Magnetic triiron tetroxide nanoparticles, their preparation method and use

Abstract

The present invention discloses magnetic triiron tetroxide nanoparticles, their preparation method and use. The magnetic triiron tetroxide nanoparticles contain triiron tetroxide and a hydrophilic polymer, and the triiron tetroxide and the hydrophilic polymer are in at least one of the following relationships: (1) the hydrophilic polymer is adsorbed on the surface of triiron tetroxide, and (2) the triiron tetroxide and the hydrophilic polymer are embedded or occluded in each other. The present invention uses a hydrophilic polymer as a stabilizer to co-precipitate ferrous ions and ferric ions to form magnetic triiron tetroxide nanoparticles, which have a high longitudinal magnetic relaxation rate r1, a low transverse longitudinal magnetic relaxation rate ratio (r2 / r1), good water solubility, high stability, good biocompatibility, and can be used as a T1-weighted magnetic resonance imaging (MRI) contrast agent to improve the contrast and sensitivity of MRI.

Description

[Technical Field]

[0001] The present invention relates to the technical field of biomedical materials, and in particular to magnetic triiron tetroxide nanoparticles, their preparation method and use. [Background technology]

[0002] Magnetic resonance imaging (MRI) has a relatively good imaging effect on soft tissues and can effectively distinguish between lesions and healthy tissue, making it widely used in clinical diagnosis. MRI contrast agents can improve the contrast and sensitivity of MRI. Currently, contrast agents are used in over 40% of MRI clinical diagnoses, making MRI contrast agents an important part of magnetic resonance imaging. MRI contrast agents react with hydrogen protons to shorten the longitudinal relaxation time (T1) or transverse relaxation time (T2). MRI contrast agents can be divided into two types based on their contrast effects: T1-weighted MRI contrast agents (positive contrast agents) and T2-weighted MRI contrast agents (negative contrast agents). T1-weighted MRI contrast agents (positive contrast agents) can generate bright signals, while T2-weighted MRI contrast agents (negative contrast agents) can generate dark signals. Compared with T2 contrast agents, T1 contrast agents can generate bright signals, which is more advantageous for clinicians to diagnose lesions; therefore, T1 contrast agents are mostly used in clinical practice. The r1 value and the r2 / r1 ratio are two important parameters for expressing the contrast effect of an MRI contrast agent. A higher r1 value and a lower r2 / r1 ratio are favorable for T1 contrast agents. Similarly, a higher r2 value and a higher r2 / r1 ratio are favorable for T2 contrast agents. Typically, T1 contrast agents are gadolinium-based contrast agents, and T2 contrast agents are iron-based contrast agents. Clinically used T1 contrast agents are primarily small molecule gadolinium chelates, including Magnevist®, Gadavist®, Dotarem®, Omniscan®, and Vasovist®. The U.S. FDA has issued a warning against gadolinium-based clinical contrast agents, citing their potential for brain deposition and nephrotoxicity, posing certain risks in clinical applications.

[0003] Iron is one of the essential elements in the human body, and triiron tetroxide has excellent biocompatibility. It is safer and more reliable to use as an MRI contrast agent in clinical diagnosis than gadolinium-based chelates. However, triiron tetroxide exists mainly as a T2 contrast agent, and its characteristic of generating dark signals has serious implications for clinical application. The r2 value of triiron tetroxide shows a positive correlation with particle size, and the saturation magnetization (M z ) and the r2 value also increased. On the other hand, triiron tetroxide with a particle size of 5 nm or less (magnetic triiron tetroxide nanoparticles (ES-MIONs)) exhibited a significantly reduced saturation magnetization and a low r2 value, making it suitable for use as a T1 contrast agent. Therefore, magnetic triiron tetroxide nanoparticles with a particle size of less than 5 nm and a high r1 and low r2 value are expected to be used in clinical diagnosis as safe, reliable T1 contrast agents with good imaging effects. Related technology exists for producing triiron tetroxide with a particle size of 5 nm or less using polymers such as PVA (polyvinyl alcohol). This triiron tetroxide exhibits the characteristics of a T1 contrast agent, but its dispersibility is poor and its imaging effect is limited. Summary of the Invention [Problem to be solved by the invention]

[0004] The present invention aims to solve at least one of the technical problems existing in the prior art by providing magnetic triiron tetroxide nanoparticles with a high r1 value, a low r2 / r1 ratio, good water solubility, high stability, and good biocompatibility.

[0005] The present invention also provides a method for producing the magnetic triiron tetroxide nanoparticles and uses thereof. [Means for solving the problem]

[0006] Specifically, the technical solutions adopted by the present invention are as follows:

[0007] A first aspect of the present invention is The present invention comprises triiron tetroxide and a hydrophilic polymer, wherein the triiron tetroxide and the hydrophilic polymer exist in at least one of the following relationships with respect to each other: (1) the hydrophilic polymer is adsorbed onto the surface of the triiron tetroxide; and (2) the triiron tetroxide and the hydrophilic polymer are embedded or occluded in each other; 1) The average particle size is greater than 2 nm and less than 5 nm. 2) Zeta potential is -10mV or less; 3) Hydrodynamic diameter is 20 nm or less; 4) The value of the longitudinal magnetic relaxation rate r1 at a magnetic field strength of 3.0 T is 5 mM. -1 s -1 The longitudinal magnetic relaxation rate r1 at a magnetic field strength of 1.0 T is larger than 10 mM. -1 s -1 That is greater than The present invention provides magnetic triiron tetroxide nanoparticles that simultaneously possess several of the above properties.

[0008] The magnetic triiron tetroxide nanoparticles according to the first aspect of the present invention have at least the following beneficial effects.

[0009] The present invention uses a hydrophilic polymer as a stabilizer to form magnetic triiron tetroxide nanoparticles (which can be synthesized by coprecipitation) with triiron tetroxide through surface adsorption, mutual embedding, or occlusion. These magnetic triiron tetroxide nanoparticles are water-soluble nanodrugs that have better water solubility and higher stability, a larger r1 value, and a smaller r2 / r1 ratio than existing triiron tetroxide surface-modified with a polymer or triiron tetroxide synthesized by the oil phase method in related technologies, making them useful as safe and reliable T1 contrast agents.

