Gadolinium-based covalent organic framework magnetic resonance contrast agent, and preparation method and use thereof

Abstract

The application provides a surface-modified gadolinium-based covalent organic framework magnetic resonance contrast agent and a preparation method and application thereof, characterized in that: tetra-(p-aminophenyl porphyrin) is used as a monomer to prepare Gd(III)-porphyrin, and then the Gd-porphyrin-based covalent organic framework polymer Gd-PCOFs contrast agent is connected by forming an imine bond with a dialsyl compound. Then, the surface of the Gd-PCOFs is modified by a molecule containing a mercapto group, so that a magnetic resonance contrast agent with uniform particle size and good dispersity is obtained, and the longitudinal relaxation rate can reach 126.35 s ‑ 1 mM ‑1 , which can be used for super-sensitive magnetic resonance imaging of solution, cells and living bodies.

Description

Technical Field

[0001] This invention relates to a multifunctional magnetic resonance imaging (MRI) contrast agent, its preparation method, and its application, and more particularly to a gadolinium-based covalent organic framework MRI contrast agent, its preparation method, and its application. Background Technology

[0002] Due to its imaging mechanism, MRI plays an irreplaceable role in soft tissue imaging. As a non-radiation imaging method, MRI causes very little harm to the patient and is considered a relatively safe clinical imaging technique. However, because some lesions are difficult to clearly visualize on MRI, contrast agents are often required to achieve good imaging results. MRI contrast agents increase the contrast between different tissues, making the lesion stand out more clearly and facilitating lesion assessment. Statistics show that approximately 45% of MRI cases require contrast agents to detect lesions. Gadolinium (Gd), a rare earth element, has seven unpaired electrons in its 4f electron orbital, giving it a very large magnetic torque. It can be used as a medium in magnetic bubble memory devices and for information storage. As a paramagnetic element, Gd… 3+ Gd ions can also be used as MRI contrast agents; however, free Gd... 3+ Due to its high ionic toxicity, Gd is not suitable for direct injection into live animals. Currently, in clinical practice, it is usually administered via Gd... 3+ Encapsulated in organic ligands, Gd can be significantly reduced in vivo, thus decreasing its toxicity. Examples include derivatives of gadopentetate, a commonly used clinical MRI contrast agent. Currently, commercially available gadopentetate derivatives typically contain only one gadolinium atom, resulting in a low relaxation rate. According to the Solomon-Bloembergen-Morgan Theory, the effective fraction of T1-weighted MRI contrast agents contains highly paramagnetic Gd... 3+ Ions, when multiple Gd 3+ When gadolinium ions are concentrated within a single molecule, forming a cluster, they can achieve a synergistic effect. This synergistic effect allows some water molecules in the contrast agent solution to potentially be directly affected by Gd. 3+ The inner sphere water molecules affected by the coordination of ions are also influenced by the adjacent Gd molecules. 3+ External water molecules affected by ions, such as two or more Gd 3+The combined effect of these factors can effectively improve the longitudinal relaxation rate of the contrast agent, thereby achieving better imaging results. Furthermore, the overall tumbling time of the contrast agent units dispersed in water also significantly affects the performance of the contrast agent. Therefore, binding gadolinium cluster molecules within a polymer layer, forming polymer-loaded gadolinium cluster nanoparticles, can significantly improve the imaging ability of the contrast agent. Contrast agents with superior imaging performance allow for a reduction in the amount of contrast agent used clinically, achieving satisfactory results while minimizing the toxicity of heavy metals in the contrast agent. Moreover, when using the same amount of heavy metals, multi-gadolinium ion contrast agents can achieve better imaging results, thus providing more reliable MRI images for clinical diagnosis.

[0003] Although many Gd 3+ Ion nanocontrast agents exhibit a significantly higher relaxation rate than typical Gd nanoparticles. 3+ While ion chelators are valuable, unmodified nanoparticles often exhibit poor biocompatibility and stability, limiting their applications. Specific polymer covalent attachment provides a method for modifying and tuning the relaxation properties of Gd nanoparticles, enhancing their surface functionality and in vivo stability and biocompatibility.

