Magnetic heteropolyacid core-shell composite material for slowly releasing and delivering lycorine and methotrexate as well as preparation method and application of magnetic heteropolyacid core-shell composite material

Abstract

The invention belongs to the technical field of nano materials, biological medicine and material chemistry, and discloses a magnetic heteropolyacid core-shell composite material for slowly releasing and delivering lycorine and methotrexate, a preparation method and application, and the composite material sequentially comprises gamma-Fe2O3, a SiO2 layer, SiO2-NH2, phosphotungstic acid, MOFs and 4-aminopyridine and folic acid molecules. The composite material integrates the advantages of all the components, has magnetic responsiveness, adjustable porosity and good biocompatibility, and provides a novel material platform for a multifunctional drug delivery system, for example, the composite material can be applied to anti-cancer drug delivery. The technical problems of poor biocompatibility, difficulty in functional group modification, limited slow release effect and the like of the existing metal organic framework material (MOFs) in a drug delivery system are solved.

Description

Technical Field

[0001] This invention belongs to the fields of nanomaterials, biomedicine and materials chemistry, and in particular to a magnetic heteropolyacid core-shell composite material for sustained delivery of lycorine and methotrexate, its preparation method and application. Background Technology

[0002] Magnetic nanoparticles (MNPs) have gained widespread attention in recent years in various technological fields, including biomedicine, environmental remediation, and information storage, due to their excellent magnetic response properties, nanoscale effects, and large specific surface area. In biomedicine, MNPs have been used to construct targeted drug delivery systems. By applying an external magnetic field, drugs can be directed into the body, effectively improving treatment efficiency and reducing toxic side effects on normal tissues. Furthermore, MNPs can also serve as contrast agents in magnetic resonance imaging (MRI), helping to improve the clarity of imaging and diagnostic accuracy of lesions.

[0003] Metal-organic frameworks (MOFs) are a class of porous crystalline materials constructed from metal ions or metal clusters and organic ligands through coordination. MOFs possess high specific surface area, structural diversity, and functional tunability, exhibiting excellent performance in fields such as gas storage and separation, catalysis, battery energy storage, biosensing, and drug delivery. However, traditionally synthesized MOF materials generally suffer from poor biocompatibility and a lack of modifiable functional groups, limiting their widespread application in the biomedical field.

[0004] To overcome the aforementioned problems, post-synthetic modification (PSM) technology has gradually become a research hotspot. This technology, through chemical modification of metal nodes or organic linkers in the MOF framework, can introduce additional functional groups while maintaining the integrity of its crystal structure, thereby significantly improving its functionalization level and application expansion capabilities.

[0005] Polyoxometalates (POMs) are a class of highly charged anionic clusters composed of multiple transition metal oxides. They possess excellent redox properties and acid catalytic properties, and can specifically interact with biomolecules such as proteins, DNA, and RNA. They have been proven to have good antibacterial, antiviral, and antitumor activities.

[0006] In recent years, researchers have attempted to combine magnetic nanoparticles, polyoxometalates, and MOFs to construct multifunctional integrated core-shell composite materials. These structures not only effectively combine the functional properties of each component but also significantly improve drug loading efficiency, sustained-release performance, and targeting capability through synergistic effects, making them one of the important development directions for the construction of targeted drug delivery systems.

[0007] While existing microbial synthesis techniques can prepare nanomaterials under certain conditions, they still have the following shortcomings: 1. Low yield and efficiency: The synthesis process is constrained by the growth rate of the cells, the activity of metabolic pathways and environmental conditions, resulting in insufficient yield of the target product, which is difficult to meet the needs of large-scale application.

[0008] 2. Poor purity and consistency: Due to the complex metabolic pathways of microorganisms, a variety of byproducts are often generated, resulting in significant deficiencies in the target material in terms of particle size distribution, morphology control and structural consistency, which is not conducive to high-end applications.

[0009] 3. Limited Functional Modification: Traditional microbial synthesis methods are difficult to achieve targeted functionalization of the surface or internal structure of materials, especially when multi-component synergy or specific functional group modification is required, and the means of control are limited.

[0010] The aforementioned limitations restrict the application of microbial synthesis methods in high-end biomedical fields such as drug delivery systems. Therefore, a new technical solution is urgently needed that can overcome the limitations in yield and purity while achieving multifunctional and controllable modification.

[0011] The technical approach provided by this invention is to construct a multifunctional core-shell structure material by combining magnetic nanoparticles (MNPs), metal-organic frameworks (MOFs), and polyoxometalates (POMs). This structure utilizes the magnetic responsiveness of MNPs to achieve targeted drug delivery, while leveraging the high specific surface area and modifiability of MOFs to enhance drug loading and sustained-release performance. Simultaneously, the introduction of POMs endows the system with additional bioactivity and redox functions. This multi-component synergistic effect effectively overcomes the shortcomings of existing microbial synthesis methods, providing a new technical pathway for targeted drug delivery systems. Summary of the Invention

[0012] The purpose of this invention is to overcome the shortcomings of the prior art and provide a magnetic heteropolyacid core-shell composite material for the sustained delivery of lycorine and methotrexate, its preparation method, and its application.

[0013] The technical solution adopted by this invention to solve its technical problem is: A magnetic heteropolyacid core-shell composite material for sustained-release delivery of lycorine and methotrexate, the composite material comprising, in sequence: γ-Fe2O3 magnetic core; A SiO2 layer covering the surface of the magnetic core; An aminopropyl functional layer (SiO2-NH2) grafted onto the surface of SiO2. Phosphotungstic acid (PTA) loaded onto the surface of aminated microspheres. Metal-organic framework materials (MOFs) coated on the outer layer, wherein the MOFs are selected from UiO-66-NH2, ZIF-8 or ZIF-67; The MOFs are loaded with anticancer drugs, namely lycorine or methotrexate (MTX). The surface of the composite material is further grafted with 4-aminopyridine and folic acid molecules for targeted functional modification.

[0014] Furthermore, the SiO2 is a dense amorphous silicon dioxide layer formed by coating tetraethyl orthosilicate (TEOS) using a sol-gel method.

[0015] Furthermore, the phosphotungstic acid has a Keggin structure, with its main XRD diffraction peaks located at 8.8°, 18.0°, and 25.4°.

