Search

CN-116854926-B - Gadolinium-based covalent organic framework magnetic resonance contrast agent and preparation method and application thereof

CN116854926BCN 116854926 BCN116854926 BCN 116854926BCN-116854926-B

Abstract

The invention provides a surface-modified gadolinium-based covalent organic framework magnetic resonance contrast agent, and a preparation method and application thereof, and is characterized in that tetra- (p-aminophenylporphyrin) is used as a monomer to prepare Gd (III) -porphyrin, and then the Gd-porphyrin-based covalent organic framework polymer Gd-PCOFs contrast agent connected with a dialdehyde-group-containing compound through an imine bond is generated. Then the Gd-PCOFs surface is modified by molecules containing sulfhydryl groups to obtain the magnetic resonance contrast agent with uniform particle size and good dispersibility, and the longitudinal relaxation rate can reach 126.35s ‑ 1 mM ‑1 under the magnetic field of 1.0T, thus the magnetic resonance contrast agent can be used for ultrasensitive magnetic resonance imaging of solutions, cells and living bodies.

Inventors

  • DING YIN
  • HU ZITAO

Assignees

  • 南京大学

Dates

Publication Date
20260508
Application Date
20230602

Claims (5)

  1. 1. A surface-modified gadolinium-based covalent organic framework magnetic resonance contrast agent is characterized in that tetra- (p-aminophenylporphyrin) is used as a monomer to prepare Gd (III) -porphyrin, then the Gd-porphyrin-based covalent organic framework polymer Gd-PCOFs contrast agent connected with a dialdehyde-group-containing compound to generate imine bond, and then the Gd-PCOFs surface is modified through a polymer molecule containing sulfhydryl groups to obtain the magnetic resonance contrast agent with uniform particle size and good dispersibility, wherein the structural unit formula is as follows
  2. 2. A method of preparing a surface modified gadolinium-based covalent organic framework magnetic resonance contrast agent as claimed in claim 1, characterized by comprising the steps of: 1) Adding 50mL of ethanol into a 150mL three-necked flask, weighing 67.4mg 5,10,15,20-tetra (4-aminophenyl) porphyrin 4NH 2 TAPP and 49.2mg GdCl 3 ·6H 2 O, adding the materials into the three-necked flask, refluxing the mixture for 4h at 200 ℃, cooling the mixture to obtain a mixed solid which is a mixture of unreacted GdCl 3 and Gd-4TAPP, dissolving the mixture with a large amount of water, centrifuging the mixture for 20min at a revolution of 16000rpm, washing the mixture with deionized water for 3 times, and freeze-drying the mixture to obtain Gd (III) -porphyrin Gd-TAPP; 2) 49.9mg of Gd-4TAPP and 25.2mg of biphenyl dicarboxaldehyde are weighed and placed in a Pyrex tube, 4mL of mixed solvent is added, the mixed solvent is o-dichlorobenzene with the volume ratio of 4:1, n-butanol is added, after 5min of ultrasonic treatment, 0.4mL of 6M acetic acid is added, the mixture is circularly and vacuum frozen and thawed three times, then the mixture is subjected to high-temperature melting tube sealing and reacted for 3 days at 120 ℃, the obtained reddish brown solid is soaked in tetrahydrofuran and dichloromethane for 2 days, and the gadolinium-based covalent organic framework magnetic resonance contrast agent Gd-PCOF is obtained through freeze drying; 3) Gd-PCOF surface modification of RAFT polymer 0.1g was added to 50mL of anhydrous N, N-Dimethylformamide (DMF), stirred in a 150mL flask until a homogeneous solution was formed, then 0.5mL of hexylamine was added, stirred at room temperature for 2h to convert the RAFT polymer end to a polymer end terminated with a thiol group, 0.01g of Gd-PCOFs nanoparticles was suspended in another 15mL of DMF, added dropwise to a solution of RAFT homopolymer end converted to a thiol group, stirred at room temperature for 24h, centrifugation and re-suspension were repeated 2 times in DMF and ethanol, respectively, to remove unreacted polymer from the RAFT polymer surface modified Gd-PCOFs nanoparticles, and then dried to obtain the final surface modified Gd-based contrast agent.
  3. 3. Use of a surface modified gadolinium-based covalent organic framework magnetic resonance contrast agent as defined in claim 1 in magnetic resonance detection.
  4. 4. Use according to claim 3, characterized in that the surface-modified gadolinium-based covalent organic framework magnetic resonance contrast agent is particularly useful for magnetic resonance imaging in vitro aqueous solutions.
  5. 5. Use according to claim 4, characterized in that the surface-modified gadolinium-based covalent organic framework magnetic resonance contrast agent is used in particular for magnetic resonance imaging of tumors in animals.

