A hydrophilic magnetic solid nanosphere, its preparation method and application

Abstract

This application discloses a hydrophilic magnetic solid nanosphere, its preparation method, and its application. The hydrophilic magnetic solid nanosphere is characterized by having a core-shell structure; the shell is a hydrophilic polymer; the core is a magnetic nanoparticle encapsulating a polymer I; the polymer I and the hydrophilic polymer are connected by amide bonds and / or ester bonds; the magnetic nanoparticles are selected from at least one substance having the general formula shown in Formula I; Zn x Fe 3‑x O4 formula I; x ranges from 0.1 to 0.9. The hydrophilic magnetic solid nanospheres are a type of superparamagnetic nanomaterial that can be used as an MRI contrast agent for diagnosis, enabling magnetically responsive T1 and T2 switching imaging.

Description

Technical Field

[0001] This application relates to a hydrophilic magnetic solid nanosphere, its preparation method and application, belonging to the field of medical materials technology. Background Technology

[0002] With the development of technology, magnetic resonance imaging (MRI) has become a non-invasive and powerful medical diagnostic technique. This diagnostic technique features flexible imaging, non-ionizing properties, patient-friendly operation, and high patient acceptance. It uses computer hardware to manipulate pulse sequences to generate signals and pathways, reconstructing images from raw data to obtain high-resolution images with excellent soft tissue contrast, providing physiological parameters and unique clinical information.

[0003] While MRI offers superior spatiotemporal resolution compared to other diagnostic techniques, the sensitivity of its probes is severely limited. Over the past few decades, researchers have attempted to improve MRI sensitivity by using magnetic nanoparticles with high signal-to-noise ratios as contrast agents, aiming to achieve imaging that provides rich biological and functional information.

[0004] Traditional MRI contrast agents can be divided into T1 and T2 contrast agents. T1 contrast agents generally possess a large permanent magnetic moment, which can shorten the T1 longitudinal relaxation time of water protons and improve imaging sensitivity, but the signal is weak in areas with high water content. T2 contrast agents, on the other hand, have a large saturation magnetic induction intensity, enabling them to distinguish between normal and diseased tissues, but they achieve imaging by reducing the imaging signal, which can easily lead to confusion between normal and diseased tissues. Therefore, the T1-T2 dual-mode imaging strategy has emerged to overcome the limitations of single-mode imaging and achieve complementary advantages. Summary of the Invention

[0005] According to one aspect of this application, a hydrophilic magnetic solid nanosphere is provided, which is a superparamagnetic nanomaterial that can be used as an MRI contrast agent for diagnosis, realizing magnetically responsive T1 and T2 switching imaging functions.

[0006] A hydrophilic magnetic solid nanosphere, wherein the hydrophilic magnetic solid nanosphere has a core-shell structure;

[0007] The shell is a hydrophilic polymer;

[0008] The core is a magnetic nanoparticle encapsulated with polymer I;

[0009] The polymer I and the hydrophilic polymer are linked by amide bonds and / or ester bonds;

[0010] The magnetic nanoparticles are selected from at least one of the substances having the general formula shown in Formula I.

[0011] Zn x Fe 3-x O4 formula I;

[0012] The value of x ranges from 0.1 to 0.9.

[0013] Optionally, x can take values ​​from 0.1 to 0.5.

[0014] Optionally, the magnetic nanoparticles are selected from Zn. 0.1 Fe 2.9 O4, Zn 0.2 Fe 2.8 O4, Zn 0.3 Fe 2.7 O4, Zn 0.4 Fe 2.6 At least one of O4.

[0015] Optionally, the shell encapsulates at least one core; the core is a magnetic nanoparticle encapsulated with polymer I;

[0016] Optionally, the shell contains at least two nuclei; the nuclei are uniformly dispersed within the shell.

[0017] Optionally, the surface of polymer I contains carboxyl groups and / or acid anhydride groups;

[0018] The monomers of the hydrophilic polymer contain carbon-carbon unsaturated bonds, hydroxyl groups and / or amino groups;

[0019] Optionally, the polymer I is selected from at least one of polyisobutylene-maleic anhydride, mercapto-polyethylene glycol-carboxyl, and amino-polyethylene glycol-carboxyl.

