Ternary supramolecular assembly with pH and temperature coordinated response as well as preparation method and application of ternary supramolecular assembly

Abstract

The invention relates to the technical field of drug targeted delivery, in particular to a pH and temperature coordinated response ternary supramolecular assembly and a preparation method and application thereof.The pH and temperature coordinated response ternary supramolecular assembly is prepared with amino-functionalized Fe-based MOFs as a nano-carrier, aloe-emodin as an anti-tumor model drug and folic acid polyethylene glycol grafted beta-cyclodextrin as a targeting agent and a nano'valve '. A composite ternary supramolecular assembly is constructed, so that an anti-cancer drug can be efficiently loaded and packaged, and active tumor targeting of the anti-cancer drug aloe-emodin as well as temperature-sensitive and pH stimulus-responsive release can be realized; the preparation method is simple and easy to implement, and the raw materials are cheap and easy to obtain, so that the preparation method has a wide application prospect in the field of targeted therapy of cancers.

Description

Technical Field

[0001] The present invention relates to the technical field of drug targeted delivery, and in particular to a ternary supramolecular assembly with coordinated response to pH and temperature, a preparation method and an application thereof. Background Art

[0002] Chemotherapy is currently the most commonly used cancer treatment. While most chemotherapy drugs have excellent anti-cancer effects, they lack selectivity for tumor cells, are rapidly metabolized in the body, have a short half-life, and are easily eliminated from the body. Blood drug concentrations quickly drop below the effective therapeutic concentration after a short period of circulation, making normal dosing ineffective. To achieve tumor eradication, increased dosing is often used, but this can cause severe systemic toxicity, resulting in side effects such as diarrhea, rash / desquamation, fatigue, skin reactions on the hands and feet, hair loss, nausea, itching, and vomiting.

[0003] With the advancement of biomedical research, drug delivery systems are playing an increasingly important role in improving drug efficacy and reducing side effects. Existing drug delivery systems suffer from a lack of responsiveness, uncontrollable drug release, poor biocompatibility, and biodegradability. Compared to normal cells, tumor cells overexpress folate receptors (FRs) on their surfaces. Active targeting of tumor cells can be achieved using folate-polyethylene glycol-functionalized cyclodextrin (FA-PEG-CD). Aloe-emodin (AE), a natural anthraquinone derivative, has been shown to exhibit diverse bioactivities, including anti-tumor, anti-inflammatory, and antibacterial properties. However, AE's low water solubility results in poor in vivo bioavailability, significantly limiting its clinical application. Therefore, combining cancer cell-specific ligands with stimulus-responsive building blocks to construct delivery systems for anti-tumor aloe-emodin improves its water solubility and biocompatibility, offering promising applications in tumor therapy and drug delivery. Summary of the Invention

[0004] In order to overcome the above technical defects, the present invention combines MIL-101(Fe) and FA-PEG-CD by means of non-covalent bonds to construct a complex ternary supramolecular assembly of anti-tumor aloe-emodin that responds synergistically to pH and temperature, which can effectively improve the bioavailability of the drug, reduce the side effects of the drug, and expand the scope of application of the drug.

[0005] In a first aspect, the present invention provides a ternary supramolecular assembly that responds in a coordinated manner to pH and temperature, comprising a core and a shell; The core is formed by loading aloe-emodin on MOF; The shell is self-assembled by FA-PEG-CD on the core.

[0006] Furthermore, the particle size of the ternary supramolecular assembly is 400-600 nm, the pH response range is 5-6, and the temperature response range is 40-45°C.

[0007] Furthermore, the MOF is prepared by the following method: dissolving ferric chloride hexahydrate and 2-aminoterephthalic acid in N,N-dimethylformamide, then adding glacial acetic acid, reacting at 110-130°C for 10-15 hours, collecting the precipitate by centrifugation, washing, and vacuum drying to obtain the MIL-101(Fe)-NH2 nanocarrier.

[0008] Furthermore, the FA-PEG-CD is prepared by the following method: folic acid, 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate and N,N-diisopropylethylamine are added to a dimethyl sulfoxide solution of hydroxypolyethylene glycol amino, reacted at room temperature for 20-50 minutes, filtered to collect the precipitate, washed, and vacuum dried to obtain HO-PEG 2K -FA; change HO-PEG 2K -FA chloroform solution, add succinic anhydride and 4-dimethylaminopyridine to dissolve, react at 50-70 ° C for 3-8 hours, collect the precipitate, vacuum dry, and activate to obtain.

