Preparation and application of SPION assembly capable of controllably releasing medicine in response to alternating magnetic field

Abstract

The invention belongs to the technical field of biomedical materials, and relates to a preparation method and application of an SPION assembly capable of controllably releasing drugs in response to an alternating magnetic field. The preparation method comprises the following steps: modifying the surfaces of maleic anhydride modified superparamagnetic iron oxide nanoparticles with an amphiphilic temperature-sensitive polymer to obtain SPIONs (at) P-PS; and assembling the SPIONs (at) P-PS, DOX and IR-1061 dye by virtue of a nano coprecipitation method, so as to obtain the SPION assembly capable of controllably releasing the medicine in response to the alternating magnetic field. The SPION assembly is in the shape of a sphere with the diameter of 60-80 nm, is good in stability, and has a good cancer cell killing effect due to the dual functions of magnetocaloric effect and controllable release of DOX.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedical materials and relates to a preparation method and application of a SPION assembly capable of controllably releasing drugs in response to an alternating magnetic field. Background Art

[0002] Currently, the field of tumor diagnosis and treatment faces many challenges, such as radiotherapy and chemotherapy drugs often cause systemic side effects, and the efficacy limitations of single treatment methods. Tumor microenvironment responsive drug carrier technology provides a new way to solve these problems. It can not only increase the accumulation of anti-tumor drugs in tumor tissues, but also accurately regulate the spatiotemporal distribution and release of drugs, thereby effectively reducing systemic toxicity. Therefore, it is particularly important to develop responsive drug delivery nanocarriers targeting specific parts of the tumor.

[0003] To date, a variety of responsive material systems have been widely explored and applied in the field of tumor diagnosis and treatment. Among them, tumor microenvironment responsive drug carriers mainly rely on pH responsive mechanisms, such as the use of hydrazone bonds, oxime bonds, acetals and β-carboxylic acid amides to construct responsive carriers. In addition, acid-responsive or pH / H2O2 dual-responsive inorganic nanomaterials, such as manganese dioxide nanoparticles (MnO2), calcium carbonate nanoparticles (CaCO3) and calcium phosphate nanoparticles (Ca3(PO4)2), have also been developed and used in the construction of drug carriers. Superparamagnetic iron oxide nanoparticles (SPIONs), as a powerful multifunctional nanomaterial, have shown great potential in the field of magnetic thermal therapy due to their unique magnetic properties, excellent biocompatibility and easy surface functionalization. In recent years, magnetic thermal research and treatment of tumors based on iron oxide nanoparticles have attracted much attention. Under the action of an alternating magnetic field, SPIONs produce a magnetothermal effect through Brownian relaxation and Neeler relaxation mechanisms, which can raise the temperature of the lesion to over 43°C, thereby dilating tumor blood vessels, accelerating drug penetration into tumor tissue, reducing tumor cell resistance, inhibiting DNA repair, and enhancing cell membrane permeability to induce cell death. More importantly, magnetic thermal therapy is not limited by penetration depth and is suitable for the treatment of deep tumors.

[0004] However, the current application of SPIONs faces certain challenges, mainly due to its generally low specific absorption rate (SAR, a key indicator for measuring magnetothermal performance), which leads to low magnetothermal conversion efficiency. In addition, due to the complexity of the tumor microenvironment, responsive drug release is affected. In order to achieve sufficient tumor killing effect, high doses of iron oxide nanoparticles are often required, which limits its wide application. To this end, researchers are committed to improving the magnetothermal conversion efficiency of materials by regulating the particle size, composition, morphology, surface modification and doping of other elements of SPIONs, thereby optimizing the magnetothermal treatment effect (for details on the magnetothermal properties of different types of magnetic nanomaterials under alternating magnetic fields, see the table below). At the same time, studies have shown that combining magnetothermal therapy with chemotherapy under the action of an alternating magnetic field can significantly improve the comprehensive effect of tumor treatment. Summary of the invention

[0005] The purpose of the present invention is to provide a preparation method and application of a SPION assembly capable of controlling the release of drugs in response to an alternating magnetic field.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows: The first aspect of the present invention provides a method for preparing a SPION assembly capable of controlled drug release in response to an alternating magnetic field, which comprises modifying an amphiphilic thermosensitive polymer on the surface of superparamagnetic iron oxide nanoparticles modified with maleic anhydride to obtain SPIONs@P-PS; then assembling SPIONs@P-PS, DOX and IR-1061 dye by a nano-coprecipitation method to obtain a SPION assembly capable of controlled drug release in response to an alternating magnetic field; The mass ratio of the amphiphilic thermosensitive polymer to the maleic anhydride modified superparamagnetic iron oxide nanoparticles is 0.5-2:1-20; the mass ratio of the SPIONs@P-PS, DOX and IR-1061 dye is 1-10:0.1-1:0.05-5.

