Hepatocyte-targeting spatially heterogeneous ferrite nanoparticles and methods of making

Abstract

The present application relates to the technical field of nanocomposite production, and particularly relates to a space heterostructure ferrite nanoparticle with liver cell targeting function and a preparation method thereof. The nanoparticle adopts gradient doping of metal elements in a core layer and a shell layer, and is modified with a ligand layer with liver cell targeting function to form a physical-chemical three-layer composite system with a space heterostructure. By regulating the types and concentrations of the doping elements, a space heterostructure distribution of the ferrite nanoparticle gradient doping is constructed. The magnetic resonance imaging contrast agent prepared on the basis can significantly enhance the enrichment effect and local recognition ability in the liver region, effectively improve the relaxation rate of the ferrite nanoparticle, optimize the contrast, imaging speed and effective imaging time window of the in vivo liver and gallbladder imaging, and improve the biocompatibility and metabolic performance of the material.

Description

Technical Field

[0001] This invention relates to the field of nanoparticle contrast agents, specifically to a hepatocyte-targeting spatially heterogeneous ferrite nanoparticle and its preparation method. Background Technology

[0002] Hepatocyte-targeting ferrite nanoparticle contrast agents typically consist of two parts: the ferrite nanoparticle bulk and the targeted modified ligand system. The key characteristics of the ferrite nanoparticle bulk, such as its crystal structure, particle size distribution, metal element composition, and magnetization, as well as the core parameters of the targeted modification system, such as the ligand type and the chemical properties of the connecting arms, collectively determine the performance of this type of contrast agent in magnetic resonance imaging (MRI).

[0003] At the MRI performance level, parameters such as the relaxivity, in vivo metabolic pathway, effective imaging time window, and imaging contrast of contrast agents directly affect their clinical efficacy and biosafety. Specifically, this manifests as their ability to regulate liver parenchymal enhancement rate and the detection rate of hepatocellular carcinoma lesions, as well as their potential impact on renal deposition. These indicators collectively constitute the key criteria for evaluating the clinical value and safety of this type of contrast agent.

[0004] To improve the imaging performance of ferrite nanoparticles in MRI, Chinese patent CN112299489A proposes an ultra-small iron oxide nanoparticle and its preparation method. The main objective is to adjust the in vitro relaxation rate of the nanoparticles through a doping strategy, employing isothermal or constant-temperature doping processes to prepare homogeneous, uniformly doped ferrite nanoparticles. Although these ferrite nanoparticles can improve the relaxation rate and imaging performance to some extent, significant challenges remain in their practical application in liver MRI. This is primarily due to the substantial differences in the behavior of nanoparticles with different doping structures in terms of in vivo circulation, tissue distribution, and targeted accumulation. Therefore, further development of nano-ferrite materials that combine good liver targeting and high sensitivity is needed to promote their effective application in liver imaging.

[0005] Therefore, it is necessary to develop hepatocyte-targeting ferrite nanoparticles with spatial heterogeneous structures and their preparation method. This method requires, based on the synergistic regulation of crystal structure, particle size distribution, surface charge, and magnetization, further precise control of the type and quantity of dopant elements and optimization of their spatial distribution structure. This will enable the ferrite nanoparticle contrast agent prepared with this core to exhibit high relaxation rate, high contrast between liver parenchyma and muscle, high enhancement rate of liver parenchyma, peak time to maximum signal-to-noise ratio, effective imaging time window, and high detection rate of liver cancer lesions. Simultaneously, it will effectively reduce the amount of deposits in the kidneys and spleen, ensuring the biosafety of the material. Summary of the Invention

[0006] This application provides a hepatocyte-targeting spatially heterogeneous ferrite nanoparticle, with the general formula: The physical-chemical three-layer complex, in which, It has a core-shell structure. With the core, It is a shell, the third layer. To create a ligand-modified layer with hepatocyte-targeting function, the core and shell layers employ gradient doping of metal element M to achieve a spatial heterogeneous distribution of metal elements. ,satisfy: In the formula for , , One of them.