[0020] Optionally, the monomer of the hydrophilic polymer is selected from at least one of acrylate compounds;

[0021] Optionally, the monomer of the hydrophilic polymer is selected from at least one of 2-hydroxyethyl methacrylate and glycosyloxyethyl methacrylate.

[0022] Optionally, the magnetic nanoparticles have a particle size of 1 nm to 20 nm;

[0023] The hydrophilic magnetic solid nanospheres have a particle size of 50 nm to 1000 nm.

[0024] Optionally, the upper limit of the particle size of the magnetic nanoparticles is selected from 4, 7, 10, and 20 nm; the lower limit is selected from 1, 4, 7, and 10 nm.

[0025] Optionally, the upper limit of the particle size of the hydrophilic magnetic solid nanospheres is selected from 80, 100, 150, 200, 300, 500, 800, and 1000 nm; and the lower limit is selected from 50, 80, 100, 150, 200, 300, 500, and 800 nm.

[0026] According to another aspect of this application, a method for preparing hydrophilic magnetic solid nanospheres according to any one of the foregoing claims is provided, the method comprising:

[0027] (S1) The raw material containing magnetic nanoparticles encapsulating polymer I and polymer monomer II of hydrophilic polymer is contacted and reacted in the presence of a catalyst to obtain a precursor.

[0028] (S2) Add a free radical initiator to the precursor and obtain the hydrophilic magnetic solid nanospheres through polymerization reaction III.

[0029] Optionally, in (S1), the conditions for reaction II are: temperature II is 10-40°C, and time II is not less than 1 hour;

[0030] The catalyst is selected from at least one of coupling agents;

[0031] The monomer II is selected from at least one of acrylate compounds;

[0032] In (S2), the free radical initiator is selected from at least one of azo compounds;

[0033] In (S2), the conditions for polymerization reaction III are: temperature III is 40℃~100℃, and time III does not exceed 8h.

[0034] Optionally, the coupling agent is selected from at least one of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, N-hydroxysuccinimide, and 4-dimethylaminopyridine.

[0035] Optionally, the acrylate compound is selected from 2-hydroxyethyl methacrylate and / or glycosyloxyethyl methacrylate.

[0036] Optionally, in (S1), the molar ratio of the magnetic nanoparticles containing polymer I, monomer II, and catalyst is:

[0037] Contains magnetic nanoparticles encapsulated with polymer I: monomer II: catalyst = 1:1~3000:1~4096000;

[0038] The number of moles of magnetic nanoparticles containing polymer I is calculated based on the number of moles of the metal elements contained therein.

[0039] Optionally, in (S1), the molar ratio of the magnetic nanoparticles containing polymer I, monomer II, and catalyst is:

[0040] Contains magnetic nanoparticles encapsulated with polymer I: monomer II: catalyst = 1:1~1500:1~1100000.

[0041] Optionally, in (S2), the molar ratio of the precursor to the free radical initiator is:

[0042] Precursor: Free radical initiator = 1:1 to 312500;

[0043] The number of moles of the precursor is calculated based on the number of moles of the metal element it contains.

[0044] According to another aspect of this application, a hydrophilic magnetic solid nanosphere is provided as an application of a magnetically responsive T1 and T2 switching MRI contrast agent.

[0045] The hydrophilic magnetic solid nanospheres comprise: magnetic nanoparticles, polymer I, and polymer II;

[0046] The magnetic nanoparticles are selected from at least one of zinc-doped ferrite nanoparticles.

[0047] The polymer II is a hydrophilic polymer;

[0048] The polymer I is coated on the magnetic nanoparticles to form intermediate I, and the nanospheres I are distributed in the polymer II;

[0049] Polymer I and polymer II are linked by amide bonds and / or ester bonds.

[0050] Optionally, the hydrophilic magnetic solid nanospheres are selected from at least one of the hydrophilic magnetic solid nanospheres described in any one of the above claims and the hydrophilic magnetic solid nanospheres prepared according to the preparation method described in any one of the above claims.

[0051] By applying an external magnetic field to the hydrophilic magnetic solid nanospheres, their particle size changes to a certain extent, and their MRI signals achieve a transition between T1-weighted and T2-weighted weighting.

[0052] The hydrophilic magnetic solid nanospheres, used as MRI contrast agents, provide complementary T1 and T2 imaging information, which can improve the accuracy of cancer diagnosis.

[0053] In this application, the amino group is -NR1R2, wherein R1 and R2 are independently selected from H and alkyl groups having 1 to 20 carbon atoms.

