Polyvinyl pyrrolidone modified ferrous oxide magnetic clusters and their preparation method and application

Abstract

The present invention provides a polyvinyl pyrrolidone-modified ferric oxide magnetic cluster and its preparation method and application, belonging to the field of material technology. The preparation method of the present invention directly removes the organic solvent from oil-soluble ferric oxide magnetic particles by rotary evaporation, and ultrasonically disperses them to prepare magnetic particle clusters in one step. The preparation method is simple, convenient and easy to operate, and can effectively reduce the operating steps of forming magnetic clusters in the prior art, and introduces fewer reagents, which is conducive to the clinical transformation of magnetic clusters. The polyvinyl pyrrolidone-modified ferric oxide magnetic clusters prepared by the present invention have uniform particle size and uniform dispersion, can convert small-sized particles with T1 imaging capability into clusters with strong T2 imaging capability, can effectively increase the T2 relaxation rate of particles, can be applied to magnetic separation or magnetic targeting technology, can be used as biomaterials, and have a wide range of applications.

Description

Technical Field

[0001] The invention belongs to the technical field of materials and relates to a polyvinyl pyrrolidone-modified ferric oxide magnetic cluster and a preparation method and application thereof. Background Art

[0002] Magnetic resonance imaging has the advantages of being radiation-free, non-invasive, with high soft tissue resolution and accurate positioning. It can also directly obtain cross-sectional information in various directions, such as the transverse, coronal, and sagittal planes of tissue, which facilitates the three-dimensional positioning of lesions. Combined with imaging probes, it plays an important role in the preoperative positioning and staging of tumors. Commonly used components with MRI capabilities are gadolinium-based contrast agents and magnetic iron nanoparticle-based contrast agents. Compared with gadolinium-based contrast agents, magnetic iron nanoparticles have advantages such as a long half-life, decomposition products that can participate in in vivo metabolism, easy surface modification, adjustable particle size and structure, and mature preparation methods. Therefore, they are widely used as MRI probes in the field of medical imaging.

[0003] High-quality magnetic iron nanoparticles are typically synthesized in an oil phase. Good water solubility is a prerequisite for the biological applications of nanomaterials. Therefore, water-soluble modification is necessary before biological applications. Developing simple and easy-to-use water-soluble modification methods for oil-phase magnetic iron nanoparticles is of great significance. Currently, commonly used modification methods include ligand exchange (citric acid, hydroxybenzoic acid, etc.), inorganic coating (silica, carbon materials), and amphiphilic polymer modification (polyethylene glycol, polystyrene, and other synthetic polymers). However, traditional modification reagents are time-consuming and expensive, hindering their clinical translation.

[0004] In the prior art, polyvinyl pyrrolidone is used to modify iron particles. First, polyvinyl pyrrolidone and iron particles are dissolved in chloroform, the organic solvent is removed, water is added for ultrasonic dispersion, and the filter membrane is filtered to obtain stable and uniform polyvinyl pyrrolidone iron particles. The patent document with publication number CN101186762A discloses a method for coating iron oxide with silica. It is necessary to first disperse the iron oxide particles in alcohol and ammonia water, and then add the polyvinyl pyrrolidone solution, through which the iron oxide is adsorbed and then ethyl orthosilicate is added for hydrolysis to complete the silicon coating. The patent document with publication number CN105562033A discloses a method for preparing a hydrophilic Fe3O4-Au double-sided particle catalyst, in which a one-step heating reflux involves polyvinyl pyrrolidone and magnetic particles, which are refluxed in toluene, dichloromethane, N, N-dimethylformamide solution and precipitated by ether to obtain single-particle PVP-modified magnetic particles. Patent document CN109663135A discloses a method for constructing magnetic clusters using ZIF-8. First, oil-soluble ferrosoferric oxide is modified by ligand exchange, and then clusters with T2 effect are obtained by wrapping them with ZIF-8.

[0005] In summary, the existing technology of polyvinyl pyrrolidone-modified magnetic particles can be divided into two categories: 1) as a modification reagent and iron salt participating in the reaction in the form of raw materials, generally requiring high temperature and involving the synthesis of magnetic particles; 2) water-soluble modification of magnetic particles by heating and other methods, and further modification by silicon coating and other methods. This type of technology still forms single particles after the polyvinyl pyrrolidone water-soluble modification process and cannot improve the relaxation rate of magnetic particles. If clusters need to be formed, more reagents need to be introduced, requiring many operation steps and a complicated process.