[0007] Preferably, the aforementioned The elemental distribution was characterized by transmission electron microscopy-elemental energy dispersive spectroscopy (EDS), and the results showed... Characteristics of elements The intensity of the X-ray signal is generally higher than that of metallic elements. Features X-ray signal intensity.

[0008] Preferably, the aforementioned The elemental distribution was characterized by transmission electron microscopy-elemental energy dispersive spectroscopy (TEM-EDS). For individual nanoparticles, the metal element distribution was analyzed. Features X-ray signals are enriched in the core region of the particles, while the characteristic X-ray signals of Mn are enriched in the shell region of the particles.

[0009] Preferably, the core The diameter is The unit is nm, and it satisfies: .

[0010] Preferably, the shell layer The thickness is The unit is nm, and it satisfies: .

[0011] Preferably, the third layer It is one of polyethylene glycol-ethoxyphenyl ligand, galactose-peptide chimeric ligand, apolipoprotein E-derived peptide, and polyethylene glycol-N-acetylgalactosamine.

[0012] Preferably, the The molecular weight range is 800 Da to 4000 Da.

[0013] Preferably, the third layer The ligand modification density is 2-8 ligands per square nanometer.

[0014] A second aspect of the present invention provides a method for preparing hepatocyte-targeting spatially heterogeneous ferrite nanoparticles, comprising the following steps:

[0015] S1, Prepare the reaction mixture under an inert atmosphere. , , according to The mixture was prepared in a molar ratio of 1:1, with oleic acid and oleyl alcohol added as surfactants. In for , , One of them yields a reaction mixture;

[0016] S2, Core Synthesis: The reaction mixture was heated at a rate of 5-10 °C / min until it reached... The thermal decomposition temperature T1, the reaction time is 10-30 min, and the nucleus is generated. Nanoparticles;

[0017] S3, shell Synthesis: The reaction mixture was further heated at a rate of 5-10 °C / min until it reached... The thermal decomposition temperature T2, the reaction time is 10-40 min, and the result is... Nanoparticles;

[0018] S4, outer layer targeting ligand modification, attaching the ligand to the layer obtained in step S3. On the surface of nanoparticles, spatially heterogeneous ferrite nanoparticles targeting hepatocytes were obtained.

[0019] Preferably, the , , In It is one of the following: carbonate, oleate, erucic acid, stearate, palmitic acid, and laurate. The thermal decomposition temperature T2 is higher than and The thermal decomposition temperature T1 is at least 20°C.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0021] 1. Improved imaging contrast and efficiency: By controlling the type and concentration of doping elements to construct a gradient-doped spatial heterostructure, the relaxation rate of ferrite nanoparticles is effectively improved. The introduction of paramagnetic elements such as manganese ions enhances the interaction between ferrite nanoparticles and surrounding water molecules, thereby significantly shortening the longitudinal relaxation time (T1) of water molecules, enhancing the magnetic resonance response signal, and optimizing image contrast. Compared to the commonly used contrast agent Gd-EOB-DTPA, its signal contrast performance is improved by approximately 150%, and the imaging time is shortened from 15–20 minutes to 3–5 minutes, which helps improve the operating efficiency of MRI equipment and reduce the residence time of the contrast agent in the body.

[0022] 2. Enhanced enrichment and local recognition capabilities in the liver region: The manganese ions enriched in the shell and the ligand modification layer targeting hepatocyte function help improve the material's directional enrichment capability in the liver region. The incorporation of manganese ions modulates the surface properties of ferrite nanoparticles, making them easier for hepatocytes to absorb, thereby enhancing the recognition capability of local areas. The recognition capability for microstructures is improved to 96%, which helps to identify changes in physiological state at an early stage and provides more comprehensive information support for related research.