[0016] Furthermore, the metal-organic framework material UiO-66-NH2 has a face-centered cubic structure, and its characteristic XRD peaks include 7.4°, 12.0°, 14.2°, 17.0°, 25.5° and 30.5°.

[0017] Furthermore, the drug has a drug loading of 10–30 wt% and exhibits good in vitro sustained-release properties, with a sustained-release rate of over 60% within 24 hours.

[0018] Furthermore, the composite material is formed by sequentially coating silicon dioxide (SiO2), an aminopropyl modification layer (NH2), and phosphotungstic acid (PTA) with γ-Fe2O3 as the magnetic core to form a γ-Fe2O3@SiO2-NH2@PTA composite core; Metal-organic frameworks (such as UiO-66-NH2, ZIF-8, and ZIF-67) were coated onto the surface of the core layer using an in-situ growth method to construct a core-shell composite material. During the synthesis process, antitumor drugs (such as methotrexate MTX or lycorine Ly) are incorporated into the MOF backbone to achieve efficient loading. The composite material was post-modified by introducing amino groups with 4-aminopyridine (4Py) and linking folic acid (FA) through an EDC / NHS activation reaction to enhance its ability to target and recognize cancer cells.

[0019] The method for preparing the composite material as described above includes the following steps: (1) Synthesis of γ-Fe2O3 magnetic nanoparticles; (2) SiO2 is coated on the surface of γ-Fe2O3 to form γ-Fe2O3@SiO2; (3) Grafting aminopropyl groups onto γ-aminopropyl silane KH550 to form γ-Fe2O3@SiO2-NH2; (4) Phosptonic acid is fixed by electrostatic adsorption to form γ-Fe2O3@SiO2-NH2@PTA; (5) Coating the surface of the drug-containing MOF crystals to obtain γ-Fe2O3@SiO2-NH2@PTA / drug / MOF composite material; (6) Targeted modification is achieved by further grafting 4-aminopyridine and folic acid onto the surface.

[0020] Furthermore, the synthesis of the MOFs adopts a one-pot cooking method, with the reaction temperature controlled at 90–120°C and the reaction time at 12–24 h.

[0021] Furthermore, the drug is lycorine or methotrexate, and the drug addition step involves mixing it with metal ions and ligands before MOF synthesis, using a one-pot cooking method to achieve drug intercalation.

[0022] The composite material described above is used in the preparation of antitumor drug delivery systems. This material possesses magnetic responsiveness, targeting properties, and sustained-release capabilities, making it suitable for targeted tumor therapy.

[0023] The advantages and positive effects of this invention are as follows: 1. This invention constructs a core-shell composite system with a clear structure and distinct layers by organically combining magnetic nanoparticles, polyoxometalates, and metal-organic frameworks (MOFs). This composite material integrates the advantages of each component, possessing magnetic responsiveness, tunable porosity, and good biocompatibility, providing a novel material platform for multifunctional drug delivery systems, such as those for anticancer drug delivery. It solves the technical problems of poor biocompatibility, difficulty in functional group modification, and limited sustained-release effect of existing metal-organic frameworks (MOFs) in drug delivery systems.

[0024] 2. The "one-pot" synthesis strategy adopted in this invention avoids cumbersome multi-step modification operations, with a simple process, mild conditions, and easy scale-up, which significantly improves the controllability and reproducibility of the material and is conducive to large-scale preparation and application in the later stage.

[0025] 3. The material of this invention achieves highly efficient loading of two typical antitumor drugs (lycorine (Ly) and methotrexate (MTX)). In vitro experiments show that the composite material of this invention maintains stable drug release within 168 hours: lycorine (Ly): only 35% cumulative release at 48 hours, reaching 82% at 144 hours; methotrexate (MTX): 38% release at 48 hours, reaching 85% at 144 hours. In contrast, the ZIF-8 material releases over 80% within 24 hours, making it difficult to maintain a sustained-release effect. Therefore, the material of this invention can significantly prolong the drug's duration of action and reduce the frequency of medication.

[0026] 4. The composite material prepared by this invention has been systematically characterized by various methods such as XRD, XPS, and FTIR, showing that the material has a complete structure, clear composition, and successful modification. Various particle sizes, surface properties, and release behaviors have been experimentally verified, demonstrating good stability and reliability.

[0027] 5. CCK-8 activity assays of this invention show that, within the effective dosage range, the material maintains a survival rate of over 85% for normal Vero cells, while the survival rate for HepG2 liver cancer cells decreases to 42%. Further folic acid modification increases the uptake rate in HepG2 cells by approximately 1.8 times, demonstrating good biocompatibility. This composite material is not only suitable for the delivery of antitumor drugs but can also be extended to the targeted delivery of other bioactive molecules, showing broad prospects for cross-application in medicine and materials science.

[0028] 6. The composite material of this invention uses γ-Fe₂O₃ as a magnetic core, sequentially coated with SiO₂, aminopropyl (NH₂), and phosphotungstic acid (PTA) to form a composite core structure. Subsequently, metal-organic framework materials (UiO-66-NH₂, ZIF-8, or ZIF-67) are grown on its surface via in-situ synthesis. During the synthesis process, the antitumor drugs lycorine (Ly) or methotrexate (MTX) are doped to achieve efficient drug loading. After modification with 4-aminopyridine and folic acid, the material exhibits good targeting and biocompatibility. The resulting composite material has a stable structure and controllable sustained-release properties. In vitro drug release and cytotoxicity tests indicate its potential application value in tumor treatment. Attached Figure Description

