Preparation method of small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material and its products and applications

Abstract

The present invention discloses a method for preparing a small molecule chemotherapy drug / biomacromolecule / metal-organic framework composite material: 1) using ferric chloride hexahydrate as a metal source and terephthalic acid as an organic ligand, a metal-organic framework is prepared by a solvothermal method; 2) the metal-organic framework structure is mixed with a small molecule chemotherapy drug in an aqueous solution, stirred overnight at room temperature, and siRNA is added and stirred to obtain a small molecule chemotherapy drug / biomacromolecule / metal-organic framework composite material. The present invention also provides a small molecule chemotherapy drug / biomacromolecule / metal-organic framework composite material obtained by the above preparation method and its use in preparing a drug for treating drug-resistant breast cancer. The composite material provided by the present invention can effectively load small molecule chemotherapy drugs and biomacromolecules, enhance the ferroptosis-inducing effect and overcome drug resistance.

Description

Technical Field

[0001] The present invention relates to the construction and application of nano-biomaterials and small molecule chemotherapy drugs / biomacromolecule combination drugs, and in particular to a preparation method of a small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material, as well as its product and application. Background Art

[0002] Cancer is one of the major threats to human life and health, and how to treat cancer remains a major medical challenge. Chemotherapy, as a major cancer treatment method, mainly uses chemotherapy drugs to induce apoptosis or necrosis of tumor cells. However, chemotherapy resistance has become the main reason for the failure of chemotherapy in clinical practice. When a tumor develops chemotherapy resistance, the tumor cells will escape the cytotoxic effects of chemotherapy drugs by reducing intracellular drug concentrations, inactivating drugs, and resisting apoptosis. However, the clinical solution to tumor resistance is to use a combination of multiple chemotherapy drugs. On the one hand, this method is not effective, and on the other hand, the combined use of multiple drugs causes serious toxic side effects. Therefore, there is no more effective treatment for the problem of tumor resistance.

[0003] Reactive oxygen species (ROS), as a key signaling molecule, are closely related to the proliferation, metastasis, and apoptosis resistance of tumor cells. When the redox balance in tumor cells is broken, excessive ROS can cause oxidative stress and play a certain role in tumor resistance. Ferroptosis is a form of cell death characterized by lipid peroxidation and has played a huge role in tumor treatment in recent years. When cells produce ferroptosis, ROS mediates mitochondrial dysfunction, which can effectively target tumor cells' resistance to apoptosis and play a key role in overcoming tumor resistance. However, tumor cells have high levels of reduced glutathione (GSH) and glutathione peroxidase 4 (GPX4), which together resist the induction of ferroptosis. There have been related studies that can use the consumption of GSH to enhance the ferroptosis-inducing ability of drugs. For example, the Chinese patent publication number CN115581710A discloses a Fe3S4 nanozyme. The Fe3S4 nanozyme reported in the invention catalyzes H2O2 in the tumor microenvironment to produce ·OH, thereby accumulating ·OH. The Fe3S4 nanozyme can consume GSH to cause tumor cell apoptosis and ferroptosis, triggering the ferroptosis process of tumor cells, and ultimately achieving a tumor treatment effect of the synergistic effect of cell apoptosis and ferroptosis.

[0004] However, studies have shown that as GSH is depleted, tumor cells upregulate the GSH synthesis pathway, leading to cellular resistance to drug-induced oxidative stress. Furthermore, methods that regulate GSH synthesis through regulatory factors such as p53 and ATF3 can only indirectly affect GSH expression. Therefore, developing drugs that can inhibit GSH synthesis at the root and simultaneously generate ROS in cells to induce ferroptosis has the potential to reverse the drug resistance of tumor cells and be used to prepare new anti-tumor drugs for combination with chemotherapy drugs to overcome tumor resistance. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for preparing a small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material, as well as the prepared composite material and its application in the preparation of drugs for treating drug-resistant breast cancer; the composite material provided by the present invention can effectively load small molecule chemotherapy drugs and biomacromolecules, enhance the ferroptosis induction effect and overcome drug resistance.

