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A kind of tumor-targeted MRI contrast agent and preparation method thereof

A tumor-targeted, contrast agent technology used in the field of medical imaging

Active Publication Date: 2020-08-07
XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For example, the Chinese patent "A Gadolinium Oxide Targeted Magnetic Resonance Contrast Agent" with the application number 201310625257.1 uses folic acid-modified PEGylated Gd 2 o 3 As a contrast agent, but the contrast agent can only target tumor cells with high folic acid receptor expression, and can only be used for early diagnosis of glioma

Method used

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  • A kind of tumor-targeted MRI contrast agent and preparation method thereof
  • A kind of tumor-targeted MRI contrast agent and preparation method thereof
  • A kind of tumor-targeted MRI contrast agent and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: Synthesis of DO3A-tris(t-Bu)-EN (DO3A-tri-tert-butylethylenediamine)

[0025] 4.0g DO3A-tris(t-Bu) (DO3A-tri-tert-butyl ester) and 4.3g K 2 CO 3 Dissolve in 40mL of acetonitrile, stir for 1h, add 0.65mL of bromoacetonitrile, continue stirring for 8h, after the reaction is complete, filter the reactant through a G4 sintered funnel, remove the solvent by rotary evaporation under reduced pressure, and obtain a gel by silica gel column chromatography . Then, the above colloidal intermediate product was dissolved with 30 mL of 7N ammonia / methanol, and after adding 1.5 g of Raney nickel (Ra-Ni) catalyst, the mixture was heated at room temperature and 50 psi H 2 After the reaction was completed, the reactant was filtered through a G4 sintered funnel, the solvent was removed by rotary evaporation under reduced pressure, and DO3A-tris(t-Bu)-EN was obtained by silica gel column chromatography.

Embodiment 2

[0026] Embodiment 2: the synthesis of Gd-DO3A-EBP

[0027] Dissolve 0.88g DO3A-tris(t-Bu)-EN, 0.8g EBP and 0.33g 1-hydroxybenzotriazole (HOBt) in 5mL DMF, add 0.35mL N-methylmorpholine (NMM), After stirring at 0°C for 15 minutes, add 0.23 mg of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), continue to stir overnight, and remove the solvent by rotary evaporation under reduced pressure after the reaction is complete. HPLC Purified and freeze-dried to obtain DO3A-EBP as a white powder. DO3A-tris(t-Bu)-SH and EBP were dissolved in DMSO, hydrogen peroxide was added, and stirred at 0°C for 2 hours to obtain DO3A-EBP linked by disulfide bonds.

[0028] Weigh 96mg DO3A-EBP, dissolve in 10mL water, add excess Gd(OAc) 3 , add 0.01N NaOH dropwise to adjust the pH to 5.5-6.0, stir the reaction at 50°C for 48h, and remove the free Gd with dipotassium ethylenediaminetetraacetic acid (EDTA) 3+ , made of Gd-DO3A-EBP.

Embodiment 3

[0029] Example 3: Synthesis of Gd-DO3A-8-Aoc-EBP

[0030]Dissolve 0.5g EBP in 40mL DMF, add 0.2g BOP reagent and 0.1g HOBt, stir at room temperature, add 0.6mL N,N-diisopropylethylamine (DIPEA) dropwise, add 0.32g suberic acid, Stir at low temperature for 1 hour, remove the solvent under vacuum, extract with 10 mL of ethyl acetate for crystallization, and purify by HPLC to obtain hemisuberic anhydride-EBP. Dissolve 0.28g DO3A-tris(t-Bu)-EN, 0.16g hemisuberic anhydride-EBP and 0.33g HOBt in 5mL DMF, add 0.35mL NMM, stir at 0°C for 15min, then add 0.1mg EDC, continue stirring to make Overnight, after the reaction was complete, the solvent was removed by rotary evaporation under reduced pressure, purified by HPLC, and freeze-dried to obtain DO3A-8-Aoc-EBP. Weigh 96mg DO3A-8-Aoc-EBP, dissolve in 10mL water, add excess Gd(OAc) 3 , add dropwise 0.01NNaOH to adjust the pH to 5.5-6.0, stir the reaction at 50°C for 48h, remove free Gd with dipotassium EDTA 3+ , to make Gd-DO3A-8-Aoc...

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Abstract

The invention provides a tumor-targeted MRI contrast agent and a preparation method thereof, characterized in that: the contrast agent includes a small-molecule gadolinium chelate part and a targeting carrier part, a small-molecule gadolinium chelate part and a target Coupling to the carrier part through a covalent bond; wherein, the small molecule gadolinium chelate part is Gd-DO3A; the targeting carrier part includes EBP molecules. The contrast agent of the present invention has good relaxation enhancement ability, and can be targetedly combined with EGFR of tumor cells, not only has a strong targeted contrast effect, but also prolongs the imaging time of the contrast agent in the body, thereby reducing the contrast agent Adding dosage has strong practicality.

Description

technical field [0001] The invention relates to the field of medical imaging, in particular to a tumor-targeting MRI contrast agent and a preparation method thereof. Background technique [0002] Dynamic magnetic resonance imaging (MRI) technology based on small molecule gadolinium chelate contrast agent has now become an important clinical examination method for malignant tumors, playing an increasingly important role in tumor discovery, diagnosis, clinical staging, curative effect evaluation and prognosis judgment. effect. Moreover, with the development of science and technology, the construction of a new generation of high-efficiency and low-toxic MRI contrast agents with tumor tissue specificity has become a research hotspot in the fields of materials and medicine. [0003] At present, the commercialized and clinically applied small molecule gadolinium chelate contrast agents mainly include gadolinium-diethyltriaminepentaacetic acid (Gd-DTPA, ) and its derivatives (Gd...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K49/14A61K49/10
CPCA61K49/108A61K49/14
Inventor 杨帆艾时斌
Owner XIEHE HOSPITAL ATTACHED TO TONGJI MEDICAL COLLEGE HUAZHONG SCI & TECH UNIV
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