[0023] 3. Improved biocompatibility and metabolic performance: The three-layer structure, gradient doping, and spatial heterogeneous configuration of ferrite nanoparticles optimize their metabolic pathways in vivo. The liver / spleen uptake ratio is greater than 4:1, indicating that the material can specifically accumulate in the liver region, reducing accumulation in other tissues such as the spleen, thus helping to minimize its impact on other tissues. Its hepatobiliary excretion rate exceeds 90%, with an excretion time shortened to less than 48 hours, accelerating the contrast agent clearance process and reducing its retention time in vivo, thereby further improving the material's biocompatibility.

[0024] 4. Optimizing the effective imaging time window: Gradient doping and spatial heterostructure help regulate the magnetic properties and stability of nanoparticles, enabling them to maintain stable imaging performance for a longer period in vivo, thereby extending the effective imaging time window. This allows image acquisition to occur at a more ideal time, contributing to improved image quality and signal stability. Attached Figure Description

[0025] The accompanying drawings are provided to further illustrate the invention and form part of the specification. They are used in conjunction with embodiments of the invention to explain the invention and do not constitute a limitation thereof. In the drawings:

[0026] Figure 1 This is a schematic diagram of a hepatocyte-targeting spatial heterogeneous ferrite nanoparticle structure according to the present invention.

[0027] Figure 2 A is a transmission electron microscope image of Embodiment 1 of the present invention. Figure 2B is a transmission electron microscope image of Embodiment 2 of the present invention. Figure 2 C is a transmission electron microscope image of Embodiment 3 of the present invention;

[0028] Figure 3 A is a metal element distribution diagram of Embodiment 1 of the present invention. Figure 3 B is the metal element distribution diagram of Embodiment 2 of the present invention. Figure 3 C is the metal element distribution diagram of Embodiment 3 of the present invention;

[0029] Figure 4 A is the T1 relaxation efficiency diagram of Embodiment 1 of the present invention. Figure 4 B is the T1 relaxation efficiency diagram of Embodiment 2 of the present invention. Figure 4 C is the T1 relaxation efficiency diagram of Embodiment 3 of the present invention;

[0030] Figure 5 Image A shows liver images of Bama pigs before and after drug administration in Example 1 of this invention. Figure 5 Image B shows liver images of Bama pigs before and after drug administration in Example 2 of this invention. Figure 5 C is an imaging image of the liver of Bama pigs before and after drug administration in Example 3 of the present invention;

[0031] Figure 6 This is a relative signal enhancement diagram of the liver in Bama pigs during hepatobiliary imaging using hepatocyte-targeted spatially heterogeneous ferrite nanoparticles from Example 1 of the present invention.

[0032] Figure 7 This represents the maximum signal-to-noise ratio of the hepatocyte-targeted spatially heterogeneous ferrite nanoparticles of Example 1 of the present invention in the liver-muscle region of Bama pigs.

[0033] In the picture: 1. 2. 3. . Detailed Implementation

[0034] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0035] Example 1

[0036] Combination Figure 1 , Figure 2 A, Figure 3 A, Figure 4 A, Figure 5 A, Figure 6 , Figure 7The present invention relates to a hepatocyte-targeting spatially heterogeneous ferrite nanoparticle. The three-layered complex of physics and chemistry, in which, It has a core-shell structure. With the core, It is a shell, the third layer. To create a ligand-modified layer with hepatocyte-targeting function, the core and shell layers employ gradient doping of metal element M to achieve a spatial heterogeneous distribution of metal elements. , , ,satisfy: .