[0009] In a second aspect, the present invention provides a method for preparing a ternary supramolecular assembly, comprising adding a drug and MOF in a mass ratio of 1:1 to an alcohol solvent, stirring the mixture in the dark for 10-15 hours at room temperature, and filtering the supernatant by centrifugation to obtain a core; adding the core to a FA-PEG-CD solution, stirring the mixture in the dark for 1-5 hours, collecting the precipitate by centrifugation, washing, and vacuum drying the ternary supramolecular assembly MIL-101(Fe)-NH2@AE@FA-PEG-CD.

[0010] Furthermore, the aloe-emodin loading rate of the core is 30-40%, and / or the encapsulation efficiency of the core is 50-60%.

[0011] Furthermore, the MOF is prepared by the following method: dissolving ferric chloride hexahydrate and 2-aminoterephthalic acid in N,N-dimethylformamide, then adding glacial acetic acid, reacting at 110-130°C for 10-15 hours, collecting the precipitate by centrifugation, washing, and vacuum drying to obtain the MIL-101(Fe)-NH2 nanocarrier.

[0012] Furthermore, the FA-PEG-CD is prepared by the following method: folic acid, 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate and N,N-diisopropylethylamine are added to a dimethyl sulfoxide solution of hydroxypolyethylene glycol amino, reacted at room temperature for 20-50 minutes, filtered to collect the precipitate, washed, and vacuum dried to obtain HO-PEG 2K -FA; change HO-PEG 2K -FA chloroform solution, add succinic anhydride and 4-dimethylaminopyridine to dissolve, react at 50-70 ° C for 3-8 hours, collect the precipitate, vacuum dry, and activate to obtain.

[0013] In a third aspect, the present invention provides the use of the ternary supramolecular assembly prepared by the above-mentioned preparation method in the preparation of tumor drugs.

[0014] Furthermore, the tumor is one or more of leukemia, liver cancer, colon cancer, lung cancer, breast cancer, gastric cancer, ovarian cancer, cervical cancer, kidney cancer, and prostate cancer.

[0015] Beneficial effects: Compared with the existing technology, the present invention uses amino-functionalized Fe-based MOFs as nanocarriers, aloe-emodin as an anti-tumor model drug, and folic acid polyethylene glycol-grafted β-cyclodextrin (FA-PEG-CD) as a targeting agent and nano "valve" to construct a composite ternary supramolecular assembly (MIL-101(Fe)-NH2@AE@FA-PEG-CD), which can not only efficiently load and encapsulate anticancer drugs, but also achieve active tumor targeting of the anticancer drug aloe-emodin and its temperature-sensitive and pH-stimulated responsive release; the preparation method of the present invention is simple and easy to implement, and the raw materials are cheap and readily available, which gives it broad application prospects in the field of targeted cancer treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 is a flow chart for preparing the ternary supramolecular assembly of the present invention; Figure 2 The SEM images of the ternary supramolecular assembly, MIL-101(Fe)-NH2; Among them, 2a is the SEM image of MIL-101(Fe)-NH2, and 2b is the SEM image of the ternary supramolecular assembly; Figure 3 3a is the SEM image of MIL-101(Fe)-NH2, and 3b is the SEM image of the ternary supramolecular assembly; Figure 4XRD diffraction patterns of MIL-101(Fe)-NH2 and MIL-101(Fe)-NH2@FA-PEG-CDXRD; Figure 5 The responsiveness of the ternary supramolecular assembly to pH and temperature; Among them, 5a is the in vitro drug release curve of the ternary supramolecular assembly; 5b is the TEM morphology of the ternary supramolecular assembly after release; Figure 6 The effect of the ternary supramolecular assembly on the antiviral efficacy in vitro; Among them, 6a is the cytotoxicity of the ternary supramolecular assembly to HepG2, 6b is the cytotoxicity of the ternary supramolecular assembly to A549, 6c is the cytotoxicity of the ternary supramolecular assembly to MCF-7, and 6d is the cytotoxicity of the ternary supramolecular assembly to BEAS-2B. DETAILED DESCRIPTION

[0017] In order to enable those skilled in the art to better understand the technical solution of the present invention, the present invention is described in detail below in conjunction with specific embodiments. The experimental methods in the following examples where specific conditions are not specified are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight. Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to the described contents can be applied to the present invention. The preferred implementation methods and materials described in the text are for demonstration purposes only.