[0006] A method for preparing a small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material, the preparation method comprising:

[0007] 1) A metal-organic framework (MOF) was prepared by a solvothermal method using ferric chloride hexahydrate as the metal source and terephthalic acid as the organic ligand.

[0008] 2) mixing the metal organic framework and the small molecule chemotherapy drug in an aqueous solution, stirring overnight at room temperature, adding the biomacromolecule and stirring, and obtaining a small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material.

[0009] The metal-organic framework structure of the present invention has the activity of delivering and protecting drugs and catalyzing the Fenton reaction: delivering small molecule chemotherapy drugs (such as doxorubicin) and biomacromolecules (SLC7A11 silencing siRNA), and protecting biomacromolecules from degradation in the blood circulation, and catalyzing hydrogen peroxide to produce ROS in cells and release small molecule chemotherapy drugs and siRNA. siRNA can silence SLC7A11, reduce the transport of cysteine into the cell, inhibit GSH biosynthesis from the root, and act together with the generated ROS on tumor cells, inducing ferroptosis and regulating apoptosis-related proteins, thereby relieving the apoptosis resistance of drug-resistant cells; at the same time, the metal-organic framework structure delivers small molecule chemotherapy drugs (such as doxorubicin) to evade P-gp recognition, reduce drug efflux, maintain effective intracellular drug concentration, and thus achieve drug resistance reversal.

[0010] Preferably, in step 1), N,N-dimethylformamide is used as solvent and acetic acid is used as reaction rate controller. In step 1), the volume of N,N-dimethylformamide is 0-100 mL.

[0011] Preferably, the mass ratio of ferric chloride hexahydrate to terephthalic acid is 1:0.55 to 1:0.65, the reaction temperature is 115-125°C, the heating rate is 5-10°C / minute, and the volume ratio of acetic acid to N,N-dimethylformamide is 1:70.0 to 1:80. The reaction rate can be controlled by controlling the temperature and the amount of acetic acid. These process conditions yield metal-organic frameworks with a size distribution of 150-200 nm.

[0012] Preferably, the mass ratio of the ferric chloride hexahydrate to terephthalic acid is 1:0.61, and the volume ratio of acetic acid to N,N-dimethylformamide is 1:76.14; and the size distribution of the metal organic framework is 120-170 nm.

[0013] Preferably, in step 2), the small molecule chemotherapy drug is doxorubicin, and the biomacromolecule is siRNA; the mass ratio of the metal organic framework to doxorubicin is 1:0.8 to 1:1.2, and the molar ratio of iron ions in the metal organic framework to siRNA is 1000:1 to 3000:1.

[0014] Preferably, the size distribution of the molecular chemotherapy drug / biomacromolecule / metal organic framework composite material is 160-200 nm.

[0015] The present invention also provides a small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material obtained according to the above preparation method. Preferably, the composite material is composed of a metal organic framework structure, the small molecule chemotherapy drug doxorubicin, and an SLC7A11 silencing siRNA.

[0016] The present invention also provides an application of the above-mentioned small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material in the preparation of a drug for treating drug-resistant breast cancer.

[0017] The metal organic framework in the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material provided by the present invention can deliver small molecule chemotherapy drugs and siRNA into tumor cells, and protect siRNA from being degraded by ribozymes in the circulation, ensuring that it plays a role in the cell. The composite material can catalyze intracellular hydrogen peroxide to produce hydroxyl radicals, play the role of Fenton reaction catalyst, oxidatively destroy mitochondria, and further, the released siRNA can silence SLC7A11 membrane protein, reduce cysteine influx, inhibit GSH biosynthesis, and ultimately induce ferroptosis and reverse tumor cell resistance. At the same time, due to the carrier delivery effect of the metal organic framework structure, small molecule chemotherapy drugs can be protected from being recognized by P-gp overexpressed on the surface of the tumor cell membrane, thereby ensuring the effective drug concentration in the cell, thereby reversing the drug resistance state of drug-resistant cells, making them more sensitive to chemotherapy drugs and enhancing the efficacy of chemotherapy drugs.