[0010] In some embodiments of the present invention, the Zeta potential of the magnetic triiron tetroxide nanoparticles is −30 mV or less, preferably −35 mV or less, more preferably −60 to −35 mV.

[0011] In some embodiments of the present invention, the hydrodynamic diameter of the magnetic iron tetroxide nanoparticles is 20 nm or less, preferably 15 nm or less.

[0012] In some embodiments of the present invention, the hydrophilic polymer comprises a copolymer or mixture of any one or more of a carboxylic acid-containing polymer, an amino-containing polymer, a hydroxy-containing polymer, an amide-containing polymer, and a polysaccharide.

[0013] In some embodiments of the present invention, the hydrophilic polymer has a molecular weight of 1,000 to 10,000, which may be appropriately selected depending on the specific situation.

[0014] In some embodiments of the present invention, the carboxylic acid-containing polymer comprises any one or more of polyglutamic acid, polyaspartic acid, polymaleic acid, poly(2-ethylacrylic acid), and polyepoxysuccinic acid.

[0015] In some embodiments of the present invention, the amino-containing polymer comprises any one or more of polylysine, polyhistidine, polyarginine, and polydimethyldiallylammonium chloride.

[0016] In some embodiments of the present invention, the hydroxy-containing polymer comprises any one or more of polyserine, polythreonine, polytyrosine, and tannic acid.

[0017] In some embodiments of the present invention, the amide-containing polymer comprises any one or more of polyglutamine, polyasparagine, polyacrylamide, and polymethacrylamide.

[0018] In some embodiments of the invention, the polysaccharide comprises one or two of hyaluronic acid and sodium alginate.

[0019] A second aspect of the present invention is The present invention provides a method for producing the magnetic triiron tetroxide nanoparticles, which comprises the step of co-precipitating iron (II) ions and iron (III) ions using a hydrophilic polymer as a stabilizer to form magnetic triiron tetroxide nanoparticles.

[0020] After co-precipitation, the ferrous ions and ferric ions react to form iron trioxide, and the iron trioxide and hydrophilic polymer form magnetic iron trioxide nanoparticles through surface adsorption, mutual embedding or occlusion.

[0021] More specifically, using a hydrophilic polymer as a stabilizer, iron (II) ions and iron (III) ions are coordinated with the hydrophilic polymer, and then an alkaline solution is added to carry out a coprecipitation reaction, thereby obtaining the magnetic triiron tetroxide nanoparticles.

[0022] In some embodiments of the present invention, the method for producing the magnetic triiron tetroxide nanoparticles comprises: The method includes the steps of heating a hydrophilic polymer solution, then mixing the hydrophilic polymer solution with an iron ion mixed solution containing divalent iron ions and trivalent iron ions to carry out a coordination reaction, and then adding an alkaline solution to carry out a co-precipitation reaction to obtain the magnetic triiron tetroxide nanoparticles.

[0023] In some embodiments of the present invention, in the iron ion mixed solution, the concentration of divalent iron ions is 30 to 500 mM, preferably 50 to 250 mM, more preferably 150 to 250 mM, and even more preferably 200 to 250 mM, and the concentration of trivalent iron ions is 60 to 1000 mM, preferably 100 to 500 mM, more preferably 300 to 500 mM, and even more preferably 350 to 500 mM.

[0024] In some embodiments of the present invention, the concentration of the hydrophilic polymer solution is 0.1 to 20 mg / mL, preferably 0.5 to 5 mg / mL.

[0025] In some embodiments of the present invention, the volume ratio of the hydrophilic polymer solution to the iron ion mixed solution is 1 to 500:1, preferably 10 to 50:1.

[0026] In some embodiments of the present invention, the hydrophilic polymer solution and the iron ion mixed solution are both aqueous solutions.

[0027] In some embodiments of the present invention, the divalent iron ions are obtained by hydrolyzing a water-soluble divalent iron salt, and the water-soluble divalent iron salt includes any one or more of ferrous chloride, ferrous nitrate, ferrous bromide, and ferrous sulfate, and preferably ferrous sulfate.

[0028] In some embodiments of the present invention, the iron(III) ions are obtained by hydrolyzing a water-soluble iron(III) salt, and the water-soluble iron(III) salt includes any one or more of iron chloride, iron nitrate, iron bromide, and iron sulfate, and preferably iron chloride.

[0029] In some embodiments of the present invention, the pH of the alkali is 10 to 12, preferably 11.5. After adding the alkali to the mixed solution of the iron ion mixed solution and the hydrophilic polymer solution, the pH of the reaction system is 8 to 10, preferably 9.5.

[0030] In some embodiments of the present invention, the alkaline solution contains at least one of sodium hydroxide and its aqueous solution, potassium hydroxide and its aqueous solution, and ammonia water, and is preferably ammonia water. Preferably, the mass concentration of the ammonia water is 0.5% to 5%, preferably 1% to 4%.

[0031] In some embodiments of the present invention, the alkali is in the form of a solution, and the volume ratio of the alkali to the hydrophilic polymer solution is 1:2-10, preferably 1:4-6.

[0032] In some embodiments of the present invention, the temperature to which the hydrophilic polymer solution is heated and the temperature of the coprecipitation reaction are each independently 25 to 100°C, preferably 100°C.

[0033] In some embodiments of the present invention, the time for the co-precipitation reaction is longer than 5 minutes, preferably 40 to 100 minutes.

[0034] A third aspect of the present invention provides the use of the above-described magnetic triiron tetroxide nanoparticles in the manufacture of an MRI contrast agent.