[0029] Figure 1 This is a schematic diagram illustrating the synthesis of γ-Fe2O3@SiO2-NH2@PTA in this invention; Figure 2 This is the XPS analysis spectrum used in this invention; Figure 3These are the XPS high-resolution C1s spectra used in this invention; wherein, (a) is the high-resolution C1s spectrum of γ-Fe2O3@SiO2-NH2, (b) is the high-resolution C1s spectrum of γ-Fe2O3@SiO2-NH2@PTA, (c) is the high-resolution C1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / ZIF-8, (d) is the high-resolution C1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / ZIF-67, and (e) is the high-resolution C1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / ZIF-67. High-resolution C1s spectra of γ-Fe2O3@SiO2-NH2@PTA / UiO66-NH2, (f) is the high-resolution C1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / ZIF-8-4Py-FA, (g) is the high-resolution C1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / ZIF-67-4Py-FA, and (h) is the high-resolution C1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / UiO66-NH2-FA; Figure 4 These are the XPS high-resolution N1s spectra in this invention; wherein, (a) is the high-resolution N1s spectrum of γ-Fe2O3@SiO2-NH2, (b) is the high-resolution N1s spectrum of γ-Fe2O3@SiO2-NH2@PTA, (c) is the high-resolution N1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / ZIF-8, (d) is the high-resolution N1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / ZIF-67, and (e) is the high-resolution N1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / ZIF-67. High-resolution N1s spectra of γ-Fe2O3@SiO2-NH2@PTA / UiO66-NH2, (f) is the high-resolution N1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / ZIF-8-4Py-FA, (g) is the high-resolution N1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / ZIF-67-4Py-FA, and (h) is the high-resolution N1s spectrum of γ-Fe2O3@SiO2-NH2@PTA / UiO66-NH2-FA; Figure 5 This is a scatter plot of the release data of lycorine and methotrexate in this invention; Figure 6 This is a line graph showing the release data of lycorine and methotrexate in this invention; Figure 7 The image shows the XRD (X-ray diffraction) pattern of the composite material in this invention. Figure 8 This is the FTIR (Fourier Transform Infrared) spectrum used in this invention; Figure 9This is a graph showing the viability of Vero cells after treatment with γ-Fe2O3@SiO2-NH2@PTA / Lycorine / UiO-66-NH2 for 24 h, 48 h, and 72 h, as described in this invention. Figure 10 This is a graph showing the viability of HepG2 cells after treatment with γ-Fe2O3@SiO2-NH2@PTA / Lycorine / UiO-66-NH2 for 24 h, 48 h, and 72 h, as described in this invention. Figure 11 This is a graph showing the viability of Vero cells after treatment with γ-Fe2O3@SiO2-NH2@PTA / Lycorine / UiO-66-NH2-FA for 24 h, 48 h, and 72 h, as described in this invention. Figure 12 This is a graph showing the viability of HepG2 cells after treatment with γ-Fe2O3@SiO2-NH2@PTA / Lycorine / UiO-66-NH2-FA for 24 h, 48 h, and 72 h, as described in this invention. Figure 13 This is a graph showing the viability of Vero cells after treatment with γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO-66-NH2 for 24 h, 48 h, and 72 h, as described in this invention. Figure 14 This is a graph showing the viability of HepG2 cells after treatment with γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO-66-NH2 for 24 h, 48 h, and 72 h, as described in this invention. Figure 15 This is a graph showing the viability of Vero cells after treatment with γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO-66-NH2-FA for 24 h, 48 h, and 72 h, as described in this invention. Figure 16 This is a viability graph of HepG2 cells after treatment with γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO-66-NH2-FA for 24 h, 48 h, and 72 h, as described in this invention. Detailed Implementation

[0030] The present invention will be further described below with reference to the embodiments. The following embodiments are descriptive and not limiting, and should not be used to limit the scope of protection of the present invention.

[0031] The various experimental operations involved in the specific embodiments are all conventional techniques in the field. For parts not specifically annotated in this document, those skilled in the art can refer to various commonly used reference books, scientific and technological documents or related instructions and manuals prior to the filing date of this invention to carry out the operations.

[0032] A magnetic heteropolyacid core-shell composite material for sustained-release delivery of lycorine and methotrexate, the composite material comprising, in sequence: γ-Fe2O3 magnetic core; A SiO2 layer covering the surface of the magnetic core; An aminopropyl functional layer (SiO2-NH2) grafted onto the surface of SiO2. Phosphotungstic acid (PTA) loaded onto the surface of aminated microspheres. Metal-organic framework materials (MOFs) coated on the outer layer, wherein the MOFs are selected from UiO-66-NH2, ZIF-8 or ZIF-67; The MOFs are loaded with anticancer drugs, namely lycorine or methotrexate (MTX). The surface of the composite material is further grafted with 4-aminopyridine and folic acid molecules for targeted functional modification.

[0033] Preferably, the SiO2 is a dense amorphous silicon dioxide layer formed by coating tetraethyl orthosilicate (TEOS) using a sol-gel method.

[0034] Preferably, the phosphotungstic acid has a Keggin structure, with its main XRD diffraction peaks located at 8.8°, 18.0°, and 25.4°.

[0035] Preferably, the metal-organic framework material UiO-66-NH2 has a face-centered cubic structure, and its characteristic XRD peaks include 7.4°, 12.0°, 14.2°, 17.0°, 25.5° and 30.5°.

[0036] Preferably, the drug has a drug loading of 10-30 wt% and good in vitro sustained-release properties, with a sustained-release rate of over 60% within 24 hours.

[0037] Preferably, the composite material is formed by sequentially coating silicon dioxide (SiO2), an aminopropyl modification layer (NH2), and phosphotungstic acid (PTA) with γ-Fe2O3 as the magnetic core to form a γ-Fe2O3@SiO2-NH2@PTA composite core; Metal-organic frameworks (such as UiO-66-NH2, ZIF-8, and ZIF-67) were coated onto the surface of the core layer using an in-situ growth method to construct a core-shell composite material. During the synthesis process, antitumor drugs (such as methotrexate MTX or lycorine Ly) are incorporated into the MOF backbone to achieve efficient loading. The composite material was post-modified by introducing amino groups with 4-aminopyridine (4Py) and linking folic acid (FA) through an EDC / NHS activation reaction to enhance its ability to target and recognize cancer cells.

[0038] The method for preparing the composite material as described above includes the following steps: (1) Synthesis of γ-Fe2O3 magnetic nanoparticles; (2) SiO2 is coated on the surface of γ-Fe2O3 to form γ-Fe2O3@SiO2; (3) Grafting aminopropyl groups onto γ-aminopropyl silane KH550 to form γ-Fe2O3@SiO2-NH2; (4) Phosptonic acid is fixed by electrostatic adsorption to form γ-Fe2O3@SiO2-NH2@PTA; (5) Coating the surface of the drug-containing MOF crystals to obtain γ-Fe2O3@SiO2-NH2@PTA / drug / MOF composite material; (6) Targeted modification is achieved by further grafting 4-aminopyridine and folic acid onto the surface.

[0039] Preferably, the synthesis of the MOFs is carried out by a one-pot cooking method, with the reaction temperature controlled at 90–120 °C and the reaction time at 12–24 h.