[0054] In this application, EDC is an abbreviation for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; PMA is an abbreviation for polyisobutylene-maleic anhydride; HEMA is an abbreviation for 2-hydroxyethyl methacrylate; AIBN is an abbreviation for azobisisobutyronitrile; GEMA is an abbreviation for glycosyloxyethyl methacrylate; and SBB is an abbreviation for sodium borate buffer.

[0055] It should be understood that, within the scope of the technical solutions disclosed in this application, the above-mentioned technical features of this application and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here.

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to one skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be used in the methods of this application. The preferred embodiments and materials described herein are for illustrative purposes only.

[0057] The beneficial effects of the technical solution described in this application include:

[0058] (1) The hydrophilic magnetic solid nanospheres provided in this application are 3D solid structures with advantages such as equal spacing between magnetic nanoparticles and uniform force, good magnetic properties, good water solubility, and good biocompatibility.

[0059] (2) The hydrophilic magnetic solid nanospheres provided in this application are a superparamagnetic nanomaterial that can be used as an MRI contrast agent for diagnosis, realizing magnetic response T1 and T2 switching imaging function.

[0060] (3) The preparation method provided in this application is simple and easy to operate, which is conducive to the control of the degree of reaction and polymerization and is suitable for large-scale production. Attached Figure Description

[0061] Figure 1 It is sample 1 # Transmission electron microscope image.

[0062] Figure 2 It is sample 2 # Transmission electron microscope (TEM) images, where A is a backscattered SEM image and B is a secondary electron SEM image.

[0063] Figure 3 It is sample 2 # Scanning electron microscope image.

[0064] Figure 4 It is sample 2 #Figure 1 shows the application of contrast agents for magnetically responsive T1 and T2 switching MRI, where Figure A is the water control and Figure B is the contrast agent with 2... # As a contrast agent, the T1-weighted image is obtained, and C is a 2... # T2-weighted images obtained as a contrast agent. Detailed Implementation

[0065] The present application is described in detail below with reference to the embodiments, but the present application is not limited to these embodiments.

[0066] Unless otherwise specified, all raw materials used in the embodiments of this application were purchased through commercial channels.

[0067] The room temperature described in this application is 25°C.

[0068] Example 1: Obtaining a magnetic nanoparticle sample coated with polymer I

[0069] Zn 0.2 Fe 2.8 Preparation of O4-PMA

[0070] Take oil phase Zn with an average particle size of 7 nm at a molar ratio of 1:50. 0.2 Fe 2.8 O4 nanoparticles were mixed with the amphiphilic polymer PMA and then stirred uniformly in a chloroform solution at room temperature using a rotary evaporator until the chloroform was completely evaporated to obtain Zn. 0.2 Fe 2.8 O4-PMA, the resulting Zn 0.2 Fe 2.8 The average particle size of O4-PMA is 15 nm, denoted as sample 1. # Zn 0.2 Fe 2.8 O4-PMA.

[0071] The oil phase Zn 0.2 Fe 2.8 The preparation method of O4 nanoparticles refers to the literature "Controlling Doping Content and Precisely Adjusting Particle Size of Zn". x Fe 3-x Contrast Properties of Zn4 Nanoparticles in Magnetic Resonance Imaging (Ma, Yuanyuan, et al. Precisely Tuning the Contrast Properties of Zn4 Nanoparticles) x Fe 3-xO4Nanoparticles in Magnetic Resonance Imaging by Controlling Their Doping Content and Size (Chemistry of Materials, 2019, 31, 18, 7255-7264) were prepared by the method described in the article; the synthesis of the amphiphilic polymer PMA and the encapsulation of Zn 0.2 Fe 2.8 The O4 was prepared according to the methods described in the literature "Polymer-coated nanoparticles: a universal tool for biolabelling experiments" (F. Zhang, E. Lees, F. Amin, P. Rivera Gil, F. Yang, P. Mulvaney, W. J. Parak, Small, 2011, 7, 22, 3113-27) and "Design of an amphiphilic polymer for nanoparticle coating and functionalization" (CALin, RASperling, JKLi, TYYang, PYLi, M. Zanella, WHChang, W. J. Parak, Small, 2008, 4, 3, 334-41).