[0004] Reversible addition-fragment chain transfer (RAFT) polymerization is arguably the most versatile living radical polymerization (LRP) technique. It has been widely applied to prepare highly specialized materials for advanced biomedical applications. Another advantage of RAFT polymers is the presence of a thioglycolic acid thio group at the end of each polymer chain. Literature indicates that, in the presence of a nucleophile, this thioglycolic acid group can be reduced to thiols, such as primary amines or sodium borohydride. Thiols have been shown to react strongly with various metal surfaces and semiconductor nanoparticles, such as gold, silver, and cadmium selenide nanoparticles. Therefore, by utilizing the interaction between the sulfur at the thioglycolic acid end of the thioglycolic acid polymer and gadolinium, polymers can be modified onto the surface of gadolinium-based covalent organic framework nanomaterials to improve their physiological stability and relaxation rate. Summary of the Invention

[0005] The purpose of this invention is to improve the low T1 relaxation rate of Gd-based contrast agents. Using tetra-(p-aminophenylporphyrin) with high nitrogen content as a monomer, Gd(III)-porphyrin is prepared by metalloporphyrin chemistry. Then, a gadoporphyrin-based covalent organic framework polymer contrast agent Gd-PCOFs is formed by reversibly imine-linked amino groups with compounds containing dialdehyde groups. This allows a single contrast agent molecule to contain multiple Gd ions, which exert a synergistic effect and effectively improve the longitudinal relaxation rate of the contrast agent.

[0006] The surface of Gd-PCOF nanoparticles was modified using RAFT polymers. Homopolymers were formed via RAFT polymerization. The general polymerization process for forming homopolymers via RAFT polymerization involves adding monomers, RAFT agents, and solvents to a 150 mL Schlenk flask as needed. The solution was degassed for 30 min and then placed under a high-purity nitrogen atmosphere. AIBN was added to a second 150 mL Schlenk flask, and after three evaporation-wash cycles, the monomer solution was transferred to a flask containing the initiator via a sleeve under a high-purity nitrogen atmosphere and heated for a certain period. The polymer was separated from the polymerization solution by evaporating the remaining monomers and solvent overnight. Furthermore, dodecyl mercaptan was used instead of RAFT polymers to modify the surface of Gd-PCOF nanoparticles. The resulting paramagnetic Gd-PCOF nanomaterials exhibited uniform particle size, good dispersibility and water solubility, and excellent magnetic properties.

[0007] Another objective of this invention is to provide a method for preparing the above-mentioned Gd-based covalent organic framework nanomaterials.

[0008] Another object of the present invention is to provide the use of the above-mentioned Gd-based covalent organic framework nanomaterials as a nuclear magnetic resonance contrast agent, wherein the amount of the paramagnetic nanoparticles used as a nuclear magnetic resonance T1-weighted contrast agent is 0.01 mmol Gd / kg body weight.

[0009] In vitro relaxation rate measurements and mouse tumor site contrast imaging were performed using a 1.0T MRI scanner (Bruker Icon, a small animal in vivo magnetic resonance imaging system). The longitudinal relaxation time (T1) and transverse relaxation time (T2) of Gd-PCOF nanoparticles and polymer-modified Gd-PCOF nanoparticles were characterized and compared with the performance of clinically used contrast agents. T1-calculated scans were performed using spin-echo imaging with repetition times (TR) of 10000, 8000, 5000, 2500, 1000, 500, 250, 150, 150, 100, 30, and 25 ms, minimum echo time (TE), a 5 nm slice thickness, a 128 × 128 matrix, and an 18 cm field of view. T2-calculated scans were performed using spin-echo imaging with a TR of 1500, four different TE values ​​of 15, 30, 45, and 60 ms, a 5 nm slice thickness, a 128 × 128 matrix, and an 18 cm field of view. All samples, including clinical contrast agents, were serially diluted in deionized water, degassed with high-purity nitrogen, and sealed in polypropylene vials. Analysis was performed using signal intensity measurements obtained through the region of interest for each sequence. i =I o，I (1-exp (-t / Ti) ).