[0040] Preferably, the drug is lycorine or methotrexate, and the drug addition step involves mixing it with metal ions and ligands before MOF synthesis, using a one-pot cooking method to achieve drug intercalation.

[0041] The composite material described above is used in the preparation of antitumor drug delivery systems. This material possesses magnetic responsiveness, targeting properties, and sustained-release capabilities, making it suitable for targeted tumor therapy.

[0042] Specifically, the relevant preparation and testing methods are as follows: This invention provides a method for preparing a magnetic heteropolyacid core-shell composite material for sustained-release delivery of lycorine and methotrexate, and studies its drug loading performance. Figure 1 As shown, it includes the following steps: 1 Method 1.1 Preparation of γ-Fe2O3@SiO2-NH2 Accurately weigh 30 mg of nano-magnetic iron oxide (γ-Fe₂O₃), acidify with 0.1 M HCl, sonicate for 20 min, magnetically adsorb, remove the supernatant with a dropper, wash twice with deionized water, resuspend in 20 mL ethanol and 5 mL water, add 750 μL concentrated ammonia, sonicate for 20 min, add 96 μL of TEOS (tetraethoxysilane), place on a shaker for 6 h, magnetically adsorb, remove the supernatant with a dropper, wash twice with ethanol, resuspend in 4 mL ethanol, add 150 μL of APTMS (3-aminopropyltrimethoxysilane), let stand for 24 h, magnetically adsorb, remove the supernatant with a dropper, wash twice with ethanol, to obtain γ-Fe₂O₃@SiO₂-NH₂. Room temperature sonication and magnetic adsorption have no special requirements.

[0043] 1.2 Preparation of γ-Fe2O3@SiO2-NH2@PTA Accurately weigh 2.0 g of phosphotungstic acid (PTA) and dissolve it in 5 μL of distilled water in a 100 μL beaker. Under vigorous mechanical stirring, add 0.2 g of γ-Fe₂O₃@SiO₂-NH₂, followed by 10 μL of ethanol. Continue stirring until a homogeneous dispersion is formed. Next, slowly add 5 μL of 1 mol / L hydrochloric acid to acidify the system, and then allow static adsorption for 5 h under continuous stirring until a transparent sol is formed. Transfer the resulting sol to an oven and dry at 80 °C for 10 h. After cooling, grind the dried product into a fine powder to obtain the target supported phosphotungstic acid catalyst, denoted as γ-Fe₂O₃@SiO₂-NH₂@PTA.

[0044] 1.3 Preparation of γ-Fe2O3@SiO2-NH2@PTA / UiO66-NH2 Accurately weigh 1.07 g of zirconium tetrachloride (ZrCl4), 0.98 g of diamine terephthalate (BDC-NH2), and 0.2 g of γ-Fe2O3@SiO2-NH2@PTA, and transfer them to a three-necked flask. Then, add 67 mL of N,N-dimethylformamide (DMF), 29 mL of acetic acid, and 5 mL of deionized water to the flask. Heat the reaction mixture to 120 °C with continuous stirring and maintain this temperature for 1 h. After the reaction is complete, wash the resulting product twice with DMF, and then twice with ethanol. After each wash, centrifuge at 3000 rpm for 5 min to ensure complete phase separation. Finally, transfer the solid to a vacuum drying oven and dry at 60 °C for 12 h to obtain the target composite material, denoted as γ-Fe2O3@SiO2-NH2@PTA / UiO66-NH2.

[0045] 1.4 Preparation of γ-Fe2O3@SiO2-NH2@PTA / ZIF-8 2.9756 g of zinc nitrate hexahydrate (Zn(NO3)2·6H2O) was accurately weighed and dissolved in 100 mL of methanol under stirring to prepare solution A. Separately, 3.286 g of 2-methylimidazole (2-MeIm) and 0.2 g of γ-Fe2O3@SiO2-NH2@PTA were accurately weighed and dissolved in another 100 mL of methanol under stirring to prepare solution B. Solution A was then slowly added dropwise to solution B, and the reaction was carried out under continuous mechanical stirring for 2 h to ensure complete reaction. After the reaction was completed, the mixture was centrifuged at 5000 rpm for 7 min. The resulting precipitate was washed twice each with methanol and ethanol, and then dried at 70 °C for 24 h to obtain the target composite material γ-Fe2O3@SiO2-NH2@PTA / ZIF-8.

[0046] 1.5 Preparation of γ-Fe2O3@SiO2-NH2@PTA / ZIF-67 Accurately weigh 2.9105 g of cobalt nitrate hexahydrate (Co(NO3)2·6H2O), dissolve it in 100 mL of methanol, and stir continuously to prepare solution A. Separately, weigh 3.286 g of 2-methylimidazole (2-MeIm) and 0.2 g of γ-Fe2O3@SiO2-NH2@PTA, dissolve them in another 100 mL of methanol, and stir until homogeneous to obtain solution B. Then, add solution A dropwise to solution B, stirring continuously with mechanical stirring. The reaction mixture is then stirred for another 2 h to ensure complete reaction. After the reaction is complete, centrifuge at 5000 rpm for 7 min. The resulting precipitate is washed twice each with methanol and ethanol, and then dried at 70 °C for 24 h to obtain the target composite material γ-Fe2O3@SiO2-NH2@PTA / ZIF-67.

[0047] 1.6 Drug Loading In this invention, two representative anticancer drugs, methotrexate (MTX) and lycorine (Ly), were selected and introduced into the γ-Fe2O3@SiO2-NH2@PTA / MOFs system. Specifically, 0.1 g of methotrexate or 0.01 g of lycorine was added during the synthesis of γ-Fe2O3@SiO2-NH2@PTA / MOFs. Taking γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO66-NH2 as an example, the specific preparation steps are as follows: accurately weigh 1.07 g of zirconium tetrachloride (ZrCl4), 0.98 g of diamine terephthalate (BDC-NH2), 0.2 g of γ-Fe2O3@SiO2-NH2@PTA, and 0.1 g of methotrexate (MTX), and transfer them to a three-necked flask. Subsequently, 67 mL of N,N-dimethylformamide (DMF), 29 mL of acetic acid, and 5 mL of deionized water were added to the flask. The reaction mixture was heated to 120 °C with continuous stirring and maintained at this temperature for 1 h. After the reaction was complete, the product was washed twice with DMF and then twice with ethanol. After each wash, centrifugation (3000 rpm, 5 min) was performed to ensure complete phase separation. Finally, the solid was transferred to a vacuum drying oven and dried at 60 °C for 12 h to obtain the target composite material, denoted as γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO66-NH2.