[0072] Example 2 Monomer II and Zn coated with polymer I 0.2 Fe 2.8 Preparation of O4-linked samples

[0073] Monomer II and Zn coated with polymer I 0.2 Fe 2.8 The connection of O4 is respectively taken from Zn coated with polymer I. 0.2 Fe 2.8 O4, monomer II, and catalyst are mixed with SBB 9 (pH=9) to form a solution, resulting in Zn coated with polymer I. 0.2 Fe 2.8 SBB solutions of O4, monomer II, and catalyst. In Zn coated with polymer I. 0.2 Fe 2.8 Comparative experiments were conducted within the range of O4:monomer II:catalyst molar ratios of 1:1 to 3000:1 to 4096000, with the specific ratios as follows:

[0074] Formula I (a series of magnetic nanoparticle samples coated with polymer I, containing Zn) 0.2 Fe 2.8 O4-PMA, monomer II is HEMA, catalyst is EDC:

[0075] A series of magnetic nanoparticle samples coated with polymer I: the molar ratio of monomer II to catalyst is 1:3000:1;

[0076] Formulation II (a series of magnetic nanoparticle samples coated with polymer I, containing Zn) 0.2 Fe 2.8 O4-PMA, monomer II is HEMA, catalyst is EDC:

[0077] A series of magnetic nanoparticle samples coated with polymer I: the molar ratio of monomer II to catalyst is 1:1:4096000;

[0078] Formula III (a series of magnetic nanoparticle samples coated with polymer I, containing Zn) 0.2 Fe 2.8 O4-PMA, monomer II is HEMA, catalyst is EDC:

[0079] A series of magnetic nanoparticle samples coated with polymer I: monomer II: catalyst = 1:500:1000000;

[0080] Formulation IV (a series of magnetic nanoparticle samples coated with polymer I, containing Zn) 0.2 Fe 2.8 O4-PMA, monomer II is HEMA, catalyst is EDC:

[0081] A series of magnetic nanoparticle samples coated with polymer I: monomer II: catalyst = 1:1500:1100000;

[0082] The ratio V (of the series of magnetic nanoparticle samples coated with polymer I is Zn) 0.2 Fe 2.8 O4-PMA, monomer II is HEMA, catalyst is EDC:

[0083] A series of magnetic nanoparticle samples coated with polymer I: monomer II: catalyst = 1:1000:1024000.

[0084] Formula VI (a series of magnetic nanoparticle samples coated with polymer I, containing Zn) 0.2 Fe 2.8 O4-PMA, monomer II is HEMA, catalyst is EDC:

[0085] A series of magnetic nanoparticle samples coated with polymer I: monomer II: catalyst = 1:1:5120.

[0086] Formula VII (a series of magnetic nanoparticle samples coated with polymer I, containing Zn) 0.2 Fe 2.8 O4-PMA, monomer II is GEMA, catalyst is EDC:

[0087] A series of magnetic nanoparticle samples coated with polymer I: monomer II: catalyst = 69.6:69.6:71.3.

[0088] The specific connection steps are as follows:

[0089] Take Zn coated with polymer I 0.2 Fe 2.8 The SBB solution of O4 and the SBB solution of monomer II were mixed thoroughly in a 1.5 mL centrifuge tube, and then the SBB solution of the catalyst was added. After mixing thoroughly, the centrifuge tube was placed in a constant temperature shaking incubator at 25°C and the reaction was carried out for 13 h. After the reaction was completed, the liquid in the centrifuge tube was removed, and the optimal reactant ratio and the best reactant ratio were determined by gel electrophoresis.

[0090] The specific steps for determining the optimal reactant ratio through gel electrophoresis experiments were performed in accordance with the method described in the literature "Electrophoretic separation of nanoparticles with a discrete number of functional groups" (RA Sperling, T. Pellegrino, JK Li, WHChang, WJ Parak, Advanced Functional Materials, 2006, 16, 7, 943-948).

[0091] The optimal ratios were determined by gel electrophoresis experiments: ratios III, IV, V, VI, and VII. Among them, ratios VI and VII were better than ratio V, and ratio V was better than ratios III and IV.

[0092] As can be seen from the above experiments, the preferred reactant ratio range is: a series of magnetic nanoparticles coated with polymer I: monomer II: catalyst = 1:1 to 1500:1 to 1100000.