[0035] In some embodiments of the invention, the MRI contrast agent is a longitudinal relaxation contrast agent (T1 contrast agent). [Effects of the Invention]

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] The magnetic triiron tetroxide nanoparticles of the present invention have a high r1 value (>5 mM -1 s -1 , 3.0T;>10mM -1 s -1, 1.0T) and a low r2 / r1 ratio (<13.0, 3.0T), comparable to gadolinium-based chelate contrast agents for clinical use. The iron-based MRI contrast agent of the present invention is synthesized by coprecipitation using a hydrophilic polymer as a stabilizer, and has good imaging effect, a low signal-to-noise ratio, good water solubility, excellent stability, a small hydrodynamic diameter, and favorable blood circulation. Moreover, the hydrophilic polymer used in the present invention is biodegradable, so it has better biocompatibility and safety than gadolinium-based chelate contrast agents for clinical use. [Brief explanation of the drawings]

[0038] [Figure 1] 1A and 1B are a transmission electron microscope image and a particle size distribution diagram of γ-PGA-ES-MION6 in Example 1. [Figure 2] FIG. 1 shows the hydrodynamic diameter and Zeta potential of γ-PGA-ES-MION6 in Example 1. [Figure 3] FIG. 1 is an MRI relaxation curve of γ-PGA-ES-MION6 in Example 1. [Figure 4] FIG. 1 is a saturation magnetization diagram of γ-PGA-ES-MION6 in Example 1. [Figure 5] 1 shows an X-ray energy spectrum and an X-ray diffraction pattern of γ-PGA-ES-MION6 in Example 1. [Figure 6] 1 shows an infrared absorption spectrum of γ-PGA-ES-MION6 in Example 1. [Figure 7] 1 shows T1-weighted MRI images of γ-PGA-ES-MION6 and pure water in Example 1, and the corresponding MRI signal intensities. [Figure 8] 1 shows MRI images formed when γ-PGA-ES-MION6 in Example 1 was injected into the body of a tumor-bearing mouse. [Figure 9] This is a transmission electron microscope image of PASP-ES-MION9 in Example 2. [Figure 10] FIG. 1 shows the hydrodynamic diameter and Zeta potential of PASP-ES-MION9 in Example 2. [Figure 11] FIG. 1 is an MRI relaxation curve of PASP-ES-MION9 in Example 2. [Figure 12] 1 shows the X-ray diffraction pattern and X-ray energy spectrum of PASP-ES-MION9 in Example 2. [Figure 13] 1 shows a T1-weighted MRI image of PASP-ES-MION9 in Example 2 and the corresponding MRI signal intensity. [Figure 14] 1 is an infrared absorption spectrum of PASP-ES-MION9 in Example 2. [Figure 15] This is an MRI image formed when PASP-ES-MION9 in Example 2 was injected into the body of a tumor-bearing mouse. [Figure 16] FIG. 1 is an MRI relaxivity diagram of HPMA-ES-MION in Example 3. [Figure 17] FIG. 1 is an MRI relaxivity diagram of PEAA-ES-MION in Example 4. [Figure 18] FIG. 10 is an MRI relaxation curve of PESA-ES-MION in Example 5. [Figure 19] FIG. 10 is an MRI relaxivity diagram of ε-PL-ES-MION in Example 6. [Figure 20] FIG. 10 is an MRI relaxivity diagram of PLH-ES-MION in Example 7. [Figure 21] FIG. 10 is an MRI relaxivity diagram of PLR-ES-MION in Example 8. [Figure 22] FIG. 10 is an MRI relaxivity diagram of PDDA-ES-MION in Example 9. [Figure 23] FIG. 10 is an MRI relaxation curve of PSer-ES-MION in Example 10. [Figure 24] FIG. 11 is an MRI relaxivity diagram of PThr-ES-MION in Example 11. [Figure 25] FIG. 12 is an MRI relaxation curve of PTyr-ES-MION in Example 12. [Figure 26] FIG. 13 is an MRI relaxivity diagram of TA-ES-MION in Example 13. [Figure 27] FIG. 10 is an MRI relaxation curve of PolyQ-ES-MION in Example 14. [Figure 28] FIG. 10 is an MRI relaxivity diagram of PHEA-ES-MION in Example 15. [Figure 29] FIG. 16 is an MRI relaxivity diagram of PAM-ES-MION in Example 16. [Figure 30] FIG. 10 is an MRI relaxivity diagram of PMAM-ES-MION in Example 17. [Figure 31] FIG. 10 is an MRI relaxivity diagram of HA-ES-MION in Example 18. [Figure 32] FIG. 10 is an MRI relaxivity diagram of SA-ES-MION in Example 19. [Figure 33] FIG. 10 is an MRI relaxation curve of γ-PGA / PASP-ES-MION in Example 20. [Figure 34] FIG. 10 is an MRI relaxivity diagram of HPMA / PASP-ES-MION in Example 21. DETAILED DESCRIPTION OF THE INVENTION

[0039] The technical solution of the present invention will be further described below with reference to specific examples. The raw materials used in the following examples can be obtained from ordinary commercial channels unless otherwise specified. The processes used are all conventional techniques in the art unless otherwise specified. Example 1