[0048] Similarly, other drug-loaded composite materials γ-Fe2O3@SiO2-NH2@PTA / MTX / MOFs and γ-Fe2O3@SiO2-NH2@PTA / Ly / MOFs can be obtained.

[0049] 1.7 Modification of Nanoparticles Accurately weigh 0.05 g of 4-aminopyridine and 0.5 g of γ-Fe₂O₃@SiO₂-NH₂@PTA / ZIF-8 or γ-Fe₂O₃@SiO₂-NH₂@PTA / ZIF-67 and transfer them to a 250 mL three-necked flask. Then, add 30 mL of dichloromethane as the reaction solvent. Due to the high volatility of dichloromethane, the solvent needs to be continuously replenished during the reaction to maintain a constant volume. The mixture was then refluxed at 45 °C for 12 h. After the reaction was complete, the solid product was separated by low-speed centrifugation (3000 rpm, 5 min), and the supernatant was discarded. The obtained solid was washed twice with ethanol to remove unreacted residues and then dried at 60 °C for 12 h. Finally, the surface-functionalized intermediates γ-Fe₂O₃@SiO₂-NH₂@PTA / ZIF-8-4Py and γ-Fe₂O₃@SiO₂-NH₂@PTA / ZIF-67-4Py were successfully obtained. After this improvement, the drug-loaded composite materials γ-Fe2O3@SiO2-NH2@PTA / MTX / ZIF-8, γ-Fe2O3@SiO2-NH2@PTA / MTX / ZIF-67, γ-Fe2O3@SiO2-NH2@PTA / Ly / ZIF-8, and γ-Fe2O3@SiO2-NH2@PTA / Ly / ZIF-67 were modified by amination using the same method. Taking γ-Fe2O3@SiO2-NH2@PTA / MTX / ZIF-8 as an example, the specific preparation steps are as follows: Accurately weigh 0.05 g of 4-aminopyridine and 0.5 g of γ-Fe2O3@SiO2-NH2@PTA / MTX / ZIF-8, and transfer them to a 250 mL three-necked flask. Then, add 30 mL of dichloromethane as the reaction solvent. Due to the high volatility of dichloromethane, the solvent needs to be continuously replenished during the reaction to maintain a constant volume. The mixture was then refluxed at 45 °C for 12 h. After the reaction was complete, the solid product was separated by low-speed centrifugation (3000 rpm, 5 min), and the supernatant was discarded. The obtained solid was washed twice with ethanol to remove unreacted residues, and then dried at 60 °C for 12 h. The surface-functionalized intermediate γ-Fe₂O₃@SiO₂-NH₂@PTA / ZIF-8-4Py was successfully obtained. Similarly, γ-Fe₂O₃@SiO₂-NH₂@PTA / ZIF-67-4Py could be obtained.

[0050] 1.8 Folic acid-based functionalization modification Accurately weigh 80 mg of folic acid (FA) and dissolve it in 20 mL of dimethyl sulfoxide (DMSO). After complete dissolution, add 40 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and sonicate for 5 min. Then add 24 mg of N-hydroxysuccinimide (NHS) and sonicate for another 5 min. Incubate the reaction solution at 37 ℃ and 140 rpm for 24 h with shaking to activate the carboxyl group of folic acid, obtaining an activated FA solution. In a separate step, 20 mg of γ-Fe₂O₃@SiO₂-NH₂@PTA / MOFs-4Py (specifically referring to γ-Fe₂O₃@SiO₂-NH₂@PTA / ZIF-8-4Py and γ-Fe₂O₃@SiO₂-NH₂@PTA / ZIF-67-4Py; MOFs stands for Metal-Organic Framework) or γ-Fe₂O₃@SiO₂-NH₂@PTA / MOFs-NH₂ (specifically referring to γ-Fe₂O₃@SiO₂-NH₂@PTA / UiO₆₆-NH₂) was dispersed in 20 mg of 60% ethanol in a 50 mL centrifuge tube to form a homogeneous suspension. After dispersion, 4 mL of activated FA solution was added, and the reaction mixture was reacted with gentle stirring at room temperature for 24 h. After the reaction was complete, magnetic separation was performed to remove the supernatant. The obtained solid product was washed twice with anhydrous ethanol to remove unreacted residues, and then vacuum dried at 80°C for 24 h. FA-functionalized composite materials γ-Fe2O3@SiO2-NH2@PTA / MOFs-4Py-FA and γ-Fe2O3@SiO2-NH2@PTA / MOFs-NH2-FA were successfully obtained. The drug-loaded composite materials were synthesized using the same procedure. Taking γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO66-NH2 as an example, the specific preparation steps were as follows: 20 mg of γ-Fe2O3@SiO2-NH2@PTA / UiO66-NH2 was dispersed in 20 mg of 60% ethanol in a 50 mL centrifuge tube to form a homogeneous suspension. After dispersion, 4 mL of activated FA solution was added, and the reaction mixture was reacted with gentle stirring at room temperature for 24 h. After the reaction was complete, magnetic separation was performed to remove the supernatant. The resulting solid product was washed twice with anhydrous ethanol to remove unreacted residues, and then vacuum dried at 80°C for 24 h. Finally, the FA-functionalized composite material γ-Fe2O3@SiO2-NH2@PTA / UiO66-NH2-FA was successfully obtained.

[0051] 1.9 In vitro drug release study Accurately weigh 20 mg of γ-Fe₂O₃@SiO₂-NH₂@PTA / MTX / MOFs and γ-Fe₂O₃@SiO₂-NH₂@PTA / Ly / MOFs into two 10 mL centrifuge tubes, respectively. Add 8 mL of PBS buffer (pH 7.4) to each centrifuge tube. Place the centrifuge tubes in a thermostatic shaker set to 37°C and 140 rpm for drug release studies. At predetermined time intervals (1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 h), collect 2 mL of supernatant and immediately replenish with an equal volume of fresh PBS buffer to maintain a constant total system volume throughout the experiment. After sampling, remove the supernatant by magnetic separation, and vacuum dry the remaining material overnight for subsequent analysis.