[0018] The endpoints of the ranges and any values ​​disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0019] Based on the present invention, the present invention aims to provide a pH and temperature coordinated response composite drug-loaded ternary supramolecular assembly, which effectively loads aloe-emodin using the porous structure of MIL-101(Fe)-NH2, and at the same time, the unsaturated metal ion Fe 3+It can coordinate with a large number of hydroxyl groups on cyclodextrin for coupling, and then it can self-assemble with FA-PEG-CD through electrostatic interaction; MIL-101(Fe) in the ternary supramolecular assembly is responsive to pH. The nanoassembly is stable under neutral pH conditions. Under the weakly acidic conditions of the tumor site (pH 5.0~6.0), MIL-101(Fe) will dissociate and the anticancer drug aloe-emodin will be released; at the same time, the temperature-sensitive PEG polymer long chain in the ternary supramolecular assembly will be structurally destroyed during hyperthermia treatment of the tumor, resulting in the dissociation of the PEG chain, thereby promoting the release of the anti-tumor drug aloe-emodin (AE).

[0020] In some specific embodiments, the particle size of the provided ternary supramolecular assembly is 400-600 nm, the pH response range is 5-6, and the temperature response range is 40-45°C; In some preferred embodiments, the particle size of the ternary supramolecular assembly is 515 nm, the pH response range is 5.5, and the temperature response range is 43°C.

[0021] In other specific embodiments, a method for preparing a ternary supramolecular assembly is provided, wherein aloe-emodin and MOF in a mass ratio of 1:1 are added to an alcohol solvent, stirred in the dark for 10-15 hours at room temperature, and the supernatant is centrifuged and filtered to obtain a core; the core is added to a FA-PEG-CD solution, stirred in the dark for 1-5 hours, and the precipitate is collected by centrifugation, washed, and vacuum-dried to obtain a ternary supramolecular assembly MIL-101(Fe)-NH2@AE@FA-PEG-CD (see Figure 1 ).

[0022] Iron-based MOFs (MIL-101(Fe)) is a porous material with excellent performance. It has multiple functional sites on the skeleton and adjustable pore size. It can respond to the micro-acidic environment of the tumor, has a large specific surface area and high porosity, and has excellent biocompatibility and passive targeting capabilities.

[0023] This design allows drug release to be more concentrated at the tumor site, improving drug utilization efficiency and therapeutic efficacy. β-CD is a natural macrocyclic host molecule that can act as a "nanovalve" to carry molecules modified on the surface of the nanocarrier through host-guest interactions, giving it the ability to stimulate responsive drug release, thereby avoiding premature drug leakage. FA-PEG-CD, obtained by modifying β-CD with folic acid and thermosensitive polyethylene glycol, has the excellent properties of active tumor targeting and temperature sensitivity.

[0024] In some examples of this embodiment, the MOF is prepared by the following method: dissolving ferric chloride hexahydrate and 2-aminoterephthalic acid in N,N-dimethylformamide, then adding glacial acetic acid, reacting at 110-130°C for 10-15 hours, collecting the precipitate by centrifugation, washing, and vacuum drying to obtain the MIL-101(Fe)-NH2 nanocarrier.

[0025] In some examples of this embodiment, the molar ratio of ferric chloride hexahydrate to 2-aminoterephthalic acid is 1:(1-1.5), for example, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5; In some examples of this embodiment, the FA-PEG-CD is prepared by the following method: folic acid, 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate and N,N-diisopropylethylamine are added to a dimethyl sulfoxide solution of hydroxypolyethylene glycol amino, reacted at room temperature for 20-50 minutes, filtered to collect the precipitate, washed, and vacuum dried to obtain HO-PEG 2K -FA; change HO-PEG 2K Add succinic anhydride and 4-dimethylaminopyridine to the chloroform solution of -FA, and react at 50-70°C for 3-8 hours. Collect the precipitate, dry it in vacuum, and activate it to obtain the product.

[0026] In some examples of this embodiment, the mass ratio of folic acid, 1H-benzotriazol-1-yloxytripyrrolidino hexafluorophosphate, N,N-diisopropylethylamine and hydroxypolyethylene glycol amino group is (1-1.2): (1.4-1.6): (0.8-1.1): (4-6); In some examples of this embodiment, HO-PEG 2K -FA, succinic anhydride and 4-dimethylaminopyridine mass ratio is 1: (0.05-0.1): (0.05-0.1); In some examples of this embodiment, the activation conditions are as follows: dissolving FA-PEG-CD in deionized water, adding EDC and NHS, stirring in a nitrogen atmosphere at 25°C, shielded from light, and activating FA-PEG 2K -COOH carboxyl group, and then add EDA-CD to the mixed solution and continue stirring. The reaction solution is concentrated under reduced pressure, purified by dialysis, and freeze-dried to obtain the product.