[0006] Therefore, there is an urgent need to study a preparation method for polyvinyl pyrrolidone-modified magnetic particle clusters. This method is simple, convenient, and easy to operate, can effectively reduce the number of operation steps, introduces fewer reagents, and is conducive to its clinical transformation. Summary of the Invention

[0007] The purpose of the present invention is to provide a polyvinyl pyrrolidone-modified ferric oxide magnetic cluster and its preparation method and application. The method adopts the method of rotary evaporation to remove organic solvent and then ultrasonic dispersion, so that small-particle oil-phase ferric oxide magnetic particles are loaded with polyvinyl pyrrolidone to form magnetic clusters with uniform particle size and good water dispersibility. The preparation method is simple, convenient and easy to operate, can effectively reduce the operating steps of forming magnetic clusters in the existing technology, and introduces fewer reagents, which is conducive to the clinical transformation of magnetic clusters.

[0008] To achieve the above object, the present invention provides a method for preparing polyvinyl pyrrolidone-modified ferromagnetic clusters, comprising the following steps:

[0009] Dissolving polyvinyl pyrrolidone in an organic solvent to obtain a polyvinyl pyrrolidone solution;

[0010] Dissolving magnetic iron oxide particles in an organic solvent to obtain a magnetic iron oxide solution;

[0011] The magnetic ferric oxide solution was added to the polyvinyl pyrrolidone solution, and ultrasonicated for 3 minutes to obtain a mixed solution;

[0012] removing the organic solvent in the mixed solution by rotary evaporation to obtain a magnetic iron oxide-polyvinyl pyrrolidone film;

[0013] dissolving the magnetic iron oxide-polyvinyl pyrrolidone film in ultrapure water to obtain a magnetic iron oxide-polyvinyl pyrrolidone aqueous solution;

[0014] The magnetic ferric oxide-polyvinyl pyrrolidone aqueous solution is filtered through a filter membrane to remove large particles, thereby obtaining the polyvinyl pyrrolidone-modified ferric oxide magnetic clusters with uniform particle size and uniform dispersion.

[0015] Preferably, the organic solvent is chloroform, tetrahydrofuran, or dichloromethane.

[0016] Preferably, the magnetic iron oxide-polyvinyl pyrrolidone film is dissolved in a certain amount of ultrapure water by ultrasonic dispersion.

[0017] Preferably, the magnetic iron oxide-polyvinyl pyrrolidone aqueous solution is filtered using a 0.22 μm or 0.45 μm filter membrane.

[0018] Preferably, in the mixed solution, the mass ratio of magnetic ferric oxide to polyvinyl pyrrolidone is 1:(10-160).

[0019] Preferably, the relative molecular weight Mw of polyvinyl pyrrolidone is 10,000-60,000.

[0020] The present invention also provides a polyvinyl pyrrolidone-modified ferric oxide magnetic cluster, which is prepared by the method described above.

[0021] The present invention also provides an application of the polyvinyl pyrrolidone-modified ferric oxide magnetic clusters as described above, which is used as a biomaterial.

[0022] The present invention also provides an application of the polyvinyl pyrrolidone-modified ferric oxide magnetic clusters as described above, which is applied in magnetic separation or magnetic targeting technology.

[0023] The advantages of the present invention using the above technical solution are:

[0024] The present invention discloses a method for preparing polyvinyl pyrrolidone-modified ferric oxide magnetic clusters. The method involves directly removing the organic solvent from oil-soluble ferric oxide magnetic particles by rotary evaporation, followed by ultrasonic dispersion, to prepare magnetic particle clusters in one step. The preparation method is simple, convenient, and easy to operate, effectively reducing the number of steps required to form magnetic clusters in the prior art, and requiring fewer reagents, which facilitates the clinical application of magnetic clusters. The polyvinyl pyrrolidone-modified ferric oxide magnetic clusters prepared by the present invention have uniform particle size and uniform dispersion. They can convert small-sized particles with T1 imaging capabilities into clusters with strong T2 imaging capabilities, effectively increasing the T2 relaxation rate of the particles, and can be applied to magnetic separation or magnetic targeting technologies. They can be used as biomaterials and have a wide range of applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0026] Figure 1 The performance characterization results of the magnetic iron oxide-polyvinyl pyrrolidone magnetic clusters prepared in Example 1 of the present invention;

[0027] Figure 2 This is a statistical graph of the water conversion rate of polyvinyl pyrrolidone-modified ferric oxide magnetic clusters prepared in Examples 1-8 of the present invention;

[0028] Figure 3 This is a graph showing the change in cluster diameter over time of the polyvinyl pyrrolidone-modified ferrous oxide magnetic clusters prepared in Example 1 of the present invention;