[0010] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0011] 1. This invention utilizes metalloporphyrin chemistry to bind multiple Gd ions to porphyrin molecules, further synthesizing a 20-80 nm gadolinium-porphyrin-based covalent organic framework polymer (Gd-PCOFs) nano-contrast agent with imine bonds. Compared to traditional small-molecule NMR contrast agents, this agent has a longer retention time in vivo and can utilize the high permeability and retention effect of solid tumors to achieve enrichment at the solid tumor site, resulting in significant imaging effects. Then, the surface of the Gd-PCOFs is modified with molecules containing thiol groups at one end to obtain an NMR contrast agent with uniform particle size and good dispersibility.

[0012] 2. The present invention contains multiple gadolinium ions in one contrast agent molecule, which can achieve excellent nuclear magnetic resonance imaging contrast effect. On the one hand, the imaging effect is better when using the same amount of gadolinium. On the other hand, the amount of contrast agent used can be reduced when achieving the same imaging effect, thereby reducing the toxicity of heavy metal gadolinium to the human body. Attached Figure Description

[0013] Figure 1 The image shows an electron microscope image of the Gd-PCOFs nanocontrast agent in this invention, exhibiting a complete rectangular sheet-like structure with good crystallinity, ranging from 20 to 80 nanometers.

[0014] Figure 2 The lateral and longitudinal relaxation rates of the poly(2-hydroxypropyl)methacrylamide-modified Gd-PCOFs nanocontrast agents in this invention are characterized: a) PHPMA-Gd-PCOFs nanocontrast agents, b) gadopentetate dimeglumine r1 and r2. Relaxation rate characterization revealed that the longitudinal relaxation rate of the PHPMA-Gd-PCOFs nanocontrast agent was 126.35 s⁻¹. -1 mM -1 The longitudinal relaxation rate of gadopentetate dimeglumine used clinically is 10.49 s. -1 mM -1 It is about 12 times that of PHPMA-Gd-PCOFs nanocontrast agent, which shows that PHPMA-Gd-PCOFs nanocontrast agent has a good T1-weighted nuclear magnetic resonance imaging effect.

[0015] Figure 3 This is an animal T1-weighted magnetic resonance imaging (MRI) image of the poly((((polyethylene glycol) methyl ether) acrylate-Gd-PCOFs nanocontrast agent) of this invention. This animal T1-weighted MRI image demonstrates that the PPEGMEA-Gd-PCOFs nanocontrast agent has excellent MRI imaging effects at the in vivo level.

[0016] Figure 4This is a statistical table showing the brightness values ​​of tumor sites at different time points in animal T1-weighted magnetic resonance imaging (MRI) images of the polyacrylate-Gd-PCOFs nanocontrast agent described in this invention. This table demonstrates the good efficacy of the PAA-Gd-PCOFs nanocontrast agent in MRI imaging of animal tumors. Detailed Implementation

[0017] The technical solution of the present invention is not limited to the specific embodiments listed below, but also includes any combination of the specific embodiments.

[0018] Example 1

[0019] The specific steps for preparing Gd-PCOF nanoparticles are as follows:

[0020] Gd-TAPP synthesis: In a 150 mL three-necked flask, 50 mL of ethanol was added, followed by the weighing of 67.4 mg of 5,10,15,20-tetra(4-aminophenyl)porphyrin (4NH2TAPP, 0.1 mmol) and 49.2 mg of GdCl3·6H2O (0.2 mmol). The mixture was refluxed at 200 °C for 4 h. After cooling, a mixture of unreacted GdCl3 and Gd-4TAPP was obtained. This mixture was dissolved in a large amount of water, centrifuged (16000 rpm × 20 min), washed three times with deionized water, and freeze-dried to obtain Gd-TAPP (78.3 mg, yield 94.5%).

[0021] Synthesis of Gd-PCOF: 49.9 mg of Gd-4TAPP (0.06 mmol) and 25.2 mg of biphenyl dicarboxaldehyde (0.12 mmol) were weighed and placed in a Pyrex tube. 4 mL of mixed solvent (o-dichlorobenzene: n-butanol = 4:1) was added. After sonication for 5 min, 0.4 mL of 6M acetic acid was added. The mixture was subjected to three cycles of vacuum freeze-thaw, and then the tube was sealed by high-temperature melting. The reaction was carried out at 120 °C for 3 days. The resulting reddish-brown solid was soaked in tetrahydrofuran and dichloromethane for 2 days and then freeze-dried to obtain Gd-PCOF (50.3 mg, yield 71.1%).