[0027] The technical solutions of the present invention are further described in detail below in conjunction with specific embodiments and drawings. It should be understood that the following embodiments are only used to explain the present invention and are not used to limit the present invention.

[0028] Example 1 Synthesis of Folic Acid Polyethylene Glycol Functionalized Cyclodextrin (FA-PEG-CD): Weigh 500 mg of hydroxy polyethylene glycol amino and dissolve it in 3 mL of dimethyl sulfoxide. Add folic acid (FA, 110 mg), 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate (156 mg) and N,N-diisopropylethylamine (97 mg) and dissolve them completely. React at room temperature for 0.5 h, pour into a large amount of ice ether for precipitation, collect the product by filtration, and dry in vacuum to obtain folic acid functionalized hydroxy polyethylene glycol (HO-PEG). 2K -FA); weigh 100 mg HO-PEG 2K -FA was dissolved in 4 mL of chloroform, and succinic anhydride (9.8 mg) and 4-dimethylaminopyridine (0.6 mg) were added to dissolve completely. The mixture was reacted at 60 °C for 5 h. The reaction solution was concentrated under reduced pressure and poured into a large amount of ice ether for precipitation. The product was collected by filtration and dried in vacuo to obtain a light yellow product FA-PEG. 2K -COOH; 0.1 g FA-PEG 2K -COOH was fully dissolved in 10 mL of deionized water, EDC (0.05 g, 0.1 mmol) and NHS (0.01 g, 0.1 mmol) were added, and the mixture was stirred in the dark at 25 °C for 2 h to activate FA-PEG. 2K -COOH carboxyl group, then, EDA-CD (0.12 g, 0.1 mmol) was added to the mixed solution and stirring was continued for 48 h. The reaction solution was concentrated under reduced pressure and further dialyzed and purified using a dialysis bag (MWCO = 3500 Da) for 3 days, and the folic acid polyethylene glycol functionalized cyclodextrin was collected by freeze drying.

[0029] The synthetic route is as follows:

[0030] Example 2 Preparation of amino-functionalized iron-based MOFs nanocarrier MIL-101(Fe)-NH2 Ferric chloride hexahydrate (0.374 g, 1.38 mM) and 2-aminoterephthalic acid (0.252 g, 1.38 mM) were dissolved in N,N-dimethylformamide (30 mL) by sonication for 30 minutes. Glacial acetic acid (120 µL) was then added to the mixture, which was transferred to a polytetrafluoroethylene hydrothermal reactor and heated continuously in a 120°C oven for 12 hours using the hydrothermal synthesis method. After cooling to room temperature, the reaction mixture was centrifuged (8000 rpm) for 5 minutes and washed three to four times with hot DMF and then anhydrous ethanol, dried under vacuum, and set aside.

[0031] Example 3 Preparation of MIL-101(Fe)-NH2@AE 10 mg of aloe-emodin was dissolved in anhydrous ethanol, followed by the addition of 10 mg of MIL-101(Fe)-NH2. The mixture was sealed and stirred in the dark at 25°C for 12 hours. After centrifugation, a small amount of the supernatant was filtered through a membrane. The absorbance at 225 nm was measured by UV-visible spectroscopy. The encapsulation efficiency (EE%) was calculated to be 55.50% and the loading rate (DL%) was 35.81%, based on the AE standard curve.

[0032] Example 4 Preparation of the ternary supramolecular assembly MIL-101(Fe)-NH2@AE@FA-PEG-CD MIL-101(Fe)-NH2@AE was added to 10 mL of FA-PEG-CD solution, stirred in the dark for 2 h, centrifuged, washed, and the precipitate was collected and vacuum dried to obtain the composite nano-drug delivery system MIL-101(Fe)-NH2@AE@FA-PEG-CD.

[0033] The performance of the ternary supramolecular assembly MIL-101(Fe)-NH2@AE@FA-PEG-CD of the present invention was verified.

[0034] (1) Structural characterization using X-ray diffractometer (XRD), scanning electron microscope (SEM) and transmission electron microscope (TEM): Scanning electron microscopy (S-4800) was used to evaluate the surface morphology of the nanoparticles. All nanoparticles were evenly dispersed onto a silicon wafer. Prior to analysis, a thin gold film was deposited in a vacuum. The sample was then observed at an accelerating voltage of 20 kV and appropriate magnification to obtain clear, regular particle images. TEM images were obtained using Lorentz transmission electron microscopy. An appropriate amount of nanoparticle powder sample was evenly spread onto a conductive copper grid for TEM scanning.