[0037] A method for preparing hepatocyte-targeting spatially heterogeneous ferrite nanoparticles, comprising the following steps:

[0038] S1, Prepare the reaction mixture by mixing ferric erucate, manganese oleate, and manganese erucate in a molar ratio of [3-0.1+1.8×(3-0.8)]:0.1:[1.8×0.8] under an inert atmosphere, and adding 3 ml of oleic acid and 10 ml of oleyl alcohol as surfactants to complete the preparation of the reaction mixture;

[0039] S2, Core Synthesis: The reaction mixture was heated at a rate of 8 °C / min to the thermal decomposition temperature of manganese oleate, 220 °C, and the reaction was continued for 15 min to generate the core. Nanoparticles;

[0040] S3, shell Synthesis: The reaction mixture was heated at a rate of 10 °C / min until it reached the thermal decomposition temperature of manganese erucate, 260 °C, and the reaction was continued for 30 min to obtain... Nanoparticles;

[0041] S4, outer layer targeted ligand modification, will ligands are attached to the product obtained in step S3 The surface of nanoparticles yields spatial heterogeneous structures that target hepatocytes. Nanoparticles.

[0042] Figure 2 A is Transmission electron microscope image, Figure 3 A is The TEM-EDS mapping results show that Mn is distributed in both the core and shell of the single particle, and the signal intensity in the shell is significantly higher than that in the core, confirming that the particle possesses... Spatial heterogeneous structures enriched in the shell. Higher longitudinal relaxation rate corresponds to higher tissue brightness in T1-weighted images. Figure 4 A shows that under a 3T magnetic field... longitudinal relaxation rate Compared to the longitudinal relaxation rate of existing gadolinium-based contrast agents in clinical use, Increase by 400%-500%. Figure 4 As shown in Figure A, compared to uniformly doped manganese ferrite nanoparticles, The T1 relaxation efficiency is improved by 200%-300%. Figure 5 As shown in Figure A, this is a magnetic resonance imaging (MRI) experiment of the liver of a Bama pig. At a lower dosage ([M+Mn]=0.84mg / kg compared to commercial gadolinium-based contrast agent [Gd]=4mg / kg), the signal enhancement was 120% within 5 minutes after administration, and the Longitudinal Relaxation Enhancement (LRE) reached its peak value earlier than that of Comparative Example 1 (10 minutes) and Comparative Example 2 (20 minutes). This indicates that the material of the present invention has a faster imaging response speed and better prospects for clinical application. Figure 7 The results show that under the same test conditions, The maximum signal-to-noise ratio (CNR) is greater than that of Comparative Example 1 and Comparative Example 2, and the time to peak is also shorter.

[0043] Example 2

[0044] Combination Figure 1 , Figure 2 B. Figure 3 B. Figure 4 B. Figure 5 B, a hepatocyte-targeting spatially heterogeneous ferrite nanoparticle of the present invention. The three-layered complex of physics and chemistry, in which, It has a core-shell structure. With the core, It is a shell, the third layer. To create a ligand-modified layer with hepatocyte-targeting function, the core and shell layers are gradient-doped with metal elements. The method of achieving spatial heterogeneous structure distribution of metallic elements, wherein , , ,satisfy: .

[0045] A method for preparing hepatocyte-targeting spatially heterogeneous ferrite nanoparticles, comprising the following steps:

[0046] S1, Prepare the reaction mixture by mixing ferric erucic acid, magnesium oleate, and manganese erucic acid in a molar ratio of [3-0.03+2.3(3-0.5)]:0.03:[2.3×0.5]=8.72:0.03:1.15 under argon protection, and adding 2.5 mL of oleic acid and 12 mL of oleyl alcohol as surfactants to obtain the reaction mixture;

[0047] S2, The core synthesis involves heating the reaction mixture at 10°C / min to the thermal decomposition temperature of magnesium oleate (220°C) and continuing the reaction for 10 min to generate the inner layer. ;

[0048] S3, shell Synthesis continued, the temperature was increased by 10℃ / min to the thermal decomposition temperature of manganese erucate (260℃), and the reaction was carried out for 40 min to produce... ,get Nanoparticles;

[0049] S4, outer layer targeted ligand modification, will Attached to the galactose-peptide chimeric ligand (Gal-YEE) obtained in step S3 By controlling the surface modification density of nanoparticles to approximately 2-3 ligands per square nanometer, a spatially heterogeneous structure targeting hepatocytes was obtained. Nanoparticles.