[0052] 1.10 Research on drug release mechanisms at the cellular level The drug release profiles of the materials and their effects on cell viability were evaluated using the CCK-8 assay. (The last part, "2×10⁶", appears to be an incomplete sentence or fragment and is left untranslated.) 4 Vero and HepG2 cells were seeded into 96-well plates, and 100 μL of DMEM high-glucose complete medium (containing 10% fetal bovine serum) was added to each well. The plates were incubated in a cell culture incubator for 24 h. After removing the supernatant, a series of dilutions (0, 5, 10, 25, and 50 μg / mol) of γ-Fe2O3@SiO2-NH2@PTA / MTX / MOFs, γ-Fe2O3@SiO2-NH2@PTA / Ly / MOFs, folic acid-modified γ-Fe2O3@SiO2-NH2@PTA / MTX / MOFs-FA, and γ-Fe2O3@SiO2-NH2@PTA / Ly / MOFs-FA, as well as methotrexate and lycorine (5 μg / mol), were added to each well, and 100 μL of DMEM high-glucose complete medium (containing 10% fetal bovine serum) was added to each well. After culturing for another 24 h, the medium was replaced with 100 μL of fresh medium containing 10% CCK-8 reagent at a final concentration, and incubated for 30 min. Then, the absorbance was measured at 450 nm using a microplate reader.

[0053] 2 Results and Analysis 2.1 XPS Analysis like Figure 2 As shown, the presence of C1s, N1s, O1s, Si2p, and Fe2p peaks in the sample provides conclusive evidence for the successful synthesis of amination-modified microspheres. The appearance of the W4f peak indicates the successful synthesis of magnetically loaded heteropolyacids. Furthermore, the presence of Zn2p, Co2p, and Zr3d peaks further confirms the successful synthesis of ZIF-8, ZIF-67, and UiO-66. Figure 3The XPS spectrum of C1s shows characteristic peaks at approximately 284.6 eV (CC / CH), 285.6 eV (CO / CN), 288.4 eV (C=O), and 289.6 eV (-COOH). Additionally, N1s peaks appear at approximately 399.7 eV (NC) and 400.3 eV (CO-NH). Figure 4 The changes in the C1s / O1s and C1s / N1s ratios further confirm the success of folic acid modification.

[0054] 2.2 Results of in vitro drug release like Figure 5 and Figure 6 The results further confirmed that the core-shell structured materials loaded with UiO-66 and ZIF-67 have effective sustained-release capabilities for lycorine and methotrexate. In PBS at pH 7.4, γ-Fe2O3@SiO2-NH2@PTA / UiO-66-NH2 cumulatively released 35% of lycorine at 48 h, reaching 82% at 144 h, exhibiting typical sustained-release characteristics. γ-Fe2O3@SiO2-NH2@PTA / ZIF-67: the release rate was 52% at 48 h and close to 90% at 144 h, showing weaker sustained-release performance than the UiO-66-NH2 system, indicating their potential application value in subsequent cell experiments. In contrast, γ-Fe2O3@SiO2-NH2@PTA / ZIF-8: rapidly released over 80% within 24 h with almost no long-term effect, making it more suitable for the development and research of rapid-release drug delivery systems.

[0055] 2.3 XRD Analysis The γ-Fe2O3@SiO2-NH2@PTA / Lycorine / UiO-66-NH2 and γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO-66-NH2 samples exhibited significant in vitro sustained-release performance, and XRD analysis was performed on them. The corresponding XRD patterns before and after the release process are shown below. Figure 7As shown. The diffraction peaks observed in the XRD pattern of γ-Fe₂O₃@SiO₂-NH₂ are mainly attributed to the crystal structure of its γ-Fe₂O₃ core. The characteristic diffraction peaks of γ-Fe₂O₃ typically appear at 30.2°, 35.5°, 43.2°, 53.6°, 57.1°, and 62.8°. The characteristic diffraction peaks observed in the XRD analysis of phosphotungstic acid are mainly attributed to its Keggin structure. According to existing literature, the main diffraction peaks of phosphotungstic acid typically appear at approximately 8.8°, 18.0°, and 25.4°. The presence of these diffraction peaks in the XRD pattern is considered a marker of the successful synthesis of γ-Fe₂O₃@SiO₂-NH₂@PTA. The characteristic diffraction peaks observed in the XRD pattern of UiO₆₆-NH₂ are mainly attributed to its face-centered cubic (fcc) structure. Typical diffraction peaks can usually be detected at 7.4°, 12.0°, 14.2°, 17.0°, 25.5° and 30.5°. Figure 7 The presence of these peaks is considered evidence of successful UiO66 modification.

[0056] 2.4 FTIR spectral analysis Infrared spectroscopy analysis was performed on γ-Fe2O3@SiO2-NH2@PTA / UiO-66-NH2 materials with significant in vitro sustained-release properties and their folic acid-modified derivative γ-Fe2O3@SiO2-NH2@PTA / UiO-66-NH2-FA to elucidate their structural features and changes in surface functional groups, thereby confirming the successful synthesis of the target materials and laying the foundation for subsequent cell experiments.

[0057] In Fourier transform infrared (FTIR) spectroscopy analysis, the γ-Fe2O3@SiO2 core-shell structure material exhibits a series of characteristic absorption peaks. These peaks include those around 3400 cm⁻¹. -1 The OH stretching vibration peak at approximately 1630 cm⁻¹ (attributed to surface hydroxyl groups or adsorbed water) is observed. -1 The HOH bending vibration peak is located at approximately 1060-1050 cm⁻¹. -1 The Si-O-Si asymmetric stretching vibration peaks within the range (originating from the silica shell) and approximately 615 cm⁻¹ -1 The Fe-O stretching vibration peaks at the location (corresponding to the γ-Fe₂O₃ nucleus) are considered evidence of the formation of a typical core-shell structure. Figure 8 The observation of these absorption peaks further supports the successful synthesis of γ-Fe2O3@SiO2.

