule drug as claimed in claim 2, wherein the concentration of the ligand solution is 2 g/mL.
7. The preparation method of the metal organic framework drug-loaded nano system based on the small molecule drug as claimed in claim 2, wherein the active drug is added into the metal salt solution and reacted for 5min at room temperature.
8. The preparation method of the metal organic framework drug-loaded nano system based on the small molecule drug as claimed in claim 2, wherein the metal salt solution and the ligand solution are mixed and reacted, and the reaction is carried out for 15min at room temperature.
9. The preparation method of the metal organic framework drug-loaded nano-system based on the small molecule drug as claimed in claim 2, wherein the concentration of the targeting functional material solution is 10 mg/mL.
10. The preparation method of the metal organic framework drug-loaded nano system based on the small molecule drug as claimed in claim 2, wherein the drug delivery precursor material is dispersed into the targeting functional material solution and mixed uniformly, and stirred at room temperature for 36 h.
11. The preparation method of the metal organic framework drug-loaded nano system based on the small molecule drug as claimed in claim 2, wherein the concentration of the drug precursor material is 2mg/mL when the drug precursor material is dispersed into the target function material solution.
12. The preparation method of the metal-organic framework drug-loaded nanosystem based on the small molecule drug as claimed in claim 2, wherein the metal salt is zinc salt.
13. The method for preparing a small molecule drug-based metal-organic framework drug-loaded nanosystem as claimed in claim 2, wherein the ligand is 2-methylimidazole.
14. The preparation method of the metal organic framework drug-loaded nano system based on the small molecule drug as claimed in claim 2, wherein the method comprises the steps of taking a chemotherapeutic agent and a DNA methylation inhibitor as active drugs:
adding an aqueous solution of a chemotherapeutic agent and a DNA methylation inhibitor into an aqueous solution of a metal salt to obtain a mixed solution, dropwise adding the mixed solution into an aqueous solution of a ligand under a stirring condition to form a suspension, centrifugally separating, washing with water, drying to obtain a solid, uniformly dispersing the solid in an aqueous solution of hyaluronic acid to form a suspension, centrifugally separating, washing with water, and drying.
15. The preparation method of the metal organic framework drug-loaded nano system based on the small molecule drug as claimed in claim 2, characterized in that mitoxantrone and hydralazine are dissolved in water, and are added dropwise into zinc nitrate hexahydrate aqueous solution under stirring, and the above mixed solution is added dropwise into 2-methylimidazole aqueous solution under stirring; centrifuging the formed suspension, washing with water, and drying to obtain a blue solid (M + H) @ ZIF-8;
uniformly dispersing (M + H) @ ZIF-8 in an aqueous solution of hyaluronic acid, stirring at room temperature, centrifuging the formed suspension, washing with water, and drying to obtain a blue solid, namely a mitoxantrone and hydralazine-based metal organic framework drug delivery system (M + H) @ ZIF/HA.
16. An immunopotentiating drug or antitumor drug comprising the small molecule drug-based metal-organic framework drug-loaded nanosystem of claim 1;
the medicine is intravenous injection.
17. The use of the small molecule drug-based metal-organic framework drug-loaded nanosystem of claim 1 in the preparation of an immune-enhancing drug or an anti-tumor drug;
the tumor is selected from malignant melanoma, skin cancer, breast cancer, ovarian cancer, lung cancer, and colon cancer.
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