[0007] Furthermore, the method for preparing the above-mentioned SPION assembly capable of controlled drug release in response to an alternating magnetic field comprises the following steps: S1: The amphiphilic thermosensitive polymer is mixed with superparamagnetic iron oxide nanoparticles modified with maleic anhydride, and the mixture is subjected to chelation reaction at room temperature for 12 hours to obtain superparamagnetic iron oxide nanoparticles modified with the thermosensitive polymer, namely SPIONs@P-PS; S2: DOX and IR-1061 dye were added to the dichloromethane containing SPIONs@P-PS, and then a polyvinyl alcohol aqueous solution was added. Ultrasonic emulsification was performed at room temperature for 3 minutes, and then dried at room temperature. After the dichloromethane was completely evaporated, the product was washed with deionized water to obtain a SPION assembly.

[0008] Furthermore, the preparation steps of the above-mentioned amphiphilic thermosensitive polymer are as follows: S1-1: N-isopropylacrylamide, 4-cyano-4-[[(dodecylthio)thiomethyl]thio]pentanoic acid and azobisisobutyronitrile were dissolved in DMSO, and the mixture was degassed by argon bubbling for 4 h, and then reacted at 60°C for 5 h and then at 80°C for 24 h. After the reaction, the mixture was cooled rapidly, and dichloromethane was added to the reaction solution for dilution, and then poured into ether for precipitation. The precipitated material was collected by filtration, and the precipitated material was dissolved in dichloromethane. The precipitation and dissolution were repeated for 3 times. Finally, the precipitated material was dried under vacuum at 60°C to obtain product 1; S1-2: The product 1 obtained in step S1-1 was dissolved in methanol, sodium borohydride was added, and the mixture was reacted at 60°C for 1 hour. During this process, the methanol was volatilized to obtain a solid substance. The solid substance was dissolved in dichloromethane and filtered. The filtrate was precipitated in ether. The precipitated substance was collected by filtration and dried in vacuo at 60°C to obtain product 2; S1-3: 2-aminoethylphosphonic acid, maleimide and pyridine were dissolved in N-methylpyrrolidone, and the mixture was reacted at 90°C for 24 hours. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was extracted with ether three times. The obtained solid was dried under vacuum at 60°C to obtain product 3; S1-4: dissolving the product 2 obtained in step S1-2 and the product 3 obtained in step S1-3 in deionized water, adjusting the pH value to 7.0, and then reacting at 60° C. for 12 h. After the reaction, dialyzing in distilled water for 120 h, and freeze-drying to obtain an amphiphilic thermosensitive polymer; Among them, the ratio of N-isopropylacrylamide, 4-cyano-4-[[(dodecylthio)thiomethyl]thio]pentanoic acid and azobisisobutyronitrile is 1mmol:0.01mmol:0.3g; the molar ratio of the product 1 and sodium borohydride is 1:1; the molar ratio of 2-aminoethylphosphonic acid, maleimide and pyridine is 1:1.5:2; the molar ratio of the product 2 and the product 3 is 1:1.

[0009] Furthermore, the preparation steps of the maleic anhydride modified superparamagnetic iron oxide nanoparticles are as follows: polyethylene glycol 1000 and ferric acetylacetonate are added to a three-necked flask, heated to 280°C under an argon atmosphere, refluxed for 1 hour, and naturally cooled to room temperature to obtain superparamagnetic iron oxide nanoparticles; the obtained superparamagnetic iron oxide nanoparticles are heated to 80°C, maleic anhydride and p-toluenesulfonic acid monohydrate are added, refluxed at 80°C for 1 hour, naturally cooled to room temperature, and then washed with toluene and acetone in turn, the product is adsorbed by an LS magnetic separation column, and washed with deionized water to obtain maleic anhydride modified superparamagnetic iron oxide nanoparticles; Wherein, the mass ratio of polyethylene glycol 1000, ferric acetylacetonate, maleic anhydride and p-toluenesulfonic acid monohydrate is 15:0.7:1.5:0.25.