[0018] Compared with the prior art, the beneficial effects of the present invention are embodied in:

[0019] (1) The metal-organic framework structure in the small molecule chemotherapy drug / biomacromolecule / metal-organic framework composite material of the present invention can simultaneously protect siRNA from degradation during delivery and protect doxorubicin from being recognized by P-gp, thereby ensuring effective intracellular drug concentration.

[0020] (2) The small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material of the present invention can inhibit the biosynthesis of GSH at the root, thereby reducing the resistance of the GSH-GPX4 system to ferroptosis and enhancing the ferroptosis induction effect.

[0021] (3) The reaction system in the preparation method provided by the present invention is mild and the conditions are controllable. The prepared composite material has good biocompatibility and good clinical translation potential. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 This is a transmission electron microscope (TEM) image of the metal organic framework structure MIL-101 prepared in Example 1;

[0023] Figure 2 This is a dynamic light scattering particle size distribution diagram of the metal organic framework structure MIL-101 prepared in Example 1;

[0024] Figure 3 TEM image of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1;

[0025] Figure 4 This is a dynamic light scattering particle size distribution diagram of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1;

[0026] Figure 5 To characterize the catalytic activity of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1 in the Fenton reaction under acidic conditions;

[0027] Figure 6 This is a bar graph showing that the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite prepared in Example 1 inhibits GSH synthesis in the drug-resistant breast cancer cell line MCF7 / ADR;

[0028] Figure 7 This is a fluorescence image of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1 inducing ROS production in the drug-resistant breast cancer cell line MCF7 / ADR;

[0029] Figure 8This is an electron microscopic image of mitochondria after the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1 induced ferroptosis in the drug-resistant breast cancer cell line MCF7 / ADR;

[0030] Figure 9 The cytotoxicity graph and IC50 comparison of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1 on the drug-resistant breast cancer cell line MCF7 / ADR;

[0031] Figure 10 This is a Western-Blot image of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1 regulating apoptosis-related proteins in the drug-resistant breast cancer cell line MCF7 / ADR;

[0032] Figure 11 This is a graph showing the inhibition of P-gp activity in the drug-resistant breast cancer cell line MCF7 / ADR by the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite prepared in Example 1;

[0033] Figure 12 This is an evaluation of the effect of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1 in treating in situ drug-resistant breast cancer mice. DETAILED DESCRIPTION

[0034] The small-molecule chemotherapy drug / biomacromolecule / metal-organic framework composite provided by this invention can act as a Fenton reaction catalyst within cells, generating large amounts of ROS, which oxidatively damage mitochondria. Further release of siRNA can silence the SLC7A11 membrane protein, reduce cysteine influx, inhibit GSH biosynthesis, and ultimately induce ferroptosis, reversing tumor cell drug resistance. Furthermore, the carrier delivery function of the metal-organic framework structure can protect the small-molecule chemotherapy drug from being recognized by P-gp overexpressed on the tumor cell membrane surface, ensuring effective drug concentration within the cell.

[0035] The present invention will be further described below with reference to specific embodiments and accompanying drawings.

[0036] Example 1: Synthesis and characterization of small molecule chemotherapy drug / biomacromolecule / metal organic framework composite materials with Fenton reaction catalytic activity

[0037] (1) Synthesis of metal-organic framework structures:

[0038] 187.0 mg of ferric chloride hexahydrate and 114.5 mg of terephthalic acid were dissolved in 15 mL of DMF. After complete dissolution, the two were mixed and stirred at room temperature for 15 minutes. 197 μL of glacial acetic acid was added to the system and stirred for 10 minutes. The mixture was then heated to 120°C at a rate of 10°C / min. When the system temperature reached 120°C, it was magnetically stirred for 40 minutes, slowly cooled to room temperature, and centrifuged (11000 rpm for 15 minutes). The supernatant was discarded, the precipitate was collected, and washed twice with DMF and water to obtain the metal-organic framework structure MIL-101, which was dispersed in water for later use.