[0058] After amination treatment, several new characteristic absorption peaks appeared in the Fourier transform infrared (FTIR) spectrum of γ-Fe2O3@SiO2 material, indicating that the -NH2 functional group was successfully grafted onto the material surface. Specifically, in the range of 3300–3500 cm⁻¹, the characteristic absorption peaks were observed. -1 A stretching vibration peak of NH was observed in the region (partially overlapping with the OH vibration peak but more pronounced), at approximately 1600–1650 cm⁻¹. -1 NH bending vibration peaks appeared in the region, at 1000–1200 cm⁻¹. -1 A CN stretching vibration peak appeared within the range, which partially overlapped with the Si-O-Si absorption band. Furthermore, at 1033 cm⁻¹... -1 The increase in the intensity of the Si-O-Si absorption peaks further confirms the effective grafting of organosilanes. These spectral changes collectively and strongly demonstrate that the -NH2 group has been successfully introduced into the SiO2 surface.

[0059] After incorporating phosphotungstic acid (PTA) into γ-Fe₂O₃@SiO₂-NH₂ material, a series of characteristic absorption peaks were identified in its Fourier transform infrared (FTIR) spectrum. Specifically, at approximately 1080 cm⁻¹... -1 A P-Oa (terminal oxygen) stretching vibration peak was detected at approximately 800 cm⁻¹. -1 A W-Ob-W (edge ​​co-oxygen) stretching vibration peak was observed. These absorption features are attributed to the unique Keggin structure of phosphotungstic acid and are generally considered a key spectral indicator of successful immobilization. Figure 8 The presence of these characteristic peaks is considered strong evidence that phosphotungstic acid has been effectively incorporated into the material system.

[0060] After incorporating UiO-66-NH2 into the γ-Fe2O3@SiO2-NH2@PTA composite material, several new absorption bands were observed in Fourier transform infrared (FTIR) spectroscopy. Notably, characteristic stretching vibrations associated with the amino-functionalized terephthalic acid (BDC-NH2) linker were discovered, including those at 1500–1600 cm⁻¹. -1 The C=C main chain vibrates within the range of 3400–3500 cm⁻¹. Furthermore, it exhibits vibrations within this range. -1 A broad absorption band was detected in the region, corresponding to the NH stretching vibration, and partially overlapping with the OH stretching band. This band is observed in the 500–800 cm⁻¹ region. -1 Obvious absorption peaks were also observed within the range, which can be attributed to the Zr-O coordination bonds within the UiO-66 framework. For example... Figure 8 As shown, the presence of these characteristic absorption peaks provides strong evidence for the successful synthesis of γ-Fe2O3@SiO2-NH2@PTA / UiO-66-NH2 composite materials.

[0061] Following folic acid (FA) functionalization, the γ-Fe2O3@SiO2-NH2@PTA / UiO-66-NH2 composite material exhibited several new absorption bands in Fourier transform infrared (FTIR) spectroscopy, providing clear evidence for successful surface modification. These bands were observed in the 1450–1550 cm⁻¹ region. -1 Additional absorption bands were observed within the range, which can be attributed to CN or C=N stretching vibrations associated with the aromatic and amide functional groups of the FA molecule. A significantly enhanced aromatic C=C skeleton vibration was observed at approximately 1600 cm⁻¹, further confirming the presence of the benzene ring in folic acid. Furthermore, absorption bands were observed in the 3300–3500 cm⁻¹ range. -1 The broad absorption band in the region becomes more pronounced, corresponding to the NH stretching vibration, which partially overlaps with the OH stretching mode. At 1640 cm⁻¹ -1 and 1550 cm -1 Weak absorption peaks were also observed nearby, corresponding to the amide I and amide II bands, respectively, indicating that amide bonds may have formed between folic acid and the amino-functionalized MOF surface. These spectral features collectively confirm that folic acid has been successfully grafted onto the composite material surface.

[0062] 2.5 Cytotoxicity and Inhibitory Effects on Cancer Cells of Composite Materials The effects of γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO66, γ-Fe2O3@SiO2-NH2@PTA / Ly / UiO66-NH2, folic acid-modified γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO66-FA, and γ-Fe2O3@SiO2-NH2@PTA / Ly / UiO66-FA on the survival rate of Vero and HepG2 cells were investigated using the CCK-8 assay.

[0063] like Figure 9 and 10As shown, treatment with γ-Fe2O3@SiO2-NH2@PTA / Ly / UiO-66-NH2 resulted in a concentration-dependent decrease in the survival rates of both Vero and HepG2 cells. At a concentration of 50 μg / mL, after 24 h of treatment with γ-Fe2O3@SiO2-NH2@PTA / Ly / UiO-66-NH2, the survival rate of Vero cells was approximately 72%, decreasing to 61% after 48 h and further decreasing to 52% after 72 h. In contrast, free Ly (5 μg / mL) reduced the survival rate to below 40% within 24 h, indicating that this composite material has a significant sustained-release advantage, avoiding the rapid cytotoxicity associated with free drugs. Under the same conditions (50 μg / mL, 72 h), the survival rate of HepG2 cells was only 36%, significantly lower than the 52% of Vero cells, indicating that this material has a stronger inhibitory effect on liver cancer cells, demonstrating potential selective cytotoxicity. Compared with free MTX (5 μg / mL, 72 h survival rate of about 25%), the HepG2 survival rate of γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO-66-NH2 was 39%, also exhibiting sustained-release characteristics.

[0064] like Figure 11 and 12 As shown, at a concentration of 50 μg / mL and a duration of 48 h, the FA-modified and unmodified samples exhibited inhibitory effects on HepG2 cells, resulting in 45% and 48% cell viability, respectively. The experimental results for FA-modified γ-Fe2O3@SiO2-NH2@PTA / lycorine / UiO-66-NH2-FA were comparable to those for the unmodified γ-Fe2O3@SiO2-NH2@PTA / lycorine / UiO-66-NH2. This consistency indicates that the two formulations have similar effects on cell viability, and a consistent cytotoxic trend was observed in both materials.

[0065] like Figure 13 and 14 As shown, the experimental results of γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO-66-NH2 on Vero and HepG2 cells are comparable to those of the previously described materials, showing consistency.

[0066] like Figure 15 and 16As shown, after treatment with γ-Fe2O3@SiO2-NH2@PTA / MTX / UiO-66-NH2-FA, the survival rates of Vero and HepG2 cells decreased with increasing concentration, exhibiting a concentration-dependent trend. Furthermore, at each tested concentration, cell survival gradually decreased with prolonged incubation time, indicating that the material possesses sustained-release properties. Comparative analysis of the two sets of data revealed that the toxic effects of this material on these two cell types showed a consistent trend.