Description

Gadolinium-based covalent organic framework magnetic resonance contrast agent and preparation method and application thereof Technical Field The invention relates to a multifunctional magnetic resonance contrast agent and a preparation method and application thereof, in particular to a gadolinium-based covalent organic framework magnetic resonance contrast agent and a preparation method and application thereof. Background Because of the contrast mechanism of MRI, it has an irreplaceable role in soft tissue contrast imaging, and as a non-radiation imaging mode, MRI has very little damage to the person under test, and is considered as a safer clinical imaging means, since some lesions are difficult to clearly show in nmr, and clinically MRI also requires contrast agent assistance to achieve good contrast effects. The MRI contrast agent can increase the contrast between different tissues, can highlight the contrast between the pathological tissues and the surrounding environment thereof so as to be more convenient for judging the disease focus condition, and according to statistics, about 45% of clinical MRI cases can reach the effect of finding the disease focus by the contrast agent. The 4f electron orbit in the atom of rare earth gadolinium (Gd) has 7 unpaired electrons, so that gadolinium has very large magnetic moment, and can be used as a medium substance in a bubble memory device and also can be used for information storage. as paramagnetic Gd 3+ ion, it can also be used as MRI contrast agent, however, free Gd 3+ ion has a relatively high toxicity, and is not suitable for direct injection into living animals, and Gd 3+ is generally coated in organic ligand in clinic at present, so as to remarkably reduce the metabolism speed of Gd element in vivo and reduce toxicity of Gd, such as the most-used nuclear magnetic resonance contrast agent gadofluconic acid derivative in clinic. Currently, commercially available gadofosvenoric acid derivatives usually contain only one gadolinium atom and have a low relaxation rate. According to the Solomon-Brober-Morgan theory (Solomon Bloembergen Morgan Theory), the effective fraction of T1-weighted NMR contrast agent has high paramagnetic Gd 3+ ions, which can achieve synergy when a plurality of Gd 3+ are concentrated in a range of one molecule to form gadolinium ion clusters. The synergistic effect ensures that partial water molecules in the contrast agent solution are possibly internal water molecules directly influenced by the coordination of Gd 3+ ions and external water molecules influenced by adjacent Gd 3+ ions, and the combined action of two or more Gd 3+ can effectively improve the longitudinal relaxation rate of the contrast agent, thereby achieving better contrast effect. In addition, the overall turnover time of the contrast agent units dispersed in water in the solution also has a significant effect on the performance of the contrast agent, so that the gadolinium cluster compound molecules are bound in the high polymer layer, namely the high polymer loaded gadolinium cluster compound nano particles are formed, and the contrast capability of the contrast agent can be improved significantly. The contrast agent with better contrast performance can reduce the consumption of the contrast agent clinically, can reduce the harm of heavy metals in the contrast agent to the body while obtaining a satisfactory effect, and can achieve better contrast effect when the same heavy metal amount is used, thereby providing more reliable nuclear magnetic resonance images for clinical diagnosis. While multi-Gd 3+ ion nanocontrast agents exhibit significantly higher relaxivity than typical Gd 3+ ion chelators, nanoparticles without surface modification are poorly biocompatible and stable, resulting in limited their application. The covalent attachment of the definite polymer provides a method for modifying and adjusting the relaxation characteristics of the nano particles for the surface modification of Gd, so that the nano particles have more surface functions and the in vivo stability and biocompatibility of the nano particles are also improved. Reversible addition-fragmentation chain transfer (RAFT) polymerization is said to be the most common Living Radical Polymerization (LRP) technique. It has been widely used for the preparation of highly specialized materials for advanced biomedical applications. Another advantage of RAFT polymers is the presence of one thiocarbonglycosylthio group at the end of each polymer chain. The literature shows that in the presence of nucleophiles, thio groups can be reduced to thiols, such as primary amines or sodium borohydride. While thiols have been shown to react strongly with various metal surfaces and surfaces of semiconductor nanoparticles, such as gold, silver and cadmium selenide nanoparticle surfaces. Therefore, the interaction between sulfur at the tail end of the sulfhydryl polymer and gadolinium is utilized to modify the m