[0039] The results are as follows Figure 1 and 2 As shown, the morphology of MIL-101 was characterized by TEM and dynamic light scattering particle size distribution, and the particle size was about 170 nm.

[0040] (2) Synthesis of small molecule chemotherapy drugs / biomacromolecules / metal organic framework composites:

[0041] A quantitative solution of MIL-101 aqueous solution was added with doxorubicin hydrochloride at a 1:1 iron ion:DOX mass ratio. The mixture was stirred at room temperature for 12 hours, centrifuged at 11,000 rpm for 15 minutes, and the supernatant was discarded to collect the precipitate. The precipitate was washed twice with water to obtain a small molecule chemotherapy drug / metal-organic framework composite material, which was dispersed in water for later use. A quantitative solution of small molecule chemotherapy drug / metal-organic framework composite material was added with siRNA at a 1000:1 iron ion:siRNA molar ratio. The mixture was stirred at room temperature for 2 hours, centrifuged at 11,000 rpm for 15 minutes, and the supernatant was discarded to collect the precipitate. The precipitate was washed once with water to obtain a small molecule chemotherapy drug / biomacromolecule / metal-organic framework composite material.

[0042] The results are as follows Figure 3 As shown, the prepared small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material was characterized by transmission electron microscopy.

[0043] The results are as follows Figure 4 As shown, the prepared small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material was characterized by hydrated particle size using a dynamic light scattering instrument, and the particle size was about 190 nm.

[0044] The results are as follows Figure 5As shown, the Fenton catalytic activity of the prepared small molecule chemotherapy drug / biomacromolecule / metal organic framework composite was characterized, using hydrogen peroxide as a substrate and TMB as an indicator. When ROS was generated in the solution, TMB was oxidized and its absorbance increased. The absorbance of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite when incubated with hydrogen peroxide and TMB was measured using a UV spectrophotometer. The results showed that the absorbance at a wavelength of 650nm gradually increased with time, indicating that the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite has strong Fenton reaction catalytic activity.

[0045] Example 2: Effects of small molecule chemotherapy drugs / biomacromolecules / metal organic framework composites on inhibiting GSH synthesis and inducing ferroptosis

[0046] Preparation of drugs: The small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1 was dispersed in DMEM+10% FBS, and simple MIL-101 and MIL-siRNA were prepared as controls.

[0047] Establishment of drug-resistant breast cancer cell model (MCF7 / ADR): MCF7 / ADR cells were cultured in DMEM+10% FBS in an incubator maintained at 37°C with 5% carbon dioxide.

[0048] Group settings:

[0049] a. Control group: drug-resistant breast cancer cells were given an equal amount of phosphate-buffered saline (PBS).

[0050] b. Treatment Group 1: The metal-organic framework structure MIL-101 was added to the culture medium of drug-resistant breast cancer cells to make the iron ion concentration reach 10 μg / mL.

[0051] d. Treatment group 2: small molecule chemotherapy drugs / biomacromolecules / metal organic framework composite materials were added to the culture medium of drug-resistant breast cancer cells to make the iron ion concentration reach 10 μg / mL.

[0052] After incubating the cells in the three groups at 37°C for 48 hours, the ROS fluorescent probe 2',7'-dichlorofluorescein diacetate (DCFH-DA, 200 μM) was added. The cells were incubated in the dark at 37°C for 30 minutes and then washed three times with PBS. Cell fluorescence was captured and quantified using a confocal laser scanning microscope (CLSM) (excitation wavelength: 488 nm, emission wavelength: 525 nm).

[0053] After incubation, the three groups of cells were washed twice with PBS, incubated with trypsin for 5 minutes to detach the cells, and then washed with PBS. After removing the culture medium, the cells were fixed with glutaraldehyde at room temperature, rinsed with PBS, dehydrated with graded ethanol, and cleared with propylene oxide. Finally, the cell samples were cut and transferred to a mesh, and imaged using TME.

