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Magnetic resonance contrast agent and its preparation and application

A magnetic resonance contrast agent and solvent technology, applied in the field of biomedicine, can solve the problems of inability to detect the lesion area for a long time, ion leakage, low relaxation rate, etc., so as to improve the biological safety in vivo, improve the imaging ability, and the preparation method. simple effect

Active Publication Date: 2022-08-09
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the widespread application of these small molecule gadolinium chelates is greatly limited by the following problems: 1. Due to its T 1 The relaxation rate is low (for example, the relaxation rate of Gd-DTPA is about 3.5mM under the 3.0T magnetic field - 1 the s -1 left and right), so larger doses are required to achieve effective contrast effects, and larger doses bring higher safety risks
2. The blood circulation time of gadolinium chelate is short, so it cannot be used to detect changes in the lesion area for a long time
3. These small molecule gadolinium chelates will produce Gd under complex physiological conditions in vivo 3+ Ion leakage, causing nephrogenic fibrosis (Nephrogenic systemic fibrosis, NSF) in patients with renal insufficiency
The patent application number CN109529058A discloses a block copolymer modified NaGdF 4 Cluster nano magnetic resonance contrast agent and preparation method thereof, the used block copolymer contains carboxyl (-COOH), and NaGdF 4 Surface Gd 3+ The ion coordination ability is weak and cannot effectively block the Gd in the contrast agent 3+ ion leakage
In addition, the resulting nanocluster contrast agent has a large size, which is not conducive to renal metabolism, and there is a safety risk of accumulation in the body
In conclusion, none of the above patents involved the in vivo safety and potential NSF hazards of gadolinium-based nanocontrast agents

Method used

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  • Magnetic resonance contrast agent and its preparation and application
  • Magnetic resonance contrast agent and its preparation and application
  • Magnetic resonance contrast agent and its preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1: Preparation of NaGdF 4 nanocrystals

[0069] Dissolve 1.2 g of sodium hydroxide completely in 4 mL of water, add 8 mL of absolute ethanol and 20 mL (or 40 mL) of oleic acid, and stir for 5-10 minutes. 1 mL of an aqueous solution of gadolinium chloride (0.5 mmol) was then added dropwise. After the gadolinium chloride aqueous solution was added dropwise, 4 mL of sodium fluoride aqueous solution (0.5 mmol) was added dropwise to it. After the dropwise addition, the solution was stirred at room temperature for 1 h. After the reaction was completed, it was precipitated with 40 mL of anhydrous ethanol and washed twice to obtain NaGdF. 4 Nanoclusters, reconstituted in cyclohexane.

[0070] Add 6mL oleic acid and 10mL octadecene to a 100mL three-necked flask, and add the prepared NaGdF to the flask 4 Nanocluster solution (0.5 mmol, 2 mL), remove low boiling point solvent (cyclohexane) and oxygen under nitrogen atmosphere, heat up to 260 ° C at 10 ° C / min, then imme...

Embodiment 2

[0071] Example 2: Preparation of OCOPs with different numbers of side chainsn

[0072] The first step: Mix 0.7-7 mmol of OEGMA, 0.2 mmol of CTA-COOH and 0.04 mmol of AIBN and fully dissolve it in 15 mL of 1,4-dioxane, add the mixed solution to a 50 mL Schlenk tube, and put it in a nitrogen atmosphere. Three cycles of freeze-pump-thaw degassing were performed to completely remove oxygen. Subsequently, the Schlenk tube was placed in a 70°C oil bath overnight to react, and then the solvent was evaporated. In the second step, the product of the first step, 0.6-1.8 mmol of OEGMA-OH and 0.04 mmol of AIBN were mixed and fully dissolved in 15 mL of 1,4-dioxane, and the polymerization was carried out in the same steps as the first step. . After the solvent was evaporated, 12 mmol of phosphorus oxychloride was used to replace the hydroxyl group on the side chain of the polymer with phosphate, and then put into a dialysis bag with a molecular weight cut-off of 2 kDA for dialysis to ful...

Embodiment 3

[0077] Example 3: Preparation of OCOP n Coated ultra-small NaGdF 4 Nanocrystals (Gd-OCOP n )

[0078] The ultra-small NaGdF prepared in Example 1 4 Nanocrystals were mixed with nitrous tetrafluoroborate in N,N-dimethylformamide to remove their surface oleic acid ligands, and then mixed with the OCOP prepared in Example 2. n Mix in water at a molar ratio of 1:5, stir overnight at room temperature, then fully evaporate the solvent, add water to the dried product and shake to fully dissolve, and finally remove impurities by ultrafiltration (5400rpm) with an ultrafiltration tube with a molecular weight cut-off of 30kDa. , 3 min) 3 times to fully remove the unwrapped polymer and impurities, put it in a glass bottle and store it at 4 ℃. attached Figure 4-7 for Gd-OCOP n Transmission electron microscopy (Gd-OCOP) 7 : OEGMA 0.8 mmol, OEGMA-OH 0.6 mmol, NaGdF 4 Nanocrystals and OCOP 7 The molar ratio of 5.9:1; Gd-OCOP 10 : OEGMA 1.4 mmol, OEGMA-OH 0.6 mmol, NaGdF 4 Nanocrys...

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Abstract

The present invention belongs to the field of biomedicine, and a magnetic resonance agent and its preparation and application have been disclosed, which includes magnetic resonance creation agents, including NAGDF 4 Nano -crystals and covered in NAGDF 4 Two lips on the surface of nano -crystals brushed polymer, what is NAGDF 4 The particle size of nano crystals is 1‑5nm.The size of the magnetic resonance agent of the present invention is super small and uniform, good water dispersability, adjustable magnetic properties, and longitudinal relaxation properties compared to clinical camera GD‑DTPA.

Description

technical field [0001] The invention belongs to the field of biomedicine, and relates to a magnetic resonance contrast agent and its preparation and application, in particular to a high-performance ultra-small magnetic resonance contrast agent with high-sensitivity magnetic resonance angiography function. Background technique [0002] High-resolution, high-sensitivity angiography is essential for the early prevention and effective treatment of vascular-related diseases such as thrombosis, atherosclerosis, and cerebrovascular disorders. With the advantages of high spatial resolution and no limitations on the depth of tissue penetration, magnetic resonance imaging has become an indispensable imaging modality for visualizing vascular abnormalities. Although local diagnostic information can be obtained through specific imaging sequences, given the inherently low sensitivity of magnetic resonance imaging, exogenous contrast agents need to be introduced to reveal the anatomy, func...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K49/12A61K49/18C08F293/00C08F8/40
CPCA61K49/12A61K49/1824C08F293/005C08F8/40
Inventor 李桢蒋志林
Owner SUZHOU UNIV
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