[0093] Monomer II obtained from proportions VI and VII reacts with Zn coated with polymer I. 0.2 Fe 2.8The relationship between the O4-linked sample number and the types and ratios of reactants is shown in Table 1. Under the conditions in Table 1, after the reaction was completed, the resulting liquid was removed, centrifuged and washed, and the resulting SBB solution was stored in a refrigerator at approximately 4°C for subsequent reactions.

[0094] Table 1

[0095]

[0096] Example 3: Preparation of hydrophilic magnetic solid nanosphere samples

[0097] Monomer II obtained from proportions VI and VII of Example 2 was mixed with Zn coated with polymer I. 0.2 Fe 2.8 O4 was used as a precursor and free radical initiator in a molar ratio of monomer II to Zn coated with polymer I. 0.2 Fe 2.8 Parallel experiments were conducted within the range of O4-linked sample (precursor): free radical initiator = 1-500: 1-312500 (molar ratio).

[0098] The specific ratio is as follows:

[0099] Formula A:

[0100] Precursor: free radical initiator = 1:1;

[0101] Formula B:

[0102] Precursor: Free radical initiator = 1:312500;

[0103] Ratio C:

[0104] Precursor: Free radical initiator = 1:6000;

[0105] Ratio D:

[0106] Precursor: Free radical initiator = 1:300000;

[0107] Formula E:

[0108] Precursor: Free radical initiator = 500:13.1;

[0109] Ratio F:

[0110] Precursor: Free radical initiator = 303:98.8.

[0111] The specific preparation steps are as follows:

[0112] Take monomer II and Zn coated with polymer I 0.2 Fe 2.8The O4-linked sample (precursor) SBB solution was added to a 1.5 mL centrifuge tube, followed by a free radical initiator solution. After thorough mixing, the centrifuge tube was placed in a cell disruptor for reaction. The reaction was then completed. The resulting hydrophilic magnetic solid nanospheres were obtained after washing and centrifugation.

[0113] By comparing and observing the morphology of the samples, the optimal amount of initiator was determined. A better ratio resulted in a product with a morphology closer to perfect spherical shape and more uniform particle size. Comparison showed that ratios C, D, E, and F performed well, with ratios E and F being superior to ratios C and D. Therefore, through the above experiments, the preferred molar ratio of precursor to free radical initiator was determined to be precursor:free radical initiator = 1–500:10–300,000.

[0114] The relationship between the numbering of the obtained hydrophilic magnetic solid nanosphere samples and the types and ratios of reactants is shown in Table 2.

[0115] Table 2

[0116]

[0117] Morphological characterization of the sample in Example 4

[0118] A JSM-7500F scanning electron microscope (SEM) and a JEOL JEM3010UHR transmission electron microscope (TEM) were used to examine 1. # Zn 0.2 Fe 2.8 O4-PMA and Sample 2 # Zn 0.2 Fe 2.8 O4-PMA-HEMA was characterized, and the results are as follows: Figures 1-3 As shown. Wherein:

[0119] Figure 1 It is sample 1 # Transmission electron microscope images, by Figure 1 It can be seen that sample 1 # The sample is a spherical sample with a uniform particle size distribution and an average particle size of 15 nm.

[0120] Figure 2 It is sample 2 # Scanning electron microscope (SEM) images, where A is a backscattered SEM image and B is a secondary electron SEM image. Figure 2 It can be seen that sample 2 # The sample is a spherical sample with a uniform particle size distribution and an average particle size of 400 nm.

[0121] Figure 3 It is sample 2 # Transmission electron microscope (TEM) images. (By...) Figure 3It can be seen that sample 2 # Each spherical particle contains multiple Zn molecules encapsulated in polymer HEMA. 0.2 Fe 2.8 O4-PMA nanoparticles, Zn 0.2 Fe 2.8 O4-PMA nanoparticles are uniformly distributed in spherical particles.

[0122] Example 5: Application of hydrophilic magnetic solid nanospheres as a magnetically responsive T1 and T2 switching MRI contrast agent

[0123] Hydrophilic magnetic solid nanospheres were prepared into solutions of different concentrations (0.1 μM, 0.3 μM, 0.5 μM, 0.7 μM, 0.9 μM, 1 μM) using water as a contrast agent, with water as a control. The samples were scanned using magnetic resonance imaging (MRI). The results are as follows: Figure 4 As shown, A is the MRI imaging of water as a reference in the T1 sequence, B is the T1 imaging of samples with different concentrations in the absence of a static magnetic field (from left to right, the concentrations of hydrophilic magnetic solid nanospheres are 0.1 μM, 0.3 μM, 0.5 μM, 0.7 μM, 0.9 μM, and 1 μM), and C is the T2 imaging of samples with different concentrations under the influence of a static magnetic field.