[0040] Preparation of magnetic triiron tetroxide nanoparticles (γ-PGA-ES-MION) Polyglutamic acid γ-PGA(M w20 mL of a 2000 (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing FeSO4 and FeCl3 was added to the flask, followed by 6 mL of aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then the mixture was allowed to cool. The sample after the reaction was completed was purified by dialysis, and the final sample was designated γ-PGA-ES-MION. The concentrations of the polyglutamic acid aqueous solution, mixed aqueous solution, and aqueous ammonia, as well as the corresponding samples, are shown in Table 1. The physical properties of the sample of Example 1 were evaluated. The iron recovery rate calculated for the sample of Example 1 was 96%, indicating a high utilization rate of raw materials and effective cost reduction. The sample of Example 1, the commercially available Gadavist, and Magnevist were each prepared into six aqueous solutions of different concentrations, and ex vivo imaging tests were performed on 1.0 T, clinical 3.0 T, and 7.0 T MRI systems to obtain the longitudinal relaxation time T1 and the transverse relaxation time T2, which were then calculated using the following formula (where c is the concentration of the magnetic substance in the contrast agent, T i is the relaxation time, where i=1 or 2), the longitudinal magnetic relaxation rate r1 and the transverse magnetic relaxation rate r2 were calculated, and the results are shown in Table 1. JPEG0007682375000001.jpg1232 [Table 1] Specifically, Figure 1 shows a transmission electron microscope (TEM) image and particle size distribution diagram of sample γ-PGA-ES-MION6 in Example 1. The electron microscope image in Figure 1(a) clearly shows that the nanoparticles are uniform in size and uniformly dispersed. One hundred nanoparticles were randomly selected from Figure 1(a) and their particle size distribution was statistically analyzed to obtain the distribution diagram in Figure 1(b). The distribution diagram clearly shows that the particle diameter of the sample is mainly around 3.5 nm. Sample γ-PGA-ES-MION6 has an average particle diameter of less than 5 nm, which suggests its potential as a T1 contrast agent. Figure 2 shows the hydrodynamic diameter and Zeta potential of sample γ-PGA-ES-MION6 in Example 1. The hydrodynamic diameter was 8.7 nm and the dispersion coefficient (PDI) was 0.265, demonstrating good dispersibility. The Zeta potential of the sample is −37.3 mV, and the aqueous phase dispersibility of the sample can be improved by charge repulsion, which is beneficial for the blood circulation of the sample. The concentrations of the polyglutamic acid aqueous solution, the mixed aqueous solution, and the ammonia water significantly affected the MRI performance of the samples. Under various synthesis conditions, sample γ-PGA-ES-MION6 exhibited the best overall MRI performance. Figure 3 shows the MRI relaxivity diagram of sample γ-PGA-ES-MION6 in Example 1 (three parallel experiments were performed using three samples: γ-PGA-ES-MION6-1, γ-PGA-ES-MION6-2, and γ-PGA-ES-MION6-3). The slope of the fitted line represents the corresponding magnetic relaxivity. As can be seen from Figure 3(a) or (b), the linear fit of the fitted line was all above 0.999, suggesting that the samples had excellent linear relationships and that the relaxation times changed linearly with changes in sample concentration. Table 1 shows the r1 values ​​and r2 / r1 ratios of samples γ-PGA-ES-MION1-8 in Example 1 at various magnetic field strengths (7.0 T, 3.0 T, or 1.0 T), and also shows the r1 values ​​and r2 / r1 ratios of commercially available products Gadavist and Magnevist at a magnetic field strength of 3.0 T. In Example 1, sample γ-PGA-ES-MION6 had an r1 value of 5.7 mM at a magnetic field strength of 3.0 T. -1s -1 The r1 value of the commercially available product is 4.6 mM -1 s -1 The saturation magnetization was higher than that of the γ-PGA-ES-MION6 in Example 1, suggesting excellent magnetic resonance imaging capabilities. Figure 4 shows the saturation magnetization of γ-PGA-ES-MION6 in Example 1. It is clear from the figure that the sample in Example 1 is paramagnetic, consistent with the properties of magnetic triiron tetroxide nanoparticles. The magnitude of saturation magnetization is positively correlated with the particle size. The saturation magnetization of the sample in Example 1 is 16 emu / g, corresponding to the particle size of less than 5 nm shown in the electron microscope image in Figure 1. The magnitude of the r2 value of the contrast agent is positively correlated with the saturation magnetization. A small saturation magnetization corresponds to a small r2 value, which corresponds to the small r2 values ​​shown in Table 1. 5 shows the X-ray energy spectrum and X-ray diffraction pattern of γ-PGA-ES-MION6 in Example 1. In the XPS pattern of FIG. 5(a), the peaks centered at 711.6 eV and 725.1 eV correspond to Fe. 2+ 2p and Fe 3+ This corresponds to the 2p binding energy, suggesting the presence of both trivalent and divalent iron, demonstrating that the sample in Example 1 is triiron tetroxide. In the XRD pattern in Figure 5(b), two characteristic peaks (2θ ≒ 35.6° and 2θ ≒ 62.9°) correspond to the triiron tetroxide crystalline layers [(311) and (440)], demonstrating that the sample in Example 1 is triiron tetroxide with a crystalline structure. Both the XRD pattern and the XPS pattern demonstrated that the triiron tetroxide of Example 1 was successfully produced, and the electron microscope image in Figure 1 also demonstrated that the magnetic triiron tetroxide nanoparticles of Example 1 were successfully produced. FIG. 6 shows the infrared absorption spectrum of γ-PGA-ES-MION6 prepared in Example 1. Both the γ-PGA infrared absorption curve and the γ-PGA-ES-MION6 infrared absorption curve show an absorption peak a (1404 cm), which is a -CH- bending vibration peak. -1) appeared, which confirmed the presence of γ-PGA in the sample. Furthermore, absorption peaks b and c, which are the stretching vibration peaks of Fe-O, appeared in the infrared absorption curve of γ-PGA-ES-MION6 but not in that of γ-PGA, further demonstrating the successful preparation of magnetic triiron tetroxide nanoparticles γ-PGA-ES-MION6. Figure 7 shows T1-weighted magnetic resonance imaging (MRI) images and corresponding MRI signal intensities of γ-PGA-ES-MION6 aqueous solutions with various concentrations in Example 1. The magnetic field strength was 3.0 T, and the scan parameters were TE = 8.6 ms and TR = 500 ms. The MRI image in Figure 7(a) clearly shows that the MRI signal of the γ-PGA-ES-MION6 aqueous solution is significantly enhanced compared to pure water (iron concentration 0), and the signal intensity tends to increase gradually with increasing iron concentration. Figure 7(b) clearly shows that when the iron concentration in the γ-PGA-ES-MION6 solution is 200 μM, the MRI signal-to-noise ratio (ΔSNR) is 240%, suggesting that the γ-PGA-ES-MION6 solution can significantly improve the MRI contrast and sensitivity, demonstrating the favorable magnetic resonance imaging performance of the γ-PGA-ES-MION6 solution in Example 1. Figure 8 shows MRI images of tumor-bearing mice injected with γ-PGA-ES-MION6 in Example 1 at a dose of 5 mg / kg. Magnetic resonance imaging (7.0 T) was performed before tail vein injection and at 0, 1, 2, 3, 4, and 8 hours after tail vein injection. As can be seen from the figure, the MRI signal of the tumor increased and then decreased with increasing sample injection time, with the MRI signal being strongest 3 hours after injection. The in vivo imaging results demonstrated that the γ-PGA-ES-MION6 sample in Example 1 had good magnetic resonance imaging effects on mouse tumors. Example 2