[0054] The results are as follows Figure 6 As shown, the delivery of siRNA by small molecule chemotherapy drugs / biomacromolecules / metal organic framework composites effectively reduces the level of intracellular GSH, thereby weakening the intracellular reducing ability and making drug-resistant cells more sensitive to ROS.

[0055] The results are as follows Figure 7 As shown, the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material causes the production of a large amount of ROS in cells, and the ROS signal is higher than that of the simple metal organic framework structure, indicating that the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material can catalyze the Fenton reaction in cells and catalyze hydrogen peroxide to produce ROS.

[0056] The results are as follows Figure 8 As shown, the biological electron microscopy images show that the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material can effectively cause ferroptosis of drug-resistant cells, destroy the structure and function of cell mitochondria, and cause structural changes such as increased mitochondrial membrane density, smaller mitochondria, and fewer mitochondrial cristae.

[0057] Example 3: Drug resistance reversal effect of small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material on drug-resistant breast cancer cells

[0058] Preparation of drugs: The small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1 was dispersed in DMEM+10% FBS, and pure DOX was prepared as a control.

[0059] Establishment of drug-resistant breast cancer cell model (MCF7 / ADR): MCF7 / ADR cells were cultured in DMEM+10% FBS in an incubator maintained at 37°C with 5% carbon dioxide.

[0060] Group settings:

[0061] a. Control group: drug-resistant breast cancer cells were given an equal amount of phosphate-buffered saline (PBS).

[0062] b. Treatment Group 1: Small molecule chemotherapy drugs / biomacromolecules / metal organic framework composite materials were added to the culture medium of drug-resistant breast cancer cells to adjust the iron ion concentration to 10 μg / mL and the DOX concentration to 10 μg / mL.

[0063] e. Treatment group 2: Add doxorubicin to the culture medium of drug-resistant breast cancer cells at a concentration of 10 μg / mL.

[0064] MCF7 / ADR cells were plated at 5×10 3 Cells were seeded at a density of 100 μL in a 96-well plate and cultured overnight. DOX and the small molecule chemotherapeutic drug / biomacromolecule / metal-organic framework composite were added to the wells and incubated for a further 48 hours in a 37°C, 5% CO2 incubator. Cytotoxicity was determined using the CCK-8 assay. 10 μL of CCK-8 solution was added to each well. After a 1-hour incubation, the absorbance at 450 nm was measured using a microplate reader.

[0065] The three groups of cells were collected in radioimmunoprecipitation lysis buffer (RIPA) containing protease inhibitors. After centrifugation, the total protein concentration in the supernatant was determined using a BCA protein assay kit. Total protein (10-100 μg) was separated by 10% SDS-PAGE electrophoresis and transferred to a polyvinylidene fluoride (PVDF) membrane. After sealing in PBS containing 5% skim milk powder, the primary antibody was added and incubated overnight at 4°C. After incubation with an HRP-conjugated secondary antibody, the membrane was rinsed with PBS containing 0.1% Tween-20 for 2 hours. The PVDF signal was detected and quantified.

[0066] Rhodamine 123 was used as a P-gp substrate to characterize P-gp transport activity. MCF-7 / ADR cells were seeded in 6-well plates and incubated overnight. After administration, cells were incubated with 5 μg / mL of rhodamine 123 for 4 hours. After washing three times with PBS, the fluorescence of rhodamine 123 was measured using CLSM.

[0067] The results are as follows Figure 9 As shown, the cytotoxicity of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material on drug-resistant breast cancer cells is significantly higher than that of simple doxorubicin, and the IC50 is only one-fifth of that of doxorubicin, indicating that it effectively reverses the drug resistance of cells.

[0068] The results are as follows Figure 10 As shown, the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material successfully regulated the apoptosis-related proteins Bcl-2 and Bax in drug-resistant breast cancer cells, reducing the expression of the anti-apoptotic protein Bcl-2 and increasing the expression of the pro-apoptotic protein Bax, indicating that it effectively reversed the resistance of drug-resistant cells to apoptosis.