[0022] Synthesis of RAFT polymer: N-(2-hydroxypropyl)methacrylamide (8.50 g) was added to tert-butanol (40.0 mL), and 2-(dodecylthiothiocarbonylthio)-2-methylpropionic acid (0.100 g) and 2,2-azobisisobutyronitrile (0.00450 g) were added under stirring. The reaction was carried out at 90 °C for 4 h to obtain (poly(2-hydroxypropyl)methacrylamide, PHPMA, conversion = 62.4%, Mn, experimental = 19070 g / mol).

[0023] Surface modification of Gd-PCOF

[0024] HPMA's RAFT polymer (0.1 g) was added to 50 mL of anhydrous N,N-dimethylformamide (DMF) and stirred in a 150 mL flask until a homogeneous solution was formed. Then, 0.5 mL of hexylamine was added, and the mixture was stirred at room temperature for 2 h to convert the RAFT polymer ends to thiol-terminated polymer ends. Gd-PCOF nanoparticles (0.01 g) were suspended in another 15 mL of DMF and placed in another 150 mL flask equipped with a stir bar and kept stirred. The RAFT homopolymer solution with thiol-terminated ends was then transferred to the Gd-PCOF nanoparticle solution. The resulting mixture was stirred at room temperature for 24 h. Unreacted polymer was removed from the RAFT polymer-modified Gd-PCOF nanoparticles by repeated centrifugation and repeated centrifugation and resuspension in DMF (twice) and ethanol (twice). The mixture was then dried to obtain the final surface-modified Gd-based contrast agent.

[0025] Example 2

[0026] The specific steps for preparing Gd-PCOF nanoparticles are as follows:

[0027] Gd-TAPP synthesis: In a 150 mL three-necked flask, 50 mL of ethanol was added, followed by the weighing of 67.4 mg of 5,10,15,20-tetra(4-aminophenyl)porphyrin (4NH2TAPP, 0.1 mmol) and 49.2 mg of GdCl3·6H2O (0.2 mmol). The mixture was refluxed at 200 °C for 4 h. After cooling, a mixture of unreacted GdCl3 and Gd-4TAPP was obtained. This mixture was dissolved in a large amount of water, centrifuged (16000 rpm × 20 min), washed three times with deionized water, and freeze-dried to obtain Gd-TAPP (78.3 mg, yield 94.5%).

[0028] Synthesis of Gd-PCOF: 49.9 mg of Gd-4TAPP (0.06 mmol) and 25.2 mg of biphenyl dicarboxaldehyde (0.12 mmol) were weighed and placed in a Pyrex tube. 4 mL of mixed solvent (o-dichlorobenzene: n-butanol = 4:1) was added. After sonication for 5 min, 0.4 mL of 6M acetic acid was added. The mixture was subjected to three cycles of vacuum freeze-thaw, and then the tube was sealed by high-temperature melting. The reaction was carried out at 120 °C for 3 days. The resulting reddish-brown solid was soaked in tetrahydrofuran and dichloromethane for 2 days and then freeze-dried to obtain Gd-COF (50.3 mg, yield 71.1%).

[0029] Synthesis of RAFT polymer: N-isopropylacrylamide (10.07 g) was added to dimethylformamide (50 mL), and 2-(dodecylthiothiocarbonylthio)-2-methylpropionic acid (0.0698 g) and 2,2-azobisisobutyronitrile (0.0290 g) were added under stirring. The reaction was carried out at 70 °C for 24 h to obtain (poly(N-isopropylacrylamide, PNIPAM, conversion = 33%). n，experimental =18 023 g / mol).