[0041] Preparation of magnetic triiron tetroxide nanoparticles (PASP-ES-MION) Polyaspartic acid PASP(M w20 mL of a 20 mL (=7000-8000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing FeSO4 and FeCl3 was added to the flask, followed by 6 mL of aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then the mixture was allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PASP-ES-MION. The concentrations of the polyaspartic acid aqueous solution, mixed aqueous solution, and aqueous ammonia, as well as the corresponding samples, are shown in Table 2. The physical properties of the sample of Example 2 were evaluated. The iron recovery rate calculated for the sample of Example 2 was 89.6%, indicating high utilization of raw materials and cost reduction. The sample of Example 2 was prepared into aqueous solutions of six different concentrations, and an in vitro imaging test was performed using a clinical 3.0T MRI system. The longitudinal relaxation time T1 and transverse relaxation time T2 were obtained, and the longitudinal magnetic relaxation rate r1 and transverse magnetic relaxation rate r2 were calculated. The results are shown in Table 2. [Table 2] Figure 9 shows a transmission electron microscope image and particle size distribution diagram of sample PASP-ES-MION9 in Example 2. The electron microscope image in Figure 9(a) clearly shows that the nanoparticles are uniform in size and uniformly dispersed. One hundred nanoparticles were randomly selected from Figure 9(a) and their particle size distribution was statistically analyzed to obtain the distribution diagram shown in Figure 9(b). The distribution diagram clearly shows that the sample particle sizes were primarily distributed between 2.6 and 5.0 nm, with an average particle size of 3.7 nm, satisfying the requirement that the particle size of triiron tetroxide as a T1 contrast agent be less than 5 nm. Figure 10 shows the hydrodynamic diameter and Zeta potential of sample PASP-ES-MION9 in Example 2. Measurements were performed on three samples (PASP-ES-MION9-1, PASP-ES-MION9-2, and PASP-ES-MION9-3). The average hydrodynamic diameter was 14.7 nm and the PDI was 0.224, demonstrating good dispersibility. The Zeta potential of the sample is −50.7 mV, and the aqueous phase dispersibility of the sample can be improved by charge repulsion, which is beneficial for the blood circulation of the sample. The concentrations of the polyaspartic acid aqueous solution, the mixed aqueous solution, and the ammonia water significantly affect the MRI performance of the samples. Under various synthesis conditions, samples PASP-ES-MION9-10 exhibited excellent overall MRI performance. Taking PASP-ES-MION9 as an example, Figure 11 shows the MRI relaxivity diagram of sample PASP-ES-MION9 in Example 2. It is clear from Figure 11(a) or (b) that the linear fit coefficients of the fitted lines were all above 0.99, indicating that the samples had excellent linear relationships. Table 2 shows the r1 value and r2 / r1 ratio of sample PASP-ES-MION9 in Example 2 at a magnetic field strength of 3.0 T. Sample PASP-ES-MION9 in Example 2 had an r1 value of 7.3 mM at a magnetic field strength of 3.0 T. -1 s -1 The r1 value of the commercially available product Gadavist in Table 1 is 4.64 mM -1 s -1Furthermore, the r2 / r1 ratio of sample PASP-ES-MION9 was only 4.9 at a magnetic field strength of 3.0 T. As a result, the r1 value of sample PASP-ES-MION9 in Example 2 was extremely high and the r2 / r1 ratio was extremely low at a magnetic field strength of 3.0 T. 12 shows the X-ray energy spectrum and X-ray diffraction pattern of PASP-ES-MION9 in Example 2. In the XPS pattern of FIG. 12(a), the peaks centered at 710.3 eV and 723.8 eV correspond to Fe. 2+ 2p and Fe 3+ This corresponds to the binding energy of 2p, suggesting the presence of both trivalent and divalent iron, demonstrating that the sample in Example 2 is triiron tetroxide. In the XRD pattern in Figure 12(b), two characteristic peaks (2θ ≒ 35.3° and 2θ ≒ 62.4°) correspond to the triiron tetroxide crystalline phases [(311) and (440)], demonstrating that the sample in Example 2 is triiron tetroxide with a crystalline structure. Both the XRDD pattern and the XPSD pattern demonstrated that the triiron tetroxide of Example 2 was successfully produced. Furthermore, the electron microscope image in Figure 9 demonstrated that the magnetic triiron tetroxide nanoparticles of Example 2 were successfully produced. FIG. 13 shows the infrared absorption spectrum of PASP-ES-MION9 prepared in Example 2. Both the PASP infrared absorption curve and the PASP-ES-MION9 infrared absorption curve show an absorption peak a (1400 cm), which is a -COO- stretching vibration peak. -1 ) appeared, which confirmed the presence of PASP in the sample. Furthermore, absorption peak b, which is the stretching vibration peak of Fe-O, appeared in the infrared absorption curve of PASP-ES-MION9 but not in the infrared absorption curve of PASP, further demonstrating the successful preparation of magnetic triiron tetroxide nanoparticles PASP-ES-MION9. Figure 14 shows T1-weighted MRI images and corresponding MRI signal intensities of PASP-ES-MION9 aqueous solutions with various concentrations in Example 2. The magnetic field strength was 3.0 T, and the scan parameters were TE = 8.4 ms and TR = 200 ms. From the MRI image (a), it is clear that the MRI signal of the aqueous solution containing the sample PASP-ES-MION9 is significantly enhanced compared to pure water (iron concentration 0). Furthermore, the signal intensity tends to increase gradually with increasing iron concentration. From (b), it is clear that when the iron concentration in the sample PASP-ES-MION9 aqueous solution is 1000 μM, the ΔSNR of MRI is 1025%, suggesting that PASP-ES-MION9 can significantly improve the contrast and sensitivity of MRI, demonstrating the excellent magnetic resonance imaging performance of PASP-ES-MION9 in Example 2. Figure 15 shows MRI images of tumor-bearing mice injected with PASP-ES-MION9 in Example 2 at a dose of 5 mg / kg. Magnetic resonance imaging (7.0 T) was performed before tail vein injection and at 0, 1, 2, 3, 4, and 8 hours after tail vein injection. As can be seen from the figure, the MRI signal of the tumor increased and then decreased with increasing sample injection time, with the MRI signal being strongest 3 hours after injection. The imaging results demonstrated that PASP-ES-MION9 in Example 2 had a good magnetic resonance imaging effect on mouse tumors. Example 3