[0010] Furthermore, the concentration of the polyvinyl alcohol aqueous solution is 5 wt %.

[0011] The second aspect of the present invention provides a SPION assembly capable of controlled drug release in response to an alternating magnetic field, which is prepared by the above-mentioned preparation method.

[0012] The third aspect of the present invention provides the use of the above-mentioned SPION assembly capable of controllably releasing drugs in response to an alternating magnetic field in the preparation of tumor therapeutic drugs.

[0013] The significant advantages of the present invention are: The present invention modifies the surface of superparamagnetic iron oxide nanoparticles modified with amphiphilic thermosensitive polymer phosphate-poly(N-isopropylacrylamide)-polyethylene glycol-COOH (P-PS) on the surface of maleic anhydride modified superparamagnetic iron oxide nanoparticles through electrostatic interaction, hydrophobic interaction and Fe-phosphate coordination effect to obtain SPIONs@P-PS, and then assembles SPIONs@P-PS, DOX and IR-1061 dye through nano-coprecipitation method to obtain a SPION assembly capable of controllably releasing drugs in response to an alternating magnetic field. The technical problems solved are summarized as follows: 1. Adjustable physicochemical properties - drugs can be controllably released under the magnetothermal stimulation generated by an alternating magnetic field; 2. Intelligent "response" - the intelligent response diagnosis and treatment platform can achieve fixed-point, timed and on-demand control. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 : Transmission electron microscopy images of SPIONs (a), SPIONs@P-PS (b) and SPION assemblies (c); Scanning electron microscopy image of SPION composite nanoparticles (d).

[0015] Figure 2 : Hydration particle size diagram and stability of SPIONs (a) and SPION assemblies (b).

[0016] Figure 3 : (a) HAADF-STEM micrograph of SPION assembly, (bf) Fe, P, N, O and C elemental mapping analysis of SPION assembly.

[0017] Figure 4 :(a) UV absorption spectrum of SPION assembly; (b) UV comparison of SPION assembly with DOX, IR1061, etc.

[0018] Figure 5: TEM images of SPION assemblies before (a), 5 min (b) and 15 min (c) after application of an alternating magnetic field (alternating magnetic field frequency 485 kHz, magnetic induction intensity 5.5 kA / m, power 10.2 kW).

[0019] Figure 6 :The relative survival rate of U87MG cells with different concentrations of SPION assemblies (a) and SPIONs (b) under the condition of introducing / not introducing alternating magnetic field (5min, frequency 485kHz, magnetic induction intensity 5.5kA / m, power 10.2kW) was determined by tetramethylrhodamine blue colorimetry. The data are shown as mean ± standard deviation (n = 3) (**p < 0.01 compared with the control group without magnetic field effect). DETAILED DESCRIPTION

[0020] In order to make the contents of the present invention easier to understand, the technical solution of the present invention is further described below in conjunction with specific implementation methods, but the present invention is not limited thereto.

[0021] Embodiment 1: A method for preparing a SPION assembly is carried out according to the following steps: S1: Synthesis of Thermosensitive Polymers S1-1: 1 mmol N-isopropylacrylamide (IPA), 0.01 mmol chain transfer agent 4-cyano-4-[[(dodecylthio)thiomethyl]thio]pentanoic acid and 0.3 g initiator azobisisobutyronitrile (AIBN) were dissolved in 10 mL DMSO, and degassed by argon bubbling for 4 h. The mixture was reacted at 60°C for 5 h and then at 80°C for 24 h. After the reaction, the temperature was rapidly lowered, 10 mL of dichloromethane was added to the reaction solution for dilution, and then poured into 5 mL of ether for precipitation. The precipitated material was collected by filtration, and the precipitated material was dissolved in 3 mL of dichloromethane. The precipitation and dissolution were repeated 3 times. Finally, the precipitated material was dried under vacuum at 60°C for 24 h to obtain product 1; S1-2: Dissolve 1 mmol of the product 1 obtained in step S1-1 in 5 mL of methanol, add 1 mmol of sodium borohydride, and react at 60°C for 1 h. During this process, methanol evaporates to obtain a solid substance. The solid substance is dissolved in 5 mL of dichloromethane and filtered. The filtrate is precipitated in 5 mL of ether. The precipitated substance is collected by filtration and dried in vacuo at 60°C for 24 h to obtain product 2. S1-3: 1 mmol 2-aminoethylphosphonic acid, 1.5 mmol maleimide and 2 mmol pyridine were dissolved in 20 mL N-methylpyrrolidone, and the mixture was reacted at 90°C for 24 h. After the reaction, the solvent was removed by vacuum distillation at 0 Pa and 40°C for 0.5 h, and the mixture was extracted with 5 mL ether for 3 times. The obtained solid was vacuum dried at 60°C for 24 h to obtain product 3; S1-4: Dissolve 1 mmol of the product 2 obtained in step S1-2 and 1 mmol of the product obtained in step S1-3 in 5 mL of deionized water, adjust the pH to 7.0 with 10 mM hydrochloric acid and NaOH, and then react at 60°C for 12 hours. After the reaction, dialyze in distilled water for 120 hours using a dialysis bag with a molecular weight cutoff of 1200 Da to remove unreacted small molecules, and freeze-dry to obtain a thermosensitive polymer phosphate-poly(N-isopropylacrylamide)-polyethylene glycol-COOH (P-PS).