[0029] Figure 4 Magnetic resonance imaging performance test results of the polyvinyl pyrrolidone-modified ferric oxide magnetic clusters prepared in Example 1 of the present invention and the small-particle water-soluble magnetic iron prepared in Comparative Example 1;

[0030] Figure 5 This is a graph showing the cytotoxicity and hemolysis test results of the polyvinylpyrrolidone-modified ferric oxide magnetic clusters prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0031] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0032] The present invention provides a method for preparing polyvinyl pyrrolidone-modified ferromagnetic clusters, comprising the following steps:

[0033] S1: dissolving a certain amount of polyvinyl pyrrolidone in an organic solvent to obtain a polyvinyl pyrrolidone solution;

[0034] S2: taking a certain amount of magnetic iron oxide particles and dissolving them in an organic solvent to obtain a magnetic iron oxide solution;

[0035] S3: adding the magnetic ferric oxide solution to the polyvinyl pyrrolidone solution, and ultrasonicating for 3 minutes to obtain a mixed solution;

[0036] S4: removing the organic solvent from the mixed solution by rotary evaporation to obtain a magnetic iron oxide-polyvinyl pyrrolidone film;

[0037] S5: dissolving the magnetic iron oxide-polyvinyl pyrrolidone film in a certain amount of ultrapure water to obtain a magnetic iron oxide-polyvinyl pyrrolidone aqueous solution;

[0038] S6: Filter the magnetic iron oxide-polyvinyl pyrrolidone aqueous solution through a filter membrane to remove large particles, thereby obtaining magnetic iron oxide-polyvinyl pyrrolidone magnetic clusters with uniform particle size and uniform dispersion.

[0039] Wherein, the organic solvent in steps S1 and S2 can be selected from chloroform, tetrahydrofuran, or dichloromethane. Selecting a single solvent eliminates the need for a complex mixture of multiple solvents. In step S5, ultrasonic dispersion is used to dissolve the magnetic iron oxide-polyvinyl pyrrolidone film in a certain amount of ultrapure water. This method does not require gas protection or heating, and is simple to operate. In step S6, the magnetic iron oxide-polyvinyl pyrrolidone aqueous solution is filtered using a 0.22 μm or 0.45 μm filter membrane.

[0040] Wherein, in the mixed solution, the mass ratio of magnetic ferric oxide to polyvinyl pyrrolidone is controlled to be 1: (10-160). The present invention can further control the conversion rate of the oil phase to the water phase by controlling the mass ratio of magnetic ferric oxide to polyvinyl pyrrolidone. The high mass ratio can make more oil phase iron transfer to the water phase, and the conversion rate is low at a low mass ratio. The relative molecular weight Mw of polyvinyl pyrrolidone is 10000-60000, preferably 40000. The relative molecular mass control of polyvinyl pyrrolidone is similar to the mass ratio control of magnetic ferric oxide to polyvinyl pyrrolidone. At the same mass ratio of magnetic ferric oxide to polyvinyl pyrrolidone, the molecular weight of polyvinyl pyrrolidone is different, and the conversion rate is different. The conversion rate is highest when the molecular weight of polyvinyl pyrrolidone is 40000.

[0041] The present invention also provides a polyvinyl pyrrolidone-modified ferric oxide magnetic cluster, which is prepared by the method described above.

[0042] The present invention also provides an application of the polyvinyl pyrrolidone-modified ferric oxide magnetic clusters as described above, which is used as a biomaterial.

[0043] The present invention also provides an application of the polyvinyl pyrrolidone-modified ferric oxide magnetic clusters as described above, which is applied in magnetic separation or magnetic targeting technology.

[0044] Example 1

[0045] A method for preparing polyvinyl pyrrolidone-modified ferric oxide magnetic clusters comprises the following steps:

[0046] S1: Dissolve a certain amount of polyvinyl pyrrolidone (Mw = 40,000) in chloroform to obtain a polyvinyl pyrrolidone solution with a concentration of 0.2 g / mL;

[0047] S2: Dissolve a certain amount of magnetic ferric oxide particles in chloroform to obtain a magnetic ferric oxide solution with a concentration of 10 mg / mL.

