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Magnetic resonance contrast agent and preparation and application thereof

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, low relaxation rate, unfavorable renal metabolism, etc., so as to improve the biological safety in vivo, the preparation method is simple, and the shortening time is shortened. The effect of relaxation time

Active Publication Date: 2021-11-23
SUZHOU UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: Preparation of NaGdF 4 nanocrystal

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

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

Embodiment 2

[0071] Embodiment 2: prepare the OCOP of different number of side chainsn

[0072] Step 1: Mix 0.7-7mmol of OEGMA, 0.2mmol of CTA-COOH and 0.04mmol of AIBN and fully dissolve in 15mL of 1,4-dioxane, add the mixed solution into a 50mL Schlenk tube, and 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 to react overnight, and then the solvent was evaporated. In the second step, the product of the first step, 0.6-1.8mmol of OEGMA-OH and 0.04mmol of AIBN are mixed and fully dissolved in 15mL of 1,4-dioxane, and the polymerization reaction is carried out in the same step as the first step . After the solvent evaporated, 12 mmol of phosphorus oxychloride was used to replace the hydroxyl group on the side chain of the polymer with phosphate, and then dialyzed in a dialysis bag with a molecular weight cut-off of 2 kDA to fully remove impurities. Finally, the solvent is evaporated to o...

Embodiment 3

[0077] Embodiment 3: preparation OCOP n coated ultra-small NaGdF 4 Nanocrystals (Gd-OCOP n )

[0078] The ultra-small NaGdF prepared in Example 1 4 The nanocrystals are mixed with nitrous tetrafluoroborate in N,N-dimethylformamide to remove the surface oleic acid ligands, and then 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 it to fully dissolve, and finally use an ultrafiltration tube with a molecular weight cut-off of 30kDa to remove impurities (5400rpm , 3min) 3 times to fully remove the unwrapped polymer and impurities, put it into a glass bottle and store it at 4°C. attached Figure 4-7 for Gd-OCOP n Transmission electron micrograph (Gd-OCOP 7 : OEGMA 0.8mmol, OEGMA-OH 0.6mmol, NaGdF 4 Nanocrystals and OCOP 7 The molar ratio of 5.9:1; Gd-OCOP 10 : OEGMA 1.4mmol, OEGMA-OH 0.6mmol, NaGdF 4 Nanocrystals and OCOP 10 The mola...

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Abstract

The invention belongs to the field of biomedicine and discloses a magnetic resonance contrast agent and preparation and application thereof. The magnetic resonance contrast agent comprises a NaGdF4 nanocrystal and an amphiphilic brush-like polymer coating the surface of the NaGdF4 nanocrystal, wherein the particle size of the NaGdF4 nanocrystal is 1-5 nm. The magnetic resonance contrast agent is ultra-small and uniform in size, good in water dispersibility and adjustable in magnetic property, and the longitudinal relaxation performance of the magnetic resonance contrast agent is remarkably enhanced compared with that of a clinical contrast agent 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 a 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 limitation of tissue penetration depth, 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 low sensitivity of magnetic resonance imaging itself, it is necessary to introduce exogenous contrast agents to reveal the anatomical struc...

Claims

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Application Information

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Patent Type & Authority Applications(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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