[0022] S2: Synthesis of maleic anhydride modified superparamagnetic iron oxide nanoparticles S2-1: 15 g polyethylene glycol 1000 (PEG 1000 ) and 0.7 g of ferric acetylacetonate (Fe(acac)3) were added into a three-necked flask, heated to 280°C under argon atmosphere and refluxed for 1 h, and naturally cooled to room temperature to obtain superparamagnetic iron oxide nanoparticles (SPIONs); S2-2: The superparamagnetic iron oxide nanoparticles obtained in step S2-1 were heated to 80°C, 1.5 g of maleic anhydride (Mal) and 0.25 g of p-toluenesulfonic acid monohydrate (TsOH·H2O) were added, refluxed at 80°C for 1 h, cooled naturally to room temperature, and then washed with toluene and acetone three times each, and the product was adsorbed using an LS magnetic separation column (Miltenyi Biotec), and the residual Fe(acac)3 and PEG were washed with deionized water. 1000 , Mal, TsOH·H2O and organic solvent to obtain maleic anhydride modified superparamagnetic iron oxide nanoparticles (SPIONs@Mal).

[0023] S3: Synthesis of SPION Assemblies S3-1: 1 mg of P-PS obtained in step S1 was added to 5 mg of SPIONs@Mal obtained in step S2, and the reaction was carried out at room temperature for 12 h to obtain thermosensitive polymer-modified superparamagnetic iron oxide nanoparticles (SPIONs@P-PS); S3-2: Add 0.1 mg of doxorubicin (DOX) and 0.05 mg of infrared fluorescent dye IR-1061 to dichloromethane containing 2 mg / mL of SPIONs@P-PS obtained in step S3-1, and then add 5 mL of 5 wt% polyvinyl alcohol (PVA, Mw: 9000-10000) aqueous solution, emulsify at room temperature for 3 min at 50 W, and then dry at room temperature. After the dichloromethane is completely evaporated, wash the product with deionized water 3 times to remove excess PVA to obtain a SPION assembly.

[0024] Figure 1 Transmission electron microscope (TEM) images of SPIONs (a), SPIONs@P-PS (b), and SPION assemblies (c) are shown, and scanning electron microscope (SEM) images of SPION assemblies (d) are also provided. From these images, it can be concluded that the SPION assemblies are spherical structures with diameters between 60 and 80 nanometers, and doxorubicin (DOX) is effectively encapsulated inside them.

[0025] Figure 2 aThe size distribution of SPIONs and SPION assemblies was analyzed by dynamic light scattering (DLS) technology, and the results showed that both had clear size distribution characteristics, which was highly consistent with the observation results of TEM and SEM. This analysis further verified that the prepared SPIONs and SPION assemblies can be effectively dispersed in water, showing high stability and good dispersion performance. Figure 2 Figure b presents the changes in the hydrated particle size of the SPION assembly at different time points after preparation. The data show that during the one-week observation period, the hydrated particle size remained almost unchanged, which strongly proves that the SPION assembly has excellent stability.

[0026] Figure 3 a The successful construction of spherical SPION assemblies was confirmed by high-angle annular dark field scanning transmission electron microscopy combined with energy dispersive X-ray spectroscopy (HAADF-STEM-EDS) and energy dispersive X-ray spectroscopy (EDC) technology, and this result is consistent with the morphology shown in the SEM image. In addition, the elemental mapping image ( Figure 3 b to 3f) reveal the uniform distribution of Fe, P, N, O and C elements within the SPION assemblies, among which the uniform distribution of P element is particularly significant, further supporting the strategy of successfully assembling SPION assemblies using thermosensitive polymers.