[0050] Figure 2 B is Transmission electron microscope image, Figure 3 B is The TEM-EDS mapping results show that Mn is mainly distributed in the shell of the nanoparticles, while Mg is mainly present in the core of the nanoparticles, confirming that the particles have a spatial heterogeneous structure with Mn enriched in the shell. Figure 4 B shows that under a 3T magnetic field... longitudinal relaxation rate . Figure 5 As shown in B, this is a magnetic resonance imaging experiment of the liver of a Bama pig. Liver signal increased by 105% after drug administration.

[0051] Example 3

[0052] Combination Figure 1 , Figure 2 C Figure 3 C Figure 4 C Figure 5 C, a hepatocyte-targeting spatially heterogeneous ferrite nanoparticle of the present invention. The three-layered complex of physics and chemistry, in which, It has a core-shell structure. With the core, It is a shell, the third layer. To create a ligand-modified layer with hepatocyte-targeting function, the core and shell layers are gradient-doped with metal elements. The method of achieving spatial heterogeneous structure distribution of metallic elements, wherein , , ,satisfy: .

[0053] A method for preparing hepatocyte-targeting spatially heterogeneous ferrite nanoparticles, comprising the following steps:

[0054] S1, Prepare the reaction mixture by mixing ferric erucate, cobalt palmitate, and manganese erucate under argon protection in the following order: The mixture was prepared by adding 2 mL of oleic acid and 18 mL of oleyl alcohol as surfactants in a molar ratio of 1:1;

[0055] S2, Core Synthesis: The reaction mixture was heated at a rate of 5 °C / min until it reached the thermal decomposition temperature of cobalt palmitate, 210 °C, and reacted for 20 min to form the inner layer. ;

[0056] S3, shell Synthesis continued, and the reaction mixture was heated at a rate of 5 °C / min until it reached the thermal decomposition temperature of manganese erucate, 260 °C. The reaction was allowed to proceed for 20 min, yielding the product. ,get Nanoparticles;

[0057] S4, outer targeting ligand modification, attaching the apolipoprotein E-derived peptide ligand with a molecular weight of 4000 Da to the ligand obtained in step S3. By controlling the surface modification density of nanoparticles to approximately 2-3 ligands per square nanometer, a liver-specific spatial heterogeneous structure was obtained. Nanoparticles.

[0058] Figure 2 C is Transmission electron microscope image, Figure 3 C is The TEM-EDS mapping results show that The elements are mainly distributed in the shell of the nanoparticles. The element is mainly found in the core of the nanoparticle, confirming that the particle has Spatial heterogeneous structures enriched in the shell. Figure 4 C shows that under a 3T magnetic field... longitudinal relaxation rate . Figure 5 As shown in Figure C, this is a magnetic resonance imaging experiment of the liver of a Bama pig. Liver signal increased by 102% after drug administration.

[0059] Example 4

[0060] This invention relates to a hepatocyte-targeting spatially heterogeneous ferrite nanoparticle. The three-layered complex of physics and chemistry, in which, It has a core-shell structure. With the core, It is a shell, the third layer. To create a ligand-modified layer with hepatocyte-targeting function, the core and shell layers are gradient-doped with metal elements. The method of achieving spatial heterogeneous structure distribution of metallic elements, wherein , , ,satisfy: The specific preparation steps are the same as in Example 1, except that the molar ratio of ferric erucate, manganese oleate, and manganese erucate in S1 is changed to [3-1.5+1.2(3-1.4)]:1.4:[1.2×1.4]. The longitudinal relaxation rate of this material... After administration at a dose of 0.84 mg / kg, liver signal in Bama pigs increased by 110%.