[0067] Overall, compared to free drugs, the composite material can increase cell survival by 15-30% within the same time period, demonstrating that its sustained-release effect can effectively reduce acute toxicity. HepG2 cell survival was consistently 10-20% lower than Vero cell survival, highlighting its preferential killing ability against cancer cells. Folic acid modification showed an additional 7-10% enhanced inhibitory effect at low doses, which is beneficial for the expansion of subsequent targeted drug delivery strategies.

[0068] Compared with existing technologies: 1. Drug loading capacity: In existing technologies, when MOFs such as UiO-66 and UiO-66-NH2 are used as carriers, their loading rate for methotrexate is typically only 20–40% (Singal). et al (Appl. Sci. 2024). In comparison, the composite material of the present invention achieves a drug loading capacity of 95.3 mg / g for lycorine and 102.7 mg / g for methotrexate, which is more than 2 to 4 times higher than the existing level, significantly improving the drug loading efficiency.

[0069] 2. In terms of sustained-release performance Previous reports indicate that Letrozole@UiO-66 releases approximately 57.55% at 72 hours, while the ZIF-8 system typically releases over 80% within 24 hours, making it difficult to maintain a long-lasting, sustained release (AMB Express 2024). The system of this invention releases only 35–38% at 48 hours and slowly increases to 82–85% at 144 hours, extending the release time by approximately six times and effectively avoiding the explosive release problem of existing materials.

[0070] 3. Cytotoxicity and selectivity Existing MOF-drug composite systems have limited effectiveness in reducing normal cell toxicity and enhancing tumor selectivity. For example, the UiO-66-NH2 system still showed a cancer cell survival rate of over 50% after 72 hours, while also exhibiting significant inhibition of normal cells. The CCK-8 assay results of this invention show that at a concentration of 50 μg / mL: the survival rate of Vero normal cells remained above 85%; the survival rate of HepG2 cancer cells decreased to approximately 42%. Compared to free drugs, the composite material exhibits 15–20% less cytotoxicity to normal cells and 13–18% higher inhibition rate against cancer cells, demonstrating stronger selective killing activity.

[0071] 4. Targeting effect Existing MOF systems mostly rely on passive targeting, resulting in limited efficiency. This invention, through folic acid modification, increased the uptake of the composite material by HepG2 cancer cells by approximately 1.8 times, while showing no significant increase in Vero cell uptake. At a low concentration (10 μg / mL), the survival rate of HepG2 cells in the FA-modified sample was 78%, compared to 85% in the unmodified sample, further demonstrating that folic acid modification significantly enhances the targeting effect on cancer cells.

[0072] Although embodiments of the invention have been disclosed for illustrative purposes, those skilled in the art will understand that various substitutions, variations, and modifications are possible without departing from the spirit and scope of the invention and the appended claims. Therefore, the scope of the invention is not limited to the contents disclosed in the embodiments.

Claims

1. A magnetic heteropolyacid core-shell composite material for the sustained-release delivery of lycorine and methotrexate, characterized in that: The composite material comprises, in sequence: γ-Fe2O3 magnetic core; A SiO2 layer covering the surface of the magnetic core; An aminopropyl functional layer grafted onto the surface of SiO2; Phosphotungstic acid loaded on the surface of aminated microspheres; Metal-organic framework materials (MOFs) coated on the outer layer, wherein the MOFs are selected from UiO-66-NH2, ZIF-8 or ZIF-67; The MOFs are loaded with anticancer drugs, namely lycorine or methotrexate. The surface of the composite material is further grafted with 4-aminopyridine and folic acid molecules for targeted functional modification.

2. The composite material according to claim 1, characterized in that: The SiO2 is a dense amorphous silicon dioxide layer formed by coating tetraethyl orthosilicate using the sol-gel method.

3. The composite material according to claim 1, characterized in that: The phosphotungstic acid has a Keggin structure, and its main XRD diffraction peaks are located at 8.8°, 18.0° and 25.4°.

4. The composite material according to claim 1, characterized in that: The metal-organic framework material UiO-66-NH2 has a face-centered cubic structure. Its characteristic XRD peaks include 7.4°, 12.0°, 14.2°, 17.0°, 25.5° and 30.5°.

5. The composite material according to claim 1, characterized in that: The drug has a loading capacity of 10–30 wt% and exhibits good in vitro sustained-release properties, with a sustained-release rate of over 60% within 24 hours.

6. The composite material according to any one of claims 1 to 5, characterized in that: The composite material is formed by sequentially coating silicon dioxide, aminopropyl modification layer and phosphotungstic acid with γ-Fe2O3 as magnetic core to form γ-Fe2O3@SiO2-NH2@PTA composite core; A metal-organic framework was coated onto the surface of the core layer using an in-situ growth method to construct a core-shell structured composite material. Antitumor drugs are incorporated into the MOF backbone during the synthesis process to achieve efficient loading. The composite material was post-modified by introducing amino groups with 4-aminopyridine and linking folic acid through an EDC / NHS activation reaction to enhance its ability to target and recognize cancer cells.

7. The method for preparing the composite material according to any one of claims 1 to 6, characterized in that: Includes the following steps: (1) Synthesis of γ-Fe2O3 magnetic nanoparticles; (2) SiO2 is coated on the surface of γ-Fe2O3 to form γ-Fe2O3@SiO2; (3) Grafting aminopropyl groups onto γ-aminopropyl silane KH550 to form γ-Fe2O3@SiO2-NH2; (4) Phosptonic acid is fixed by electrostatic adsorption to form γ-Fe2O3@SiO2-NH2@PTA; (5) Coating the surface of the drug-containing MOF crystals to obtain γ-Fe2O3@SiO2-NH2@PTA / drug / MOF composite material; (6) Targeted modification is achieved by further grafting 4-aminopyridine and folic acid onto the surface.

8. The preparation method according to claim 7, characterized in that: The MOFs were synthesized using a one-pot method, with the reaction temperature controlled at 90–120 °C and the reaction time at 12–24 h.

9. The preparation method according to claim 7, characterized in that: The drug is lycorine or methotrexate. The drug addition step involves mixing it with metal ions and ligands before MOF synthesis, and also using a one-pot cooking method to achieve drug intercalation.

10. The use of the composite material as described in any one of claims 1 to 6 in the preparation of an antitumor drug delivery system.

Images