[0042] Preparation of magnetic iron tetroxide nanoparticles (HPMA-ES-MION) 2 mg / mL polymaleic acid HPMA (M w 20 mL of a 2000% (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated HPMA-ES-MION. Performance tests were conducted on the sample of Example 3. The iron recovery rate calculated for the sample of Example 3 was 87.2%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 3 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain longitudinal relaxation times T1 and transverse relaxation times T2 (three parallel tests were conducted using three samples: HPMA-ES-MION-1, HPMA-ES-MION-2, and HPMA-ES-MION-3). As shown in Figure 16, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 3 was 6.9±0.3 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 32.3±1.9mM -1 s -1 The r2 / r1 ratio was 4.7±0.4. Example 3 demonstrated a high r1 value, a low r2 / r1 ratio, and was useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 4

[0043] Preparation of magnetic iron tetroxide nanoparticles (PEAA-ES-MION) 2 mg / mL poly(2-ethylacrylic acid) PEAA (M w 20 mL of a 2000% aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PEAA-ES-MION. Performance tests were conducted on the sample of Example 4. The iron recovery rate calculated for the sample of Example 4 was 89.1%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 4 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain the longitudinal relaxation time T1 and the transverse relaxation time T2 (three parallel tests were conducted using three samples, PEAA-ES-MION-1, PEAA-ES-MION-2, and PEAA-ES-MION-3). As shown in Figure 17, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 4 was 7.8±0.2 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 19.8±1.7mM -1 s -1 The r2 / r1 ratio was 2.5±0.3. As a result, it was demonstrated that Example 4 has an extremely high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 5

[0044] Preparation of magnetic iron tetroxide nanoparticles (PESA-ES-MION) 2mg / mL Polyepoxysuccinic Acid PESA (M w 20 mL of a 2000 (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen for 1 hour, then heated to reflux at 100 °C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100 °C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PESA-ES-MION. A performance test was conducted on the sample of Example 5. The iron recovery rate calculated for the sample of Example 5 was 93.2%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 5 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain the longitudinal relaxation time T1 and the transverse relaxation time T2 (three parallel tests were conducted using three samples, PESA-ES-MION-1, PESA-ES-MION-2, and PESA-ES-MION-3). As shown in Figure 18, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 5 was 7.2±0.2 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 26.1±2.1mM -1 s -1 The r2 / r1 ratio was 3.6±0.3. As a result, it was demonstrated that Example 5 has an extremely high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 6

[0045] Preparation of magnetic triiron tetroxide nanoparticles (ε-PL-ES-MION) 2 mg / mL polylysine ε-PL (M w 20 mL of a 2000 (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen for 1 hour, then heated to reflux at 100 °C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100 °C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated ε-PL-ES-MION. A performance test was conducted on the sample of Example 6. The iron recovery rate calculated for the sample of Example 6 was 82.6%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 6 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain the longitudinal relaxation time T1 and the transverse relaxation time T2 (three parallel tests were conducted using three samples, ε-PL-ES-MION-1, ε-PL-ES-MION-2, and ε-PL-ES-MION-3). As shown in Figure 19, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The relaxation rate (i=1 or 2) was used. As a result, in a 3.0T MRI system, the r1 value of Example 6 was 6.2±0.3 mM. -1 s -1 , r2 value is 32.5±3.8mM -1 s -1 The r2 / r1 ratio was 5.3±0.9. As a result, it was demonstrated that Example 6 has an extremely high r1 value, a high r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 7

[0046] Preparation of magnetic triiron tetroxide nanoparticles (PLH-ES-MION) 2mg / mL polyhistidine PLH(M w 20 mL of a 2000 (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100 °C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100 °C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PLH-ES-MION. Performance tests were conducted on the sample of Example 7. The iron recovery rate calculated for the sample of Example 7 was 85.7%, indicating high utilization of raw materials and cost reduction. The sample of Example 7 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain longitudinal relaxation times T1 and transverse relaxation times T2 (three parallel tests were conducted using three samples, PLH-ES-MION-1, PLH-ES-MION-2, and PLH-ES-MION-3). As shown in Figure 20, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 7 was 5.7±0.4 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 46.6±7.0mM -1 s -1 The r2 / r1 ratio was 8.3±1.5. As a result, it was demonstrated that Example 7 has an extremely high r1 value, a high r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 8

[0047] Preparation of magnetic iron tetroxide nanoparticles (PLR-ES-MION) 2mg / mL Polyarginine PLR(M w 20 mL of a 2000 (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100 °C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100 °C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PLR-ES-MION. A performance test was conducted on the sample of Example 8. The iron recovery rate calculated for the sample of Example 8 was 83.9%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 8 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain the longitudinal relaxation time T1 and the transverse relaxation time T2 (three parallel tests were conducted using three samples, PLR-ES-MION-1, PLR-ES-MION-2, and PLR-ES-MION-3). As shown in Figure 21, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 8 was 5.2±0.2 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 55.0±9.1mM -1 s -1 The r2 / r1 ratio was 10.6±1.8. As a result, it was demonstrated that Example 8 has an extremely high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 9

[0048] Preparation of magnetic triiron tetroxide nanoparticles (PDDA-ES-MION) 2 mg / mL polydimethyldiallylammonium chloride PDDA (M w 20 mL of a 2000 (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PDDA-ES-MION. Performance tests were conducted on the sample of Example 9. The iron recovery rate calculated for the sample of Example 9 was 90.4%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 9 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia). The longitudinal relaxation time T1 and transverse relaxation time T2 (three parallel tests were conducted using three samples, PDDA-ES-MION-1, PDDA-ES-MION-2, and PDDA-ES-MION-3) were obtained. As shown in Figure 22, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 9 was 7.1±0.5 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 70.0±9.1mM -1 s -1 The r2 / r1 ratio was 9.9±1.8. As a result, it was demonstrated that Example 9 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 10

[0049] Preparation of magnetic iron tetroxide nanoparticles (PSer-ES-MIONs) 2mg / mL polyserine PSer (M w 20 mL of a 2000% aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PSer-ES-MION. A performance test was conducted on the sample of Example 10. The iron recovery rate calculated for the sample of Example 10 was 88.2%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 10 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain the longitudinal relaxation time T1 and the transverse relaxation time T2 (three parallel tests were conducted using three samples, PSer-ES-MION-1, PSer-ES-MION-2, and PSer-ES-MION-3). As shown in Figure 23, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 10 was 5.8±0.25 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 63.4±8.7mM -1 s -1 The r2 / r1 ratio was 11.0±1.3. As a result, it was demonstrated that Example 10 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 11