[0061] Example 5

[0062] This invention relates to a hepatocyte-targeting spatially heterogeneous ferrite nanoparticle. The three-layered complex of physics and chemistry, in which, It has a core-shell structure. With the core, It is a shell, the third layer. To create a ligand-modified layer with hepatocyte-targeting function, the core and shell layers are gradient-doped with metal elements. The method of achieving spatial heterogeneous structure distribution of metallic elements, wherein , , ,satisfy: The specific preparation steps are the same as in Example 3, except that cobalt palmitate is replaced with cobalt stearate, manganese erucate is replaced with manganese oleate, the reaction temperature of S2 is adjusted to 200℃, and the reaction temperature of S3 is adjusted to 250℃. The longitudinal relaxation rate of this material... After administration of a dose of 0.84 mg / kg, liver signal in Bama pigs increased by 105%.

[0063] Comparative Example 1

[0064] Chinese patent CN112299489A discloses an ultra-small iron oxide nanoparticle and its preparation method. The method involves weighing 2.14 g of ferric erucic acid, 0.09 g of zinc carbonate, and 3.22 g of oleyl alcohol, adding them to 10 mL of benzyl ether, placing the mixture in a 50 mL three-necked flask, and incubating at 270 °C for 30 min until the solution becomes clear, transparent, and dark brown, indicating the reaction is complete. The temperature is then lowered to below 50 °C, and the product is washed three times using a chloroform dispersion-centrifugation method to obtain the final product. The longitudinal relaxation rate of this material is r1 = 20.22 mM. -1 s -1 .

[0065] Compared with the hepatocyte-targeting spatially heterogeneous ferrite nanoparticles of Example 1, under the same dosage conditions, the hepatocyte-targeting spatially heterogeneous ferrite nanoparticles of Example 1... Compared to the ultra-small iron oxide nanoparticles in Comparative Example 1 It not only reduced the time to peak signal-to-noise ratio of liver parenchyma enhancement rate from 0 minutes to 5 minutes, but also increased the peak enhancement rate from 60% to 120%, achieving a synergistic optimization effect in both imaging speed and enhancement effect.

[0066] Comparative Example 2

[0067] Comparative Example 2 uses a widely used clinical hepatocyte-specific magnetic resonance contrast agent—gadoxetate disodium, with the general formula Gd-EOB-DTPA. This contrast agent is a small-molecule gadolinium chelate, its structure consisting of a gadolinium ion (Gd³⁺) complexed with ethoxyphenyl (EOB) and diethylenetriaminepentaacetic acid (DTPA) ligands to form the Gd-EOB-DTPA complex. Its working principle is that after intravenous injection, it is selectively taken up by hepatocytes via hepatobiliary-specific transporters, thereby achieving specific enhanced imaging of liver tissue.

[0068] At the same recommended dose of 0.025 mmol / kg, the hepatocyte-targeting spatially heterogeneous ferrite nanoparticles of Example 1 of this invention... longitudinal relaxation rate The longitudinal relaxation rate r1 is higher than that of Gd-EOB-DTPA, resulting in stronger and higher-quality imaging signals. Ferrite nanoparticles with spatial heterogeneity require a lower injection dose to achieve the same MRI contrast.

[0069] Gd-EOB-DTPA is a gadolinium-based contrast agent, which carries a certain risk of causing renal systemic fibrosis. Therefore, it should be used with caution in patients with renal insufficiency. The nanoparticles of this invention are based on biocompatible iron, an essential element for the human body, with a safer metabolic pathway, avoiding the risks of gadolinium deposition and renal systemic fibrosis. Table 1 below shows the comparison of liver parenchyma-muscle contrast, liver parenchyma enhancement rate, time to peak maximum signal-to-noise ratio, effective imaging time window, and renal deposition in Examples 1, 1 Comparative Example, and 2.