[0048] S3: adding 0.5 mL of the magnetic ferric oxide solution to 3 mL of the polyvinyl pyrrolidone solution, and sonicating for 3 min to obtain a mixed solution;

[0049] S4: removing chloroform from the mixed solution by rotary evaporation to obtain a magnetic iron oxide-polyvinyl pyrrolidone film;

[0050] S5: dissolving the magnetic iron oxide-polyvinyl pyrrolidone film in 5 mL of ultrapure water to obtain a magnetic iron oxide-polyvinyl pyrrolidone aqueous solution;

[0051] S6: Filter the magnetic iron oxide-polyvinyl pyrrolidone aqueous solution through a 0.22 μm filter membrane to remove large particles, thereby obtaining magnetic iron oxide-polyvinyl pyrrolidone magnetic clusters with uniform particle size and uniform dispersion.

[0052] Examples 2-8

[0053] The only difference between the preparation method of polyvinyl pyrrolidone-modified ferric oxide magnetic clusters and the preparation method of Example 1 is that the mass ratio of magnetic ferric oxide to polyvinyl pyrrolidone is controlled differently. The mass ratios of magnetic ferric oxide to polyvinyl pyrrolidone in Examples 2-8 are 1:10, 1:20, 1:40, 1:60, 1:80, 1:100, and 1:160, respectively.

[0054] Comparative Example 1

[0055] Small-sized water-soluble citric acid-modified ferric oxide particles were obtained by water conversion using the sodium citrate method. The preparation process is as follows:

[0056] Dissolve 0.1g of dried ferric oxide particles in 5mL of chloroform to prepare a 20mg / mL magnetic sphere solution. Dissolve 0.2g of citric acid monohydrate in 20mL of N,N-dimethylformamide (DMF) to prepare a 10mg / mL solution. Add the citric acid-DMF solution to the ferric oxide particle chloroform solution and stir for 2h. Then, heat to 80°C and react for 2h. Add 75mL of methyl tert-butyl ether (v / v = 1:3) to precipitate. Centrifuge and remove the supernatant. Disperse the precipitate with water to obtain citric acid-modified ferric oxide particles.

[0057] The performance test is as follows

[0058] (1) The performance characterization results of the magnetic iron oxide-polyvinyl pyrrolidone magnetic clusters prepared in Example 1 are as follows Figure 1Figure a shows a transmission electron microscopy image of Fe2O3 loaded with polyvinylpyrrolidone to form a cluster structure. Figure b shows elemental mapping, where b1 is a dark field image, b2 is C, b3 is N, b4 is Fe, b5 is O, and b6 is an elemental fusion image. As can be seen in Figures a and b, the elemental mapping shows that the Fe2O3 particles are uniformly dispersed within the clusters. Dynamic light scattering was used to measure the hydrated diameter and distribution of the clusters. The results, shown in Figure c, indicate a hydrated particle size of 128.2 nm. Figure d shows the zeta potential of the clusters, which is -2.0 mV. The TEM method involved dropping 5 μL of sample onto a copper grid, drying it, and then testing it. The TEM was performed using a JEM 2100 and the mapping was performed using a FEI Tencai G2 F30. The hydrated particle size was measured using a 1 mL solution using a NanoZS instrument.

[0059] (2) After digestion treatment, the cluster samples prepared in Examples 1-8 were taken and the iron ion concentration was measured by ICP-OES (inductively coupled plasma emission spectrometer), and the water conversion rate was calculated to obtain Figure 2 The water conversion rate statistics chart shows that when the mass ratio of magnetic iron oxide to polyvinyl pyrrolidone is 1:120 (corresponding to Example 1), the water conversion rate of polyvinyl pyrrolidone-modified ferric oxide magnetic clusters is the highest. The digestion process is as follows: 1 mL of concentrated nitric acid is added to 0.5 mL of the sample solution after water conversion, heated at 80°C for 20 minutes, and then 2 mL of hydrogen peroxide is added dropwise. The solution is heated to a light yellow or colorless state, and the volume of the above solution is adjusted to 10 mL. The iron concentration transferred into the aqueous phase is calculated based on the measured concentration to obtain the amount of iron after water conversion. Similarly, 10 mg of solid iron oxide particles before water conversion are digested according to the above method, and the amount of iron added is measured. Water conversion rate = the amount of iron after water conversion / the amount of iron added, that is, the water conversion rate.

[0060] (3) The stability of the magnetic clusters of the polyvinyl pyrrolidone modified ferric oxide magnetic cluster sample prepared in Example 1 was evaluated by monitoring the changes in the particle size of the magnetic clusters at different times. Figure 3 The curve of cluster diameter changing with time shows that during the monitoring time (14 days), the particle size of the polyvinyl pyrrolidone-modified ferric oxide magnetic clusters basically did not change, indicating that it has good stability.