[0030] Surface modification of Gd-PCOF

[0031] 0.1 g of NIPAM's RAFT polymer was added to 50 mL of anhydrous N,N-dimethylformamide (DMF) and stirred in a 150 mL flask until a homogeneous solution was formed. Then, 0.5 mL of hexylamine was added, and the mixture was stirred at room temperature for 2 h to convert the RAFT polymer ends to thiol-terminated polymer ends. 0.01 g of Gd-PCOF nanoparticles was suspended in another 15 mL DMF solution and kept stirred in a separate 150 mL flask equipped with a stir bar. The thiol-terminated RAFT homopolymer solution was then transferred to the Gd-PCOF nanoparticle solution. The resulting mixture was stirred at room temperature for 24 h. Unreacted polymer was removed from the RAFT polymer-modified Gd-PCOF nanoparticles by repeated centrifugation and repeated centrifugation and resuspension in DMF (twice) and ethanol (twice). The final surface-modified Gd-based contrast agent was then obtained by drying.

[0032] Example 3

[0033] The specific steps for preparing Gd-PCOF nanoparticles are as follows:

[0034] Gd-TAPP synthesis: In a 150 mL three-necked flask, 50 mL of ethanol was added, followed by the weighing of 67.4 mg of 5,10,15,20-tetra(4-aminophenyl)porphyrin (4NH2TAPP, 0.1 mmol) and 49.2 mg of GdCl3·6H2O (0.2 mmol). The mixture was refluxed at 200 °C for 4 h. After cooling, a mixture of unreacted GdCl3 and Gd-4TAPP was obtained. This mixture was dissolved in a large amount of water, centrifuged (16000 rpm × 20 min), washed three times with deionized water, and freeze-dried to obtain Gd-TAPP (78.3 mg, yield 94.5%).

[0035] Synthesis of Gd-PCOF: 49.9 mg of Gd-4TAPP (0.06 mmol) and 25.2 mg of biphenyl dicarboxaldehyde (0.12 mmol) were weighed and placed in a Pyrex tube. 4 mL of mixed solvent (o-dichlorobenzene: n-butanol = 4:1) was added. After sonication for 5 min, 0.4 mL of 6M acetic acid was added. The mixture was subjected to three cycles of vacuum freeze-thaw, and then the tube was sealed by high-temperature melting. The reaction was carried out at 120 °C for 3 days. The resulting reddish-brown solid was soaked in tetrahydrofuran and dichloromethane for 2 days and then freeze-dried to obtain Gd-COF (50.3 mg, yield 71.1%).

[0036] Synthesis of RAFT polymer: Poly(ethylene glycol) methyl acrylate (12.8 mL), anhydrous dioxane (13.5 mL), 2-(dodecylthiothiocarbonylthio)-2-methylpropionic acid (0.096 g), and 2,2-azobisisobutyronitrile (0.0024 g) were reacted at 60 °C for 18 h (poly(((polyethylene glycol)methyl ether) acrylate), PPEGMEA, conversion = 49%, M n，experimental =19,042 g / mol).

[0037] Surface modification of Gd-PCOF

[0038] 0.1 g of the RAFT polymer of PEGMEA was added to 50 mL of anhydrous N,N-dimethylformamide (DMF) and stirred in a 150 mL flask until a homogeneous solution was formed. Then, 0.5 mL of hexylamine was added, and the mixture was stirred at room temperature for 2 h to convert the RAFT polymer ends to thiol-terminated polymer ends. 0.01 g of Gd-PCOF nanoparticles was suspended in another 15 mL of DMF and kept stirred in another 150 mL flask equipped with a stir bar. The RAFT homopolymer solution with thiol-terminated ends was then transferred to the Gd-PCOF nanoparticle solution. The resulting mixture was stirred at room temperature for 24 h. Unreacted polymer was removed from the RAFT polymer-modified Gd-PCOF nanoparticles by repeated centrifugation and repeated centrifugation and resuspension in DMF (twice) and ethanol (twice). The final surface-modified Gd-based contrast agent was then obtained by drying.