[0050] Preparation of magnetic triiron tetroxide nanoparticles (PThr-ES-MION) 2mg / mL Polythreonine PThr(M w 20 mL of a 2000 (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100 °C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100 °C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PThr-ES-MION. A performance test was conducted on the sample of Example 11. The iron recovery rate calculated for the sample of Example 11 was 85.7%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 11 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia). The longitudinal relaxation time T1 and transverse relaxation time T2 (three parallel tests were conducted using three samples, PThr-ES-MION-1, PThr-ES-MION-2, and PThr-ES-MION-3) were obtained. As shown in Figure 24, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 11 was 6.6±0.4 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 57.2±2.5mM -1 s -1 The r2 / r1 ratio was 8.7±0.8. As a result, it was demonstrated that Example 11 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 12

[0051] Preparation of magnetic triiron tetroxide nanoparticles (PTyr-ES-MION) 2mg / mL Polytyrosine PTyr (M w 20 mL of a 2000 (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100 °C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100 °C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PTyr-ES-MION. Performance tests were conducted on the sample of Example 12. The iron recovery rate calculated for the sample of Example 12 was 83.2%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 12 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia). The longitudinal relaxation time T1 and transverse relaxation time T2 (three parallel tests were conducted using three samples, PTyr-ES-MION-1, PTyr-ES-MION-2, and PTyr-ES-MION-3) were obtained. As shown in Figure 25, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 12 was 6.4±0.2 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 59.7±5.8mM -1 s -1 The r2 / r1 ratio was 9.4±1.2. As a result, it was demonstrated that Example 12 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 13

[0052] Preparation of magnetic triiron tetroxide nanoparticles (TA-ES-MION) 2 mg / mL tannic acid TA (M w 20 mL of a 1700 (FeSO4) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated TA-ES-MION. Performance tests were conducted on the sample of Example 13. The iron recovery rate calculated for the sample of Example 13 was 92.7%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 13 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain the longitudinal relaxation time T1 and the transverse relaxation time T2 (three parallel tests were conducted using three samples, TA-ES-MION-1, TA-ES-MION-2, and TA-ES-MION-3). As shown in Figure 26, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 13 was 7.3±0.4 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 58.9±3.2mM -1 s -1 The r2 / r1 ratio was 8.1±0.8. As a result, it was demonstrated that Example 13 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 14

[0053] Preparation of magnetic iron tetroxide nanoparticles (PolyQ-ES-MION) 2mg / mL Polyglutamine PolyQ (M w 20 mL of a 2000 (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PolyQ-ES-MION. Performance tests were conducted on the sample of Example 14. The iron recovery rate calculated for the sample of Example 14 was 87.5%, indicating high utilization of raw materials and cost reduction. The sample of Example 14 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia). The longitudinal relaxation time T1 and transverse relaxation time T2 (three parallel tests were conducted using three samples, PolyQ-ES-MION-1, PolyQ-ES-MION-2, and PolyQ-ES-MION-3) were obtained. As shown in Figure 27, 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 14 was 7.0±0.2 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 56.8±0.8mM -1 s -1 The r2 / r1 ratio was 8.1±0.3. As a result, it was demonstrated that Example 14 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 15

[0054] Preparation of magnetic triiron tetroxide nanoparticles (PHEA-ES-MION) 2mg / mL Polyasparagine PHEA (M w 20 mL of a 2000 (=2000) aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100 °C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100 °C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PHEA-ES-MION. Performance tests were conducted on the sample of Example 15. The iron recovery rate calculated for the sample of Example 15 was 85.4%, indicating high utilization of raw materials and cost reduction. The sample of Example 15 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain longitudinal relaxation times T1 and transverse relaxation times T2 (three parallel tests were conducted using three samples, PHEA-ES-MION-1, PHEA-ES-MION-2, and PHEA-ES-MION-3). As shown in Figure 28, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 15 was 6.9±0.4 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 49.2±7.2mM -1 s -1 The r2 / r1 ratio was 7.2±0.8. As a result, it was demonstrated that Example 15 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 16

[0055] Preparation of magnetic triiron tetroxide nanoparticles (PAM-ES-MION) 2 mg / mL polyacrylamide PAM (M w 20 mL of a 2000% aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PAM-ES-MION. A performance test was conducted on the sample of Example 16. The iron recovery rate calculated for the sample of Example 16 was 84.3%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 16 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain the longitudinal relaxation time T1 and the transverse relaxation time T2 (three parallel tests were conducted using three samples, PAM-ES-MION-1, PAM-ES-MION-2, and PAM-ES-MION-3). As shown in Figure 29, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 16 was 7.2±0.2 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 50.2±6.8mM -1 s -1 The r2 / r1 ratio was 6.9±0.9. As a result, it was demonstrated that Example 16 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 17

[0056] Preparation of magnetic triiron tetroxide nanoparticles (PMAM-ES-MION) 2 mg / mL polymethacrylamide PMAM (M w 20 mL of a 2000% aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated PMAM-ES-MION. Performance tests were conducted on the sample of Example 17. The iron recovery rate calculated for the sample of Example 17 was 90.7%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 17 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain the longitudinal relaxation time T1 and the transverse relaxation time T2 (three parallel tests were conducted using three samples, PMAM-ES-MION-1, PMAM-ES-MION-2, and PMAM-ES-MION-3). As shown in Figure 30, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 17 was 6.5±0.3 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 55.8±4.8mM -1 s -1 The r2 / r1 ratio was 8.5±0.5. As a result, it was demonstrated that Example 17 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 18

[0057] Preparation of magnetic triiron tetroxide nanoparticles (HA-ES-MION) 2mg / mL hyaluronic acid HA (M w 20 mL of a 2000% aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated HA-ES-MION. A performance test was conducted on the sample of Example 18. The iron recovery rate calculated for the sample of Example 18 was 89.5%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 18 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain the longitudinal relaxation time T1 and the transverse relaxation time T2 (three parallel tests were conducted using three samples, HA-ES-MION-1, HA-ES-MION-2, and HA-ES-MION-3). As shown in Figure 31, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 18 was 6.5±0.2 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 71.8±5.1mM -1 s -1 The r2 / r1 ratio was 11.0±0.6. As a result, it was demonstrated that Example 18 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 19