[0061] (4) The magnetic resonance imaging performance of the polyvinyl pyrrolidone-modified ferric oxide magnetic clusters prepared in Example 1 and the small-particle water-soluble magnetic iron prepared in Comparative Example 1 was tested using a 3T joint imaging magnetic resonance imaging system. Figure 4As shown in Figure 1, Figure a shows the magnetic resonance imaging capability test results of the two, and Figure b shows the relaxation rate test results of the two. As can be seen from the figure, the polyvinyl pyrrolidone-modified iron oxide magnetic clusters have greatly improved T2 imaging capabilities compared to citric acid-modified iron oxide particles, and the relaxation rate has increased by about 20 times.

[0062] (5) Cytotoxicity and hemolysis tests were performed on the polyvinylpyrrolidone-modified ferric oxide magnetic clusters prepared in Example 1 to evaluate their safety as biomaterials. The test results are as follows: Figure 5 As shown in Figure a, the results of the cytotoxicity test are shown, and the results of the hemolysis test are shown. As can be seen from the figure, at the test concentration (0–5 mg mL -1 ) range, the cluster materials had little effect on cell viability. At higher concentrations (0-10 mg mL -1 ) range to maintain a low hemolysis rate (<5%). Therefore, it is shown that the polyvinyl pyrrolidone modified ferric oxide magnetic clusters prepared by the present invention have good biocompatibility.

[0063] The advantages of the present invention using the above technical solution are:

[0064] The present invention discloses a method for preparing polyvinyl pyrrolidone-modified ferric oxide magnetic clusters. The method involves directly removing the organic solvent from oil-soluble ferric oxide magnetic particles by rotary evaporation, followed by ultrasonic dispersion, to prepare magnetic particle clusters in one step. The preparation method is simple, convenient, and easy to operate, effectively reducing the number of steps required to form magnetic clusters in the prior art, and requiring fewer reagents, which facilitates the clinical application of magnetic clusters. The polyvinyl pyrrolidone-modified ferric oxide magnetic clusters prepared by the present invention have uniform particle size and uniform dispersion. They can convert small-sized particles with T1 imaging capabilities into clusters with strong T2 imaging capabilities, effectively increasing the T2 relaxation rate of the particles, and can be applied to magnetic separation or magnetic targeting technologies. They can be used as biomaterials and have a wide range of applications.

[0065] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing polyvinyl pyrrolidone modified ferric oxide magnetic clusters, characterized in that: The following steps are involved: Dissolving polyvinyl pyrrolidone in an organic solvent to obtain a polyvinyl pyrrolidone solution; Dissolving magnetic iron oxide particles in an organic solvent to obtain a magnetic iron oxide solution; The magnetic ferric oxide solution was added to the polyvinyl pyrrolidone solution, and ultrasonicated for 3 minutes to obtain a mixed solution; removing the organic solvent in the mixed solution by rotary evaporation to obtain a magnetic iron oxide-polyvinyl pyrrolidone film; dissolving the magnetic iron oxide-polyvinyl pyrrolidone film in ultrapure water to obtain a magnetic iron oxide-polyvinyl pyrrolidone aqueous solution; Filtering the magnetic ferric oxide-polyvinyl pyrrolidone aqueous solution with a filter membrane to remove large particles, thereby obtaining the polyvinyl pyrrolidone-modified ferric oxide magnetic clusters with uniform particle size and uniform dispersion; The organic solvents are all chloroform, tetrahydrofuran, or dichloromethane; In the mixed solution, the mass ratio of magnetic iron oxide to polyvinyl pyrrolidone is 1:120; The relative molecular weight Mw of polyvinyl pyrrolidone is 40,000.

2. The method for preparing polyvinyl pyrrolidone modified ferromagnetic clusters according to claim 1, characterized in that: The magnetic iron oxide-polyvinyl pyrrolidone film is dissolved in a certain amount of ultrapure water by ultrasonic dispersion.

3. The method for preparing polyvinyl pyrrolidone modified ferromagnetic clusters according to claim 1, characterized in that: The magnetic iron oxide-polyvinyl pyrrolidone aqueous solution is filtered using a 0.22 μm or 0.45 μm filter membrane.

4. A polyvinyl pyrrolidone modified ferric oxide magnetic cluster, characterized in that: The method is prepared according to any one of claims 1 to 3.

5. A use of the polyvinyl pyrrolidone modified ferromagnetic clusters as claimed in claim 4, characterized in that: Use it as a biomaterial.

6. A use of the polyvinyl pyrrolidone modified ferromagnetic clusters as claimed in claim 4, characterized in that: It is applied in magnetic separation or magnetic targeting technology.

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