[0039] Example 4

[0040] The specific steps for preparing Gd-PCOF nanoparticles are as follows:

[0041] Gd-TAPP synthesis: In a 150 mL three-necked flask, 50 mL of ethanol was added, followed by the weighing of 67.4 mg of 5,10,15,20-tetra(4-aminophenyl)porphyrin (4NH2TAPP, 0.1 mmol) and 49.2 mg of GdCl3·6H2O (0.2 mmol). The mixture was refluxed at 200 °C for 4 h. After cooling, a mixture of unreacted GdCl3 and Gd-4TAPP was obtained. This mixture was dissolved in a large amount of water, centrifuged (16000 rpm × 20 min), washed three times with deionized water, and freeze-dried to obtain Gd-TAPP (78.3 mg, yield 94.5%).

[0042] Synthesis of Gd-PCOF: 49.9 mg of Gd-4TAPP (0.06 mmol) and 25.2 mg of biphenyl dicarboxaldehyde (0.12 mmol) were weighed and placed in a Pyrex tube. 4 mL of mixed solvent (o-dichlorobenzene: n-butanol = 4:1) was added. After sonication for 5 min, 0.4 mL of 6M acetic acid was added. The mixture was subjected to three cycles of vacuum freeze-thaw, and then the tube was sealed by high-temperature melting. The reaction was carried out at 120 °C for 3 days. The resulting reddish-brown solid was soaked in tetrahydrofuran and dichloromethane for 2 days and then freeze-dried to obtain Gd-COF (50.3 mg, yield 71.1%).

[0043] Synthesis of RAFT polymer: Acrylic acid (20.0 mL), dimethylformamide (45.5 mL), 2-(dodecylthiothiocarbonylthio)-2-methylpropionic acid (0.762 g), and 2,2-azobisisobutyronitrile (0.0343 g) were reacted at 70 °C for 24 h (polyacrylate, PAA, conversion = 94%). n，experimental =12,856 g / mol).

[0044] Surface modification of Gd-PCOF

[0045] 0.1 g of AA's RAFT polymer was added to 50 mL of anhydrous N,N-dimethylformamide (DMF) and stirred in a 150 mL flask until a homogeneous solution was formed. Then, 0.5 mL of hexylamine was added, and the mixture was stirred at room temperature for 2 h to convert the RAFT polymer ends to thiol-terminated polymer ends. 0.01 g of Gd-PCOF nanoparticles was suspended in another 15 mL of DMF and kept stirred in another 150 mL flask equipped with a stir bar. The RAFT homopolymer solution with thiol-terminated ends was then transferred to the Gd-PCOF nanoparticle solution. The resulting mixture was stirred at room temperature for 24 h. Unreacted polymer was removed from the RAFT polymer-modified Gd-PCOF nanoparticles by repeated centrifugation and repeated centrifugation and resuspension in DMF (twice) and ethanol (twice). The final surface-modified Gd-based contrast agent was then obtained by drying.

[0046] Example 5

[0047] The specific steps for preparing Gd-PCOF nanoparticles are as follows:

[0048] Gd-TAPP synthesis: In a 150 mL three-necked flask, 50 mL of ethanol was added, followed by the weighing of 67.4 mg of 5,10,15,20-tetra(4-aminophenyl)porphyrin (4NH2TAPP, 0.1 mmol) and 49.2 mg of GdCl3·6H2O (0.2 mmol). The mixture was refluxed at 200 °C for 4 h. After cooling, a mixture of unreacted GdCl3 and Gd-4TAPP was obtained. This mixture was dissolved in a large amount of water, centrifuged (16000 rpm × 20 min), washed three times with deionized water, and freeze-dried to obtain Gd-TAPP (78.3 mg, yield 94.5%).

[0049] Synthesis of Gd-PCOF: 49.9 mg of Gd-4TAPP (0.06 mmol) and 25.2 mg of biphenyl dicarboxaldehyde (0.12 mmol) were weighed and placed in a Pyrex tube. 4 mL of mixed solvent (o-dichlorobenzene: n-butanol = 4:1) was added. After sonication for 5 min, 0.4 mL of 6M acetic acid was added. The mixture was subjected to three cycles of vacuum freeze-thaw, and then the tube was sealed by high-temperature melting. The reaction was carried out at 120 °C for 3 days. The resulting reddish-brown solid was soaked in tetrahydrofuran and dichloromethane for 2 days and then freeze-dried to obtain Gd-COF (50.3 mg, yield 71.1%).

