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Preparation method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles

A technology of nuclear magnetic resonance imaging and nanoparticles, applied in preparations for in vivo experiments, pharmaceutical formulations, etc., can solve problems such as low relaxation rate, fast excretion speed, and increased safety hazards

Inactive Publication Date: 2011-09-14
EAST CHINA UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although these small-molecule MRI contrast agents are stable, low-toxic and have good imaging effects, due to the low relaxation rate, more contrast agents need to be injected each time, which increases some potential safety hazards, and these The excretion speed of contrast agent molecules in the human body is fast, and it is easy to penetrate from blood vessels to the cytoplasm, which is not conducive to blood vessel imaging
Although studies have shown that combining small molecule contrast agents with dendrimers through certain chemical constructions can greatly increase their relaxation rate and prolong their circulation time in blood (J Biol Inorg Chem (2007) 12: 406-420 ), but its application is restricted by the difficulty of synthesizing and purifying dendrimers
It has also been found that small molecule contrast agents with long-chain alkanes exist in a micellar state in a higher concentration of aqueous solution (J Biol Inorg Chem (2002) 7: 757-769), and the contrast agents at this time also have higher However, because micelles cannot exist stably at low concentrations, this directly leads to their inability to be applied clinically

Method used

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  • Preparation method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles
  • Preparation method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles
  • Preparation method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles

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Embodiment 1

[0043] Preparation of DOTA derivatives: 10g of triethylenetetramine and 10g of 40% aqueous solution of glyoxal in acetonitrile, reacted in ice bath for 2 hours, then added 4-10 ml of dibromoethane and 40g of potassium carbonate, 60 React at ~80°C for 24 hours, cool and filter, dissolve with a small amount of dichloromethane and precipitate with n-hexane, spin the solution to dryness, and purify through the column, and react the obtained product with 1.5 equivalents of hexadecane iodide in toluene at 60°C After 4 to 6 days, remove the solvent, wash with ether, add 10 equivalents of hydroxylamine hydrochloride, reflux in ethanol for 2 hours, remove the solvent, add aqueous sodium hydroxide solution, extract three times with chloroform, remove chloroform, add hydrochloric acid to precipitate, and precipitate Recrystallize in ethanol, alkalization, extraction, and drying. The resulting product is reacted with bromoacetic acid in an aqueous solution at 40-100°C for 4-10 hours, and t...

Embodiment 2

[0045] Preparation of Gd-DOTA derivatives: Dissolve 200mg of DOTA derivatives in 5ml of water, adjust the pH to 5-8, add 1.2 equivalents of gadolinium chloride, react at 20-100°C for 24 hours, and then adjust the pH to 9 or so, filter with a microporous membrane, pass through an ion exchange resin, and remove the solvent water to obtain a derivative with Gd-DOTA (Formula 1).

Embodiment 3

[0047] Weigh a certain amount of Gd-DOTA and Tween 60 according to the molar ratio of 1:2 to 4:1, add 5 to 20 ml of deionized water, add 0.1 to 0.4 g of styrene, 0.1 to 0.2 g of Divinylbenzene, 2-20 mg of cetyl alcohol, 2-20 mg of AIBN, 60-90 ° C under the protection of nitrogen, reacted for 6-10 hours, filtered and dialyzed for 3-6 days, the obtained emulsion was uniformly dispersed, and the latex particles The diameter is 20-50 nanometers (such as figure 1 ), prepare different concentrations of solutions, and use magnetic resonance imaging to measure the relaxation rate. The transverse relaxation time has a good linear relationship with the concentration of gadolinium ions (such as figure 2 ), the final calculated transverse relaxation rate r 1 =8.9mMS -1 , as the concentration of gadolinium ions decreases, the brightness of the image also shows a downward trend (such as image 3 ).

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Abstract

The present invention relates to a nuclear magnetic resonance imaging contrast agent, in particular to a method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles prepared through fine emulsion polymenrization. The nuclear magnetic resonance imaging contrast agents are prepared from the composition of 1, 4, 7, 10-tetrazo heterocycle dodecane with long-chain alkane and gadolinium (Gd-DOTA for short) or the composition of diethylenetriamine pentaacetic acid and gadolinium (Gd-DTPA for short) for carrying out fine emulsion polymenrization preparation with high molecular monomers. The Gd-DOTA derivatives (Gd-DOTA derivatives for short) with the long-chain alkane and the Gd-DTPA derivatives (Gd- DTPA derivatives for short) with the long-chain alkane respectively have the structures as the first formula and the second formula, wherein the value of n is between 8 and 24.

Description

technical field [0001] The invention relates to a nuclear magnetic resonance imaging contrast agent, in particular to a method for preparing a high-sensitivity nuclear magnetic resonance imaging contrast agent based on polymer nanoparticles by miniemulsion polymerization. Background technique [0002] Magnetic resonance imaging (MRI) technology has received unprecedented attention and application in the field of modern medical diagnosis. It can provide people with high-quality three-dimensional soft tissue imaging pictures under the condition of avoiding ion radiation. It is the main technology for disease diagnosis in the field of modern medicine. one. The signal intensity obtained by MRI mainly depends on the hydrogen nucleus density and the relaxation rate of water protons at the examination site, and the difference in hydrogen nucleus density and relaxation time between different tissues in the human body, between normal tissues and diseased tissues in the same tissue I...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K49/12
Inventor 胡爱国陈争艳龚沛陈莹莹王伟
Owner EAST CHINA UNIV OF SCI & TECH