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Magnetic resonance imaging contrast agent and preparation method and application thereof

A magnetic resonance imaging and contrast agent technology, applied in the application field of the product, to achieve high sensitivity, significant permeation and diffusion effect, and high relaxation rate

Active Publication Date: 2020-06-16
SUZHOU INST OF NANO TECH & NANO BIONICS CHINESE ACEDEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there is no report on the use of aptamers as targeting molecules for the targeted delivery of gadolinium-based complexes.

Method used

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

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preparation example Construction

[0040] Another aspect of the embodiments of the present invention also provides a method for preparing a magnetic resonance imaging contrast agent, which includes:

[0041] reacting at least α,ω-distacysamine polyethylene glycol with α-cyclodextrin to form pseudopolyrotaxanes;

[0042] At least reacting the pseudopolyrotaxane with Z-tyrosine, a Carter condensing agent, 1-hydroxybenzotriazole, and N,N-diisopropylethylamine to form a Z-tyrosine-terminated polyrotaxane alkyl;

[0043] At least reacting the Z-tyrosine-terminated polyrotaxane with propargylcarbonylimidazole to form a surface alkynyl-modified rapidly reductively cleavable polyrotaxane;

[0044] At least reacting the rapidly reductively cleavable polyrotaxane modified by the surface alkyne group with the lysine second-generation dendrimer whose terminal group is azide to form a cleavable polyrotaxane grafted by the lysine second-generation dendrimer ;

[0045] At least the cleavable polyrotaxane grafted with the s...

Embodiment 1

[0091] In this embodiment, a preparation method of an aptamer-targeted and rapidly reductively cleavable polyrotaxane as a carrier for MRI contrast agents comprises the following steps:

[0092] Step 1: Polyethylene glycol (Mw=4000) was refluxed with toluene and dried to remove water. Then, dry polyethylene glycol and N,N'-carbonyldiimidazole were added into the reaction flask at a molar ratio of 1:15, and the reaction flask was filled with dry nitrogen through three cycles of vacuuming and nitrogen filling. Mix in anhydrous tetrahydrofuran under the protection of nitrogen, and stir at room temperature for 18 hours to obtain active intermediate α, ω-biscarbonylimidazole polyethylene glycol, by-products and other impurities.

[0093] After the reaction in step 1, the solution was precipitated in ether, filtered by suction, redissolved in anhydrous tetrahydrofuran and reprecipitated in ether, repeated three times to remove unreacted reagents, collected the precipitate, and dried...

Embodiment 2

[0107] In this embodiment, a preparation method of an aptamer-targeted and rapidly reductively cleavable polyrotaxane as a carrier for MRI contrast agents comprises the following steps:

[0108] Step 1: This step is similar to Step 1 in Example 1, only the molar ratio of dry polyethylene glycol and N,N'-carbonyldiimidazole is adjusted to 1:20, and the stirring time at room temperature is adjusted to 24 hours.

[0109] Step 2: This step is completely similar to Step 2 in Example 1, except that the active intermediate PEG-CI and cystamine are dissolved in anhydrous THF at a molar ratio of 1:50. Under the protection of nitrogen, the tetrahydrofuran solution of PEG-CI was slowly added dropwise to the cystamine solution, and stirred at room temperature for 24 hours.

[0110] Step 3: This step is completely similar to Step 3 in Example 1, except that after 12 hours of reaction, the precipitate is collected by centrifugation. And, the obtained viscous suspension was stirred at room ...

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Abstract

The invention discloses a magnetic resonance imaging contrast agent and a preparation method and application thereof. The preparation method comprises the following steps: reacting alpha,omega-biscystamine polyethylene glycol with alpha-cyclodextrin to form pseudopolyrotaxane; then terminating pseudopolyrotaxane with Z-tyrosine to obtain Z-tyrosine terminated polyrotaxane; then reacting the Z-tyrosine terminated polyrotaxane with propargyl carbonylimidazole to form polyrotaxane surface-modified by alkynyl groups and capable of being quickly reduced and cracked; reacting the polyrotaxane surface-modified by alkynyl groups with a lysine second-generation dendrimer with azide as an end group by means of click chemistry so as to form lysine second-generation dendrimer-grafted cleavable polyrotaxane; and bonding the lysine second-generation dendrimer-grafted cleavable polyrotaxane with a gadolinium chelate, and loading gadolinium to form the gadolinium chelate-modified lysine second-generation dendrimer-grafted cleavable polyrotaxane. The magnetic resonance imaging contrast agent is good in biocompatibility, low in toxicity and high in relaxation rate; and in addition, an AS1411 aptameris introduced as a targeting molecule to realize multivalent targeting of tumor cells and tumors with cell membrane overexpression of nucleolin, so in-vivo magnetic resonance imaging of tumors is facilitated.

Description

technical field [0001] The invention relates to a contrast agent for magnetic resonance imaging and its preparation method, as well as the application of the magnetic resonance imaging contrast agent in the preparation of products with tumor detection function, belonging to the technical field of pharmaceutical preparation. Background technique [0002] With the development of science and technology, magnetic resonance imaging has become an effective means of clinical detection of diseases. Compared with other clinical imaging techniques, magnetic resonance imaging has many advantages in revealing anatomical structures, especially in detecting inflammatory tissues and solid tumors. In addition, magnetic resonance imaging also has no ionizing radiation damage, and multi-parameter imaging provides doctors with a large amount of diagnostic information and three-dimensional positioning capabilities. However, in order to further improve the sensitivity and accuracy of imaging, c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K49/18A61K49/08A61K49/12C08G83/00
CPCA61K49/085A61K49/128A61K49/1845C08G83/007
Inventor 裴仁军祖广月曹翼
Owner SUZHOU INST OF NANO TECH & NANO BIONICS CHINESE ACEDEMY OF SCI
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