[0050] Surface modification of Gd-PCOF: The surface of Gd-PCOF nanoparticles was modified with dodecyl mercaptan (1.00 mL) instead of RAFT polymer.

[0051] Table 1 Clinical magnetic resonance imaging contrast agents, unmodified and polymer-modified gadolinium-based covalent organic framework magnetic resonance imaging contrast agents r1, r2, r2 / r1

[0052] sample gadopentetate dimeglumine Gd-PCOF Example 1 Example 2 Example 3 Example 4 Example 5 <![CDATA[r1(s -1 mM -1 )]]> 10.49 17.23 126.35 88.45 95.12 37.20 5.92 <![CDATA[r2(s -1 mM -1 )]]> 16.68 25.32 155.41 113.15 129.36 44.17 25.75 r2 / r1 1.59 1.47 1.23 1.28 1.36 1.19 4.35

Claims

1. A surface-modified gadolinyl covalent organic framework magnetic resonance contrast agent, characterized by preparing Gd(III)-porphyrin as a monomer using tetra-(p-aminophenylporphyrin), then forming an imine-linked gadoporphyrin-based covalent organic framework polymer Gd-PCOFs contrast agent with a dialdehyde-containing compound, and then modifying the surface of Gd-PCOFs with a polymer molecule containing thiol groups to obtain a magnetic resonance contrast agent with uniform particle size and good dispersibility, the structural unit formula of which is as follows:

2. The method for preparing a surface-modified gadolinium-based covalent organic framework magnetic resonance imaging agent according to claim 1, characterized in that... Includes the following steps: 1) In a 150 mL three-necked flask, add 50 mL of ethanol, then weigh 67.4 mg of 5,10,15,20-tetra(4-aminophenyl)porphyrin 4NH2TAPP and 49.2 mg of GdCl3·6H2O and add them to the flask. Reflux at 200 °C for 4 h. After cooling, the mixed solid is a mixture of unreacted GdCl3 and Gd-4TAPP. Dissolve it in a large amount of water, centrifuge at 16000 rpm for 20 min and wash three times with deionized water. Freeze-dry to obtain Gd(III)-porphyrin Gd-TAPP. 2) Weigh 49.9 mg Gd-4TAPP and 25.2 mg biphenyl dicarboxaldehyde into a Pyrex tube, add 4 mL of mixed solvent (o-dichlorobenzene:n-butanol, volume ratio 4:1), sonicate for 5 min, add 0.4 mL of 6M acetic acid, cyclically freeze-thaw three times, then seal the tube by high-temperature melting, and react at 120 °C for 3 days; the resulting reddish-brown solid is soaked in tetrahydrofuran and dichloromethane for 2 days, and then freeze-dried to obtain gadolinium-based covalent organic framework magnetic resonance contrast agent Gd-PCOF; 3) Surface modification of Gd-PCOF: 0.1 g of RAFT polymer was added to 50 mL of anhydrous N,N-dimethylformamide (DMF) and stirred in a 150 mL flask until a homogeneous solution was formed. Then, 0.5 mL of hexylamine was added and stirred at room temperature for 2 h to convert the RAFT polymer ends to polymer ends terminated with thiol groups. 0.01 g of Gd-PCOF nanoparticles were suspended in another 15 mL of DMF and added dropwise to the RAFT homopolymer solution with thiol-terminated ends. The mixture was stirred at room temperature for 24 h. The mixture was centrifuged and resuspended twice each in DMF and ethanol to remove unreacted polymer from the RAFT polymer-modified Gd-PCOF nanoparticles. The mixture was then dried to obtain the final surface-modified Gd-based contrast agent.

3. The application of the surface-modified gadolinium-based covalent organic framework magnetic resonance contrast agent as described in claim 1 in magnetic resonance imaging.

4. The application according to claim 3, characterized in that... The surface-modified gadolinium-based covalent organic framework magnetic resonance contrast agent is specifically used for magnetic resonance imaging in in vitro aqueous solutions.

5. The application according to claim 4, characterized in that... The surface-modified gadolinium-based covalent organic framework magnetic resonance contrast agent is specifically used for in vivo tumor magnetic resonance imaging in animals.

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