[0035] like Figure 2 As shown in Figure 2, SEM morphological characterization shows that MIL-101(Fe)-NH2 has a complete regular octahedral configuration and a particle size of approximately 515 nm. After surface functionalization modification of MIL-101(Fe)-NH2@AE@FA-PEG-CD, SEM showed that FA-PEG-CD had successfully encapsulated MIL-101(Fe)-NH2, and the edges and corners were no longer distinct after encapsulation. Figure 3 As shown, the TEM image also shows similar morphology and size to the SEM image, and the translucent shell of the composite nanocarrier can be clearly seen.

[0036] Combined with the XRD diffraction pattern, such as Figure 4As shown in the figure, the crystal form of MIL-101(Fe)-NH2 system remains intact during the surface functionalization process using FA-PEG-CD.

[0037] (2) Investigation of the in vitro drug release behavior of MIL-101(Fe)-NH2@AE@FA-PEG-CD PBS buffer was selected to simulate the normal physiological neutral environment (pH 7.4) and the weakly acidic environment of tumor cells (pH 5.4) as the release medium for AE in MIL-101(Fe)-NH2@AE@FA-PEG-CD. Experimental conditions: MIL-101(Fe)-NH2@AE@FA-PEG-CD was dissolved in 3.0 mL of water, placed in a dialysis bag (MWCO = 3500), and the dialysis bag was tied tightly. It was then suspended in a conical flask containing 30 mL of phosphate buffer solution (pH = 7.4 and 5.4). In vitro release experiments were carried out at 37°C and 43°C, respectively. At predetermined time intervals, 3.0 mL of dialysate was taken and supplemented with the same volume of fresh buffer solution to maintain a constant dialysate volume. The drug release effect under different pH environments was investigated (see Figure 5 ).

[0038] like Figure 5 As shown in (a), after 48 h of in vitro release testing, the cumulative release rates at pH = 7.4, T = 37°C and 43°C were all less than 20%; while the cumulative release rates at pH = 5.4, T = 37°C and 43°C were 64.4% and 78.3%, respectively. This indicates that the surface-targeted nano-"valve" of MIL-101(Fe)-NH2@AE@FA-PEG-CD modified with FA-PEG-CD inhibited drug leakage, thus exhibiting good pH and temperature synergistic responsive release characteristics. like Figure 5 As shown in Figure b, SEM morphology reveals that upon release at pH 5.4 and T 43°C, MIL-101(Fe)-NH2@AE@FA-PEG-CD collapses and degrades, but aggregation persists after disaggregation, likely due to the influence of the long PEG chains. Release experiments demonstrate that MIL-101(Fe)-NH2@AE@FA-PEG-CD exhibits excellent pH / temperature synergistic stimuli-responsiveness, reducing drug release in simulated normal physiological environments and enabling sustained release in a simulated tumor microenvironment.

[0039] (3) Investigating the in vitro effectiveness of MIL-101(Fe)-NH2@AE@FA-PEG-CD The CCK8 assay was used to detect the in vitro cell activity of MIL-101(Fe)-NH2@AE@FA-PEG-CD against three tumor cell lines (HepG2, A549, and MCF-7) and normal cells BEAS-2B.

[0040] Each cell type was divided into three groups: AE, MIL-101(Fe)-NH2@FA-PEG-CD, and MIL-101(Fe)-NH2@AE@FA-PEG-CD. Experimental Procedure: A549, MCF-7, and HepG2 tumor cells, as well as BEAS-2B normal cells, in logarithmic growth phase were seeded at a density of 6×103 cells per well in 96-well plates and incubated in a 37°C incubator with 5% CO2 for 24 hours. Subsequently, 100 μL / well of AE, MIL-101(Fe)-NH2@FA-PEG-CD, and MIL-101(Fe)-NH2@AE@FA-PEG-CD at different concentrations (0, 10, 20, 50, 80, and 100 μg / mL) was added for 48 hours. Complete medium without any drug was used as the control group. After the cells were cultured, the culture medium was removed and the cells were washed three times with PBS. 150 μL / well of culture medium containing 10% CCK-8 was added and the cells were incubated for another 2 h in a 37°C incubator containing 5% CO2.