[0124] As can be seen from the above, the hydrophilic magnetic solid nanospheres provided in this application are a novel contrast agent for switching between T1 and T2 in magnetic resonance imaging. By changing the magnetism, the switching between T1 and T2 contrast agents can be achieved, which is expected to play a significant role in the field of MRI diagnostic technology.

[0125] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A hydrophilic magnetic solid nanosphere, characterized in that, The hydrophilic magnetic solid nanospheres have a core-shell structure. The shell is a hydrophilic polymer; The core is a magnetic nanoparticle encapsulated with polymer I; The polymer I and the hydrophilic polymer are linked by amide bonds and / or ester bonds; The magnetic nanoparticles are selected from at least one of the substances having the general formula shown in Formula I. Zn x Fe 3-x O4 of formula I; The value of x ranges from 0.1 to 0.9; The polymer I is selected from at least one of polyisobutylene-maleic anhydride, mercapto-polyethylene glycol-carboxyl, and amino-polyethylene glycol-carboxyl. The shell contains at least two nuclei; the nuclei are uniformly dispersed within the shell.

2. The hydrophilic magnetic solid nanosphere according to claim 1, characterized in that, The magnetic nanoparticles are selected from Zn. 0.1 Fe 2.9 O4, Zn 0.2 Fe 2.8 O4, Zn 0.3 Fe 2.7 O4, Zn 0.4 Fe 2.6 At least one of O4.

3. The hydrophilic magnetic solid nanosphere according to claim 1, characterized in that, The monomers of the hydrophilic polymer contain carbon-carbon unsaturated bonds, hydroxyl groups, and / or amino groups.

4. The hydrophilic magnetic solid nanosphere according to claim 1, characterized in that, The monomer of the hydrophilic polymer is selected from at least one of acrylate compounds.

5. The hydrophilic magnetic solid nanosphere according to claim 4, characterized in that, The monomer of the hydrophilic polymer is selected from at least one of 2-hydroxyethyl methacrylate and glycosyloxyethyl methacrylate.

6. The hydrophilic magnetic solid nanosphere according to claim 1, characterized in that, The magnetic nanoparticles have a particle size of 1 nm to 20 nm; The hydrophilic magnetic solid nanospheres have a particle size of 50 nm to 1000 nm.

7. The method for preparing hydrophilic magnetic solid nanospheres according to any one of claims 1 to 6, characterized in that, The preparation method includes: (S1) The raw material containing magnetic nanoparticles encapsulating polymer I and polymer monomer II of hydrophilic polymer is contacted and reacted in the presence of a catalyst to obtain the precursor. (S2) Add a free radical initiator to the precursor and obtain the hydrophilic magnetic solid nanospheres by polymerization reaction III.

8. The preparation method according to claim 7, characterized in that, In (S1), the conditions for reaction II are: temperature II is 10~40℃, and time II is not less than 1h; The catalyst is selected from at least one of coupling agents; The monomer II is selected from at least one of acrylate compounds; In (S2), the free radical initiator is selected from at least one of azo compounds; In (S2), the conditions for polymerization reaction III are: temperature III is 40℃~100℃, and time III does not exceed 8h.

9. The application of a hydrophilic magnetic solid nanosphere as a magnetically responsive T1 and T2 switching MRI contrast agent, characterized in that, The hydrophilic magnetic solid nanospheres comprise: magnetic nanoparticles, polymer I, and polymer II; The magnetic nanoparticles are selected from at least one of zinc-doped ferrite nanoparticles. The polymer II is a hydrophilic polymer; The polymer I is coated on the magnetic nanoparticles to form intermediate I, and the nanospheres I are distributed in the polymer II; Polymer I and polymer II are linked by amide bonds and / or ester bonds; The hydrophilic magnetic solid nanospheres are selected from at least one of the hydrophilic magnetic solid nanospheres according to any one of claims 1 to 6, and the hydrophilic magnetic solid nanospheres prepared by the preparation method according to claim 7 or 8.

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