[0069] The results are as follows Figure 11 As shown, the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material significantly inhibited the efflux activity of P-gp protein on drug-resistant breast cancer cells, indicating that it effectively inhibited P-gp-mediated drug efflux, thereby increasing the effective drug concentration in the cells.

[0070] Example 4: Drug resistance reversal effect of small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material in an in situ drug-resistant breast cancer mouse model

[0071] Preparation of drugs: The small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material prepared in Example 1 was dispersed in DMEM+10% FBS, and simple MIL-101 and MIL-siRNA were prepared as controls.

[0072] Establishment of an in situ drug-resistant breast cancer animal model: The anti-tumor activity was determined in 4-week-old female Balb / c nude mice. 7 MCF7 / ADR cells were suspended in 100 μL of serum-free PBS and injected into the fourth mammary fat pad on the right side of mice. Exogenous estrogen was supplemented using an estradiol transdermal patch. All mice were sacrificed 5 weeks later. Tumor volume was measured as follows: Volume = Length × Width 2 ×0.5.

[0073] Group settings:

[0074] a. Control group: drug-resistant breast cancer cells were given an equal amount of phosphate-buffered saline (PBS).

[0075] b. Treatment Group 1: Small molecule chemotherapy drugs / biomacromolecules / metal organic framework composite materials were added to the culture medium of drug-resistant breast cancer cells, with the DOX dosage being 5 mg / kg.

[0076] e. Treatment Group 2: The small molecule chemotherapy drug DOX was added to the culture medium of drug-resistant breast cancer cells at a DOX dosage of 5 mg / kg.

[0077] PBS, DOX and small molecule chemotherapy drugs / biomacromolecules / metal organic framework composites were injected into the tail vein at corresponding doses every five days. The tumor volume was measured regularly and the mice were killed after 5 weeks.

[0078] The results are as follows Figure 12 As shown, the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material significantly inhibited tumor growth in the in situ drug-resistant breast cancer animal model, and the effect was better than that of the simple small molecule chemotherapy drug DOX and had a significant difference, indicating that the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material reversed tumor resistance in the in situ drug-resistant breast cancer animal model.

[0079] The present invention confirms the Fenton reaction catalytic activity and drug delivery effect of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material through material characterization experiments and in vitro and in vivo experiments, and verifies the effect of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material in inducing ferroptosis and reversing drug resistance in drug-resistant breast cancer cells. Finally, it verifies the effect of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material in treating drug-resistant breast cancer in vivo and in vitro, providing a potential nanomaterial for clinical research on drug-resistant breast cancer tumor drugs.

Claims

1. A method for preparing a small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material for treating drug-resistant breast cancer, characterized in that: The preparation method comprises: 1) Metal-organic frameworks (MOFs) were prepared by a solvothermal method using ferric chloride hexahydrate as the metal source and terephthalic acid as the organic ligand. 2) mixing the metal-organic framework and the small molecule chemotherapy drug in an aqueous solution, stirring at room temperature overnight, adding the biomacromolecule and stirring to obtain a small molecule chemotherapy drug / biomacromolecule / metal-organic framework composite material; In step 1), N,N-dimethylformamide is used as solvent and acetic acid is used as reaction rate controller; The mass ratio of ferric chloride hexahydrate to terephthalic acid is 1:0.55-0.65, the reaction temperature is 115-125°C, the heating rate is 5°C / min-10°C / min, and the volume ratio of acetic acid to N,N-dimethylformamide is 1:70-80; In step 2), the small molecule chemotherapy drug is doxorubicin, the biomacromolecule is siRNA, and the siRNA is used to silence the SLC7A11 membrane protein; the mass ratio of the metal organic framework to doxorubicin is 1:0.8-1.2, and the molar ratio of iron ions in the metal organic framework to siRNA is 1000-3000:1; The size distribution of the metal organic framework is 120-170 nm; The size distribution of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material is 160-200 nm.

2. A small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material obtained according to the preparation method of claim 1.

3. Use of the small molecule chemotherapy drug / biomacromolecule / metal organic framework composite material according to claim 2 in the preparation of a drug for treating drug-resistant breast cancer.

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