[0058] Preparation of magnetic triiron tetroxide nanoparticles (SA-ES-MION) 2 mg / mL sodium alginate SA (M w 20 mL of a 2000% aqueous solution was placed in a three-neck flask and deoxygenated by bubbling nitrogen through it for 1 hour, then heated to reflux at 100°C. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated SA-ES-MION. Performance tests were conducted on the sample of Example 19. The iron recovery rate calculated for the sample of Example 19 was 89.5%, indicating high utilization of raw materials and cost reduction. The sample of Example 19 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia) to obtain longitudinal relaxation times T1 and transverse relaxation times T2 (three parallel tests were conducted using three samples, SA-ES-MION-1, SA-ES-MION-2, and SA-ES-MION-3). As shown in Figure 32, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 19 was 7.0±0.4 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 57.2±10.7mM -1 s -1 The r2 / r1 ratio was 8.2±1.7. As a result, it was demonstrated that Example 19 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 20

[0059] Preparation of magnetic triiron tetroxide nanoparticles (γ-PGA / PASP-ES-MION) 2mg / mL polyglutamic acid γ-PGA / polyaspartic acid PASP (polyglutamic acid M w =2000, Polyaspartic acid M w 20 mL of a 1:1 (mass ratio) mixture of γ-PGA and γ-PASP-ES-MION was heated to reflux in a three-neck flask and deoxygenated by bubbling nitrogen through for 1 hour. 0.4 mL of a mixed aqueous solution containing 0.25 M FeSO4 and 0.5 M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated γ-PGA / PASP-ES-MION. A performance test was conducted on the sample of Example 20. The iron recovery rate calculated for the sample of Example 20 was 93.7%, indicating a high utilization rate of raw materials and cost reduction. The sample of Example 20 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia). The longitudinal relaxation time T1 and transverse relaxation time T2 (three parallel tests were conducted using three samples: γ-PGA / PASP-ES-MION-1, γ-PGA / PASP-ES-MION-2, and γ-PGA / PASP-ES-MION-3) were obtained. As shown in Figure 33, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 20 was 6.7±0.4 mM in a 3.0 T MRI system. -1 s -1 , r2 value is 63.4±8.7mM -1 s -1 The r2 / r1 ratio was 9.5±0.7. As a result, it was demonstrated that Example 20 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility. Example 21

[0060] Preparation of magnetic iron tetroxide nanoparticles (HPMA / PASP-ES-MION) 2mg / mL polymaleic acid HPMA / polyaspartic acid PASP (polymaleic acid M w =2000, Polyaspartic acid M w 20 mL of a mixture (1:1 mass ratio) of 0.25M FeSO4 and 0.5M FeCl3 was heated to reflux in a three-neck flask and deoxygenated by bubbling with nitrogen for 1 hour. 0.4 mL of a mixed aqueous solution containing 0.25M FeSO4 and 0.5M FeCl3 was added to the flask, followed by 6 mL of 1% aqueous ammonia. The reaction was carried out at 100°C with magnetic stirring for 1 hour, and then the mixture was allowed to cool. The completed reaction sample was purified by dialysis, and the final sample was designated HPMA / PASP-ES-MION. Performance tests were conducted on the sample of Example 21. The iron recovery rate calculated for the sample of Example 21 was 90.1%, indicating high utilization of raw materials and cost reduction. The sample of Example 21 was prepared into six different aqueous solutions and subjected to in vitro imaging tests using a 3.0T clinical MRI system (Philips, Ingenia). The longitudinal relaxation time T1 and transverse relaxation time T2 (three parallel tests were conducted using three samples: HPMA / PASP-ES-MION-1, HPMA / PASP-ES-MION-2, and HPMA / PASP-ES-MION-3) were obtained. As shown in Figure 34, the 1 / T i Plot the relationship between the change in T and iron concentration, and calculate the slope of the fitted line. i The magnetic relaxation rate (i=1 or 2) was set. As a result, the r1 value of Example 21 was 6.4±0.1 mM in a 3.0T MRI system. -1 s -1 , r2 value is 26.1±2.8mM -1 s -1 The r2 / r1 ratio was 4.1±0.4. As a result, it was demonstrated that Example 21 has a high r1 value, a low r2 / r1 ratio, and is useful as a T1-weighted MRI contrast agent with good biocompatibility.

[0061] The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principles of the present invention are equivalent replacement forms and shall be included within the protection scope of the present invention.

Claims

1. The present invention comprises triiron tetroxide and a hydrophilic polymer, and the triiron tetroxide and the hydrophilic polymer are present in at least one of the following relationships with respect to each other: (1) the hydrophilic polymer is adsorbed on the surface of triiron tetroxide; and (2) the triiron tetroxide and the hydrophilic polymer are embedded or occluded in each other; 1) The average particle size is greater than 2 nm and less than 5 nm; 2) The zeta potential is −10 mV or less; 3) the hydrodynamic diameter is 20 nm or less; 4) Longitudinal magnetic relaxation rate r at a magnetic field strength of 3.0 T １ The value is 5 mM －１ s －１ is larger than the longitudinal magnetic relaxation rate r １ The value is 10 mM －１ s －１ It is greater than The present invention has the following characteristic: And, the present invention has any one or more of the characteristics 2), 3), and 4) at the same time; The magnetic triiron tetroxide nanoparticles are characterized in that the hydrophilic polymer comprises one or more of polyaspartic acid, polymaleic acid, poly(2-ethylacrylic acid), polyepoxysuccinic acid, polylysine, and polyacrylamide.

2. 2. The method for producing magnetic triiron tetroxide nanoparticles according to claim 1, further comprising the step of co-precipitating divalent iron ions and trivalent iron ions using a hydrophilic polymer as a stabilizer to form the magnetic triiron tetroxide nanoparticles.

3. The manufacturing method according to claim 2, further comprising the steps of heating a hydrophilic polymer solution, mixing the hydrophilic polymer solution with an iron ion mixed solution containing divalent iron ions and trivalent iron ions, carrying out a coordination reaction, and then adding an alkaline solution to carry out a coprecipitation reaction to obtain the magnetic triiron tetroxide nanoparticles.

4. A contrast agent for magnetic resonance imaging comprising the magnetic iron tetroxide nanoparticles described in claim 1 as an active ingredient.

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