[0027] Figure 4 a shows the ultraviolet–visible (UV-VIS) absorption spectrum of the SPION assembly, and a broad absorption peak was observed in the range of approximately 850 to 950 nm, which can be attributed to the internally loaded IR-1061 molecules. Figure 4b Through the fitting comparison of ultraviolet absorption spectra, the absorption characteristics of SPION assemblies were compared and analyzed with those of SPIONs, DOX, bovine serum albumin (BSA), IR-1061, and P-PS. In particular, the characteristic absorption peak of the SPION assembly at 480 nanometers is consistent with the absorption peak position of free DOX, which directly proves that DOX has been successfully loaded into the SPION assembly. At the same time, the assembled SPION assembly also showed significant magnetic enhancement. All the above results together indicate the successful preparation of the SPION assembly.

[0028] In order to verify the dissociation of SPION assemblies under magnetothermal response, we used TEM to observe the gradual dissociation of SPION assemblies under the action of an alternating magnetic field (frequency 485kHz, magnetic induction intensity 5.5kA / m, power 10.2kW). Figure 5 It can be found that the magnetocaloric effect can change the integrity and morphology of SPION assemblies. Figure 5 a is a TEM image of the SPION assembly before the alternating magnetic field. After 5 minutes of turning on the alternating magnetic field, the vesicles were destroyed. Figure 5 As shown in b, after 15 minutes of operation, it further decomposes into small clusters or even single SPIONs ( Figure 5 c).

[0029] This study used the standard tetramethylrhodamine colorimetric method to deeply explore the cytotoxicity and magnetothermal effect of SPIONs (superparamagnetic iron oxide nanoparticles) and their assemblies at different concentrations at the cellular level. The experimental design included mixing a series of concentrations of SPIONs and SPION assemblies with brain astrocytoma glioblastoma U87-MG cells, applying an alternating magnetic field for 5 minutes, and incubating them together for 24 hours. The relative survival rate of the cells was measured to evaluate their biological effects. The specific results are as follows: Figure 6 a and 6b. In the absence of an alternating magnetic field, after 24 hours of co-incubation, both SPIONs and SPION assemblies showed extremely low toxicity to U87-MG cells at a concentration of up to 400μg / mL. However, when an alternating magnetic field was introduced, the situation changed significantly: within the same incubation time, the survival rate of U87-MG cells decreased significantly with the increase in the concentration of SPIONs or SPION assemblies, among which the effect of SPION assemblies was particularly significant. Specifically, under the condition of introducing an alternating magnetic field, the 100μg / mL SPION assembly treatment group caused the survival rate of U87-MG cells to drop to less than 35%, and when the concentration was increased to 400μg / mL, the survival rate further dropped to about 5%; in contrast, at the same concentration, the survival rates of U87-MG cells in the SPIONs treatment group were 75% and 45%, respectively.

[0030] The above results strongly support the following conclusions: for SPIONs with smaller particle sizes, their magnetothermal therapeutic effect is relatively limited; while SPION assemblies, by virtue of their dual mechanism of magnetothermal effect and DOX (such as hypothetical chemotherapy drugs) release, show more excellent cancer cell killing ability.

[0031] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention should fall within the scope of the present invention.

Claims

1. A method for preparing a SPION assembly capable of controlled drug release in response to an alternating magnetic field, characterized in that: The amphiphilic thermosensitive polymer was modified on the surface of maleic anhydride-modified superparamagnetic iron oxide nanoparticles to obtain SPIONs@P-PS. SPIONs@P-PS, DOX and IR-1061 dye were assembled by nano-coprecipitation method to obtain SPION assemblies that can controllably release drugs in response to alternating magnetic fields.

2. The preparation method according to claim 1, characterized in that: The mass ratio of the amphiphilic thermosensitive polymer to the superparamagnetic iron oxide nanoparticles modified by maleic anhydride is 0.5-2:1-20; the mass ratio of the SPIONs@P-PS, DOX and IR-1061 dye is 1-10:0.1-1:0.05-5.