[0041] like Figure 6 As shown, MIL-101(Fe)-NH2@AE@FA-PEG-CD exhibited inhibitory effects on HepG2, A549, and MCF-7 tumor cells, with a particularly high inhibition rate of ~70% against A549 cells. Furthermore, compared to free AE, MIL-101(Fe)-NH2@AE@FA-PEG-CD significantly reduced its cytotoxicity against normal BEAS-2B cells, achieving a survival rate of up to 80%, demonstrating the significant inhibitory effect of MIL-101(Fe)-NH2@FA-PEG-CD on tumor cells and its excellent biocompatibility.

[0042] Finally, it should be noted that the above description is only a preferred embodiment of the present invention. Under the guidance of the present invention, those skilled in the art can make various similar expressions without violating the purpose and claims of the present invention. Such changes fall within the scope of protection of the present invention.

Claims

1. A ternary supramolecular assembly with coordinated response to pH and temperature, characterized in that: Including core and shell; The core is formed by loading aloe-emodin on MOF; The shell is self-assembled by FA-PEG-CD on the core.

2. The ternary supramolecular assembly according to claim 1, characterized in that The particle size of the ternary supramolecular assembly is 400-600 nm, the pH response range is 5-6, and the temperature response range is 40-45°C.

3. The ternary supramolecular assembly according to claim 1, characterized in that The MOF is prepared by the following method: dissolving ferric chloride hexahydrate and 2-aminoterephthalic acid in N,N-dimethylformamide, then adding glacial acetic acid, reacting at 110-130°C for 10-15 hours, collecting the precipitate by centrifugation, washing, and vacuum drying to obtain the MIL-101(Fe)-NH2 nanocarrier.

4. The ternary supramolecular assembly according to claim 1, characterized in that The FA-PEG-CD is prepared by the following method: folic acid, 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate and N,N-diisopropylethylamine are added to a dimethyl sulfoxide solution of hydroxypolyethylene glycol amino, reacted at room temperature for 20-50 minutes, filtered to collect the precipitate, washed, and vacuum dried to obtain HO-PEG 2K -FA; change HO-PEG 2K -FA chloroform solution, add succinic anhydride and 4-dimethylaminopyridine to dissolve, react at 50-70 ° C for 3-8 hours, collect the precipitate, vacuum dry, and activate to obtain.

5. The method for preparing the ternary supramolecular assembly according to claim 1, wherein: Aloe-emodin and MOF in a mass ratio of 1:1 were added to an alcohol solvent, stirred in the dark for 10-15 hours at room temperature, and the supernatant was centrifuged and filtered to obtain the core. The core was added to a FA-PEG-CD solution, stirred in the dark for 1-5 hours, and the precipitate was collected by centrifugation, washed, and vacuum-dried to obtain the ternary supramolecular assembly MIL-101(Fe)-NH2@AE@FA-PEG-CD.

6. The preparation method according to claim 5, characterized in that The aloe-emodin loading rate of the core is 30-40%, and / or the encapsulation rate of the core is 50-60%.

7. The preparation method according to claim 5, characterized in that The MOF is prepared by the following method: dissolving ferric chloride hexahydrate and 2-aminoterephthalic acid in N,N-dimethylformamide, then adding glacial acetic acid, reacting at 110-130°C for 10-15 hours, collecting the precipitate by centrifugation, washing, and vacuum drying to obtain the MIL-101(Fe)-NH2 nanocarrier.

8. The preparation method according to claim 5, characterized in that The FA-PEG-CD is prepared by the following method: folic acid, 1H-benzotriazole-1-yloxytripyrrolidino hexafluorophosphate and N,N-diisopropylethylamine are added to a dimethyl sulfoxide solution of hydroxypolyethylene glycol amino, reacted at room temperature for 20-50 minutes, filtered to collect the precipitate, washed, and vacuum dried to obtain HO-PEG 2K -FA; change HO-PEG 2K Add succinic anhydride and 4-dimethylaminopyridine to the chloroform solution of -FA and dissolve it. React at 50-70℃ for 3-8 hours. Collect the precipitate, dry it in vacuum and activate it to obtain the product.

9. Use of the ternary supramolecular assembly according to any one of claims 1 to 4 or the ternary supramolecular assembly prepared by the preparation method according to any one of claims 5 to 8 in the preparation of tumor drugs.

10. The use according to claim 9, characterized in that The tumor is one or more of leukemia, liver cancer, colon cancer, lung cancer, breast cancer, stomach cancer, ovarian cancer, cervical cancer, kidney cancer, and prostate cancer.

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