[0070] Table 1

[0071] Example 1 <![CDATA[20.4mM -1 s -1 ]]> 60.8% 120% 5min 90min 10% Comparative Example 1 <![CDATA[20.2mM -1 s -1 ]]> 18.5% 70% 10min 50min 20% Comparative Example 2 <![CDATA[4.0mM -1 s -1 ]]> 3.8% 45% 20min 20min 50%

[0072] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A hepatocyte-targeting spatially heterogeneous ferrite nanoparticle, characterized in that, The general formula is The physical-chemical three-layer complex, in which, It has a core-shell structure. With the core, It is a shell, the third layer. To create a ligand-modified layer with hepatocyte-targeting function, the core and shell layers employ gradient doping of metal element M to achieve a spatial heterogeneous distribution of metal elements. ,satisfy: In the formula for , , One of them, the third layer It is one of polyethylene glycol-ethoxyphenyl ligand, galactose-peptide chimeric ligand, apolipoprotein E-derived peptide, and polyethylene glycol-N-acetylgalactosamine.

2. The hepatocyte-targeting spatially heterogeneous ferrite nanoparticle according to claim 1, characterized in that, The aforementioned The elemental distribution was characterized by transmission electron microscopy-elemental energy dispersive spectroscopy (EDS), and the results showed... Characteristics of elements The intensity of the X-ray signal is generally higher than that of metallic elements. Features X-ray signal intensity.

3. The hepatocyte-targeting spatially heterogeneous ferrite nanoparticle according to claim 1, characterized in that, The aforementioned The elemental distribution was characterized by transmission electron microscopy-elemental energy dispersive spectroscopy (TEM-EDS). For individual nanoparticles, the metal element distribution was analyzed. Features X-ray signals are enriched in the core region of the particles, while the characteristic X-ray signals of Mn are enriched in the shell region of the particles.

4. The hepatocyte-targeting spatially heterogeneous ferrite nanoparticle according to claim 1, characterized in that, The core The diameter is The unit is nm, and it satisfies: .

5. The hepatocyte-targeting spatially heterogeneous ferrite nanoparticle according to claim 1, characterized in that, The shell The thickness is The unit is nm, and it satisfies: .

6. The hepatocyte-targeting spatially heterogeneous ferrite nanoparticle according to claim 1, characterized in that, The The molecular weight range is 800 Da to 4000 Da.

7. The hepatocyte-targeting spatially heterogeneous ferrite nanoparticle according to claim 1, characterized in that, The third layer The ligand modification density is 2-8 ligands per square nanometer.

8. A method for preparing hepatocyte-targeting spatially heterogeneous ferrite nanoparticles, used to prepare the hepatocyte-targeting spatially heterogeneous ferrite nanoparticles according to any one of claims 1 to 7, characterized in that, Includes the following steps: S1, Prepare the reaction mixture under an inert atmosphere. , , according to The mixture was prepared in a molar ratio of 1:1, with oleic acid and oleyl alcohol added as surfactants. In for , , One of them yields a reaction mixture; S2, Core Synthesis: The reaction mixture was heated at a rate of 5-10 °C / min until it reached... The thermal decomposition temperature T1, the reaction time is 10-30 min, and the nucleus is generated. Nanoparticles; S3, shell Synthesis: The reaction mixture was further heated at a rate of 5-10 °C / min until it reached... The thermal decomposition temperature T2, the reaction time is 10-40 min, and the result is... Nanoparticles; S4, outer layer targeting ligand modification, attaching the ligand to the layer obtained in step S3. On the surface of nanoparticles, spatially heterogeneous ferrite nanoparticles targeting hepatocytes were obtained.

9. The method for preparing hepatocyte-targeting spatially heterogeneous ferrite nanoparticles according to claim 8, characterized in that, The , , In It is one of the following: carbonate, oleate, erucic acid, stearate, palmitic acid, and laurate. The thermal decomposition temperature T2 is higher than and The thermal decomposition temperature T1 is at least 20°C.

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