3. The preparation method according to claim 2, characterized in that: The following steps are involved: S1: The amphiphilic thermosensitive polymer is mixed with superparamagnetic iron oxide nanoparticles modified with maleic anhydride, and the mixture is subjected to chelation reaction at room temperature for 12 hours to obtain superparamagnetic iron oxide nanoparticles modified with the thermosensitive polymer, namely SPIONs@P-PS; S2: DOX and IR-1061 dye were added to the dichloromethane containing SPIONs@P-PS, and then a polyvinyl alcohol aqueous solution was added. Ultrasonic emulsification was performed at room temperature for 3 minutes, and then dried at room temperature. After the dichloromethane was completely evaporated, the product was washed with deionized water to obtain a SPION assembly.

4. The preparation method according to claim 2, characterized in that: The preparation steps of the amphiphilic thermosensitive polymer are as follows: S1-1: N-isopropylacrylamide, 4-cyano-4-[[(dodecylthio)thiomethyl]thio]pentanoic acid and azobisisobutyronitrile were dissolved in DMSO, and the mixture was degassed by argon bubbling for 4 h, and then reacted at 60°C for 5 h and then at 80°C for 24 h. After the reaction, the mixture was cooled rapidly, and dichloromethane was added to the reaction solution for dilution, and then poured into ether for precipitation. The precipitated material was collected by filtration, and the precipitated material was dissolved in dichloromethane. The precipitation and dissolution were repeated for 3 times. Finally, the precipitated material was dried under vacuum at 60°C to obtain product 1; S1-2: The product 1 obtained in step S1-1 was dissolved in methanol, sodium borohydride was added, and the mixture was reacted at 60°C for 1 hour. During this process, the methanol was volatilized to obtain a solid substance. The solid substance was dissolved in dichloromethane and filtered. The filtrate was precipitated in ether. The precipitated substance was collected by filtration and dried in vacuo at 60°C to obtain product 2; S1-3: 2-aminoethylphosphonic acid, maleimide and pyridine were dissolved in N-methylpyrrolidone, and the mixture was reacted at 90°C for 24 hours. After the reaction, the solvent was removed by distillation under reduced pressure, and the mixture was extracted with ether three times. The obtained solid was dried under vacuum at 60°C to obtain product 3; S1-4: Dissolve the product 2 obtained in step S1-2 and the product 3 obtained in step S1-3 in deionized water, adjust the pH value to 7.0, and then react at 60°C for 12 hours. After the reaction, dialyze in distilled water for 120 hours, and freeze-dry to obtain an amphiphilic thermosensitive polymer.

5. The preparation method according to claim 4, characterized in that: The ratio of N-isopropylacrylamide, 4-cyano-4-[[(dodecylthio)thiomethyl]thio]pentanoic acid and azobisisobutyronitrile is 1 mmol: 0.01mmol:0.3g; the molar ratio of the product 1 to sodium borohydride is 1:1; the molar ratio of the 2-aminoethylphosphonic acid, maleimide and pyridine is 1:1.5:2; the molar ratio of the product 2 to the product 3 is 1:

1.

6. The preparation method according to claim 2, characterized in that: The preparation steps of the maleic anhydride modified superparamagnetic iron oxide nanoparticles are as follows: adding polyethylene glycol 1000 and ferric acetylacetonate into a three-necked flask, heating to 280° C. under an argon atmosphere, reflux for 1 hour, and naturally cooling to room temperature to obtain superparamagnetic iron oxide nanoparticles; heating the obtained superparamagnetic iron oxide nanoparticles to 80° C., adding maleic anhydride and p-toluenesulfonic acid monohydrate, reflux at 80° C. for 1 hour, and naturally cooling to room temperature, and then washing with toluene and acetone in turn, using an LS magnetic separation column to adsorb the product, and washing with deionized water to obtain maleic anhydride modified superparamagnetic iron oxide nanoparticles.

7. The preparation method according to claim 6, characterized in that: The mass ratio of the polyethylene glycol 1000, ferric acetylacetonate, maleic anhydride and p-toluenesulfonic acid monohydrate is 15:0.7:1.5:0.

25.

8. The preparation method according to claim 2, characterized in that: The concentration of the polyvinyl alcohol aqueous solution is 5 wt %.

9. A SPION assembly capable of controlled drug release in response to an alternating magnetic field, characterized in that: Prepared by the preparation method according to any one of claims 1 to 8.

10. Use of the SPION assembly according to claim 9 in preparing tumor therapeutic drugs.

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