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A kind of organic gadolinium nanoparticle and its preparation method and application

A nanoparticle and organic technology, applied in the field of organic gadolinium nanoparticles and its preparation, can solve the problems of unfavorable clinical observation contrast, MRI image distortion, fibrosis, etc., and achieve the effect of overcoming the easy release of toxic gadolinium ions and the difficulty of dissociation

Active Publication Date: 2022-03-15
SUZHOU ZHECI PHARM TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, commercially available gadolinium chelate-based T 1 Contrast agents have the following problems: 1) have certain nephrotoxicity, which can cause nephrogenic systemic fibrosis in some patients [Zou Z, Zhang HL, Roditi GH, et al. Nephrogenic systemic fibrosis: review of 370 biopsy-confirmed cases. JACCCardiovasc Imaging, 2011, 4 (11): 1206-16; Peak AS, Sheller A. Risk factors for developing gadolinium-induced nephrogenic systemic fibrosis. Ann Pharmacother, 2007, 41 (9): 1481-5.], Crobner first in 2006 It was reported that nephrogenic systemic fibrosis may be related to gadolinium chelate [Grobner T.Gadolinium: a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systmic fibrosis. Nephrol Dial Transplant,2006,21(4):1104-8.] , FDA warned its clinical application because of its nephrotoxicity [Mendichovszky IA, Marks SD, Simcock CM, et al. -3.]
3) Gadolinium chelate base T 1 The contrast agents are all small molecules, and there is no targeting to any tissue or cell; 4) Longitudinal relaxation rate (r 1 ) is low, only about 4mM -1 the s -1 , resulting in poor MRI imaging
Although T 2 Contrast agents have obvious advantages, but their clinical applications are few, and most T 2 Contrast agents have been withdrawn from the market [Wang YXJ.Current status of superparamagnetic iron oxide contrast agents for liver magnetic resonance imaging.World J Gastroenterol,2015,21(47):13400-2], mainly because T 2 The contrast agent has the following problems: (1) T 2 The signal is a dark signal, which is not conducive to clinical observation and comparison, and is easily confused with dark signals caused by other pathogenic factors, such as hemorrhage, calcification, metal deposition, etc. [Na HB, SongIC, Hyeon T. Inorganic nanoparticles for MRI contrast agents. Adv Mater ,2009,21:2133-48]; (2)T 2 The high magnetic moment of the contrast agent will cause susceptibility artifacts, destroy the background around the lesion, cause image blurring, and cause local distortion of the MRI image [Bulte JWM, Kraitchman DL. Iron oxide MR contrast agents formolecular and cellular imaging. :484-99]; (3)T 2 The particle size of the contrast agent is large (60-180nm), and the degradation and clearance rate in the body is slow, which may cause long-term toxicity[Gu L, Fang RH, SailorMJ, et al.In vivo clearance and toxicity of monodisperse iron oxidenanocrystals[J ].ACS Nano,2012,6(6):4947-54];(4)T 2 - Processing time for weighted MRI compared to T 1 - Weighted MRI is much longer, which is not conducive to clinical application

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  • A kind of organic gadolinium nanoparticle and its preparation method and application
  • A kind of organic gadolinium nanoparticle and its preparation method and application
  • A kind of organic gadolinium nanoparticle and its preparation method and application

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Effect test

Embodiment 1

[0041] Preparation of organic gadolinium nanoparticle-based magnetic resonance imaging contrast agent with polymaleic acid (molecular weight 2000) as hydrophilic polymer:

[0042] In the first step, weigh 240mg of polymaleic acid and add it to a two-necked round-bottomed flask (equipped with a condenser), add 60mL of pure water to the round-bottomed flask to dissolve it, put the round-bottomed flask in an oil bath at 110°C, stir and heat 15 minutes; the second step, add 1.2mL 0.12mol / L gadolinium chloride solution in the round bottom flask, react for 30 minutes; the third step, add 9mL saturated ammonia solution in the round bottom flask, react for 30 minutes; the fourth The first step is to take the round-bottom flask out of the oil bath, and perform dialysis and purification on the obtained sample after natural cooling to obtain an organic gadolinium nanoparticle-based magnetic resonance imaging contrast agent with polymaleic acid as a hydrophilic polymer.

[0043] The hydra...

Embodiment 2

[0045] Preparation of organic gadolinium nanoparticle-based magnetic resonance imaging contrast agent using poly(2-ethylacrylic acid) (molecular weight 5000) as hydrophilic polymer:

[0046] In the first step, weigh 240mg of poly(2-ethylacrylic acid) and add it to a two-necked round-bottomed flask (equipped with a condenser), add 60mL of pure water to the round-bottomed flask to dissolve it, and put the round-bottomed flask in an oil bath at 110°C , stir and heat for 15 minutes; the second step, add 1.2mL 0.12mol / L gadolinium chloride solution to the round bottom flask, and react for 30 minutes; the third step, add 9mL saturated ammonia solution to the round bottom flask, and react for 30 minutes Minutes; the fourth step, the round bottom flask is taken out from the oil bath, and the obtained sample is purified by dialysis after natural cooling, and the organic gadolinium nanoparticle based poly(2-ethylacrylic acid) can be obtained as a hydrophilic polymer. Magnetic resonance ...

Embodiment 3

[0049] Preparation of organic gadolinium nanoparticle-based magnetic resonance imaging contrast agent with polyglutamic acid (molecular weight 2000) as hydrophilic polymer:

[0050] In the first step, weigh 240mg of polyglutamic acid and add it to a two-necked round-bottomed flask (equipped with a condenser), add 60mL of pure water to the round-bottomed flask to dissolve it, put the round-bottomed flask in an oil bath at 110°C, stir and heat 15 minutes; the second step, add 1.2mL 0.12mol / L gadolinium chloride solution in the round bottom flask, react for 30 minutes; the third step, add 9mL saturated ammonia solution in the round bottom flask, react for 30 minutes; the fourth The first step is to take the round-bottomed flask out of the oil bath, and dialyze and purify the obtained sample after cooling to obtain an organic gadolinium nanoparticle-based magnetic resonance imaging contrast agent with polyglutamic acid as a hydrophilic polymer.

[0051] The hydraulic diameter (d h ...

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Abstract

The invention discloses an organic gadolinium nanoparticle and its preparation method and application. The organic gadolinium nanoparticle is a particle combined with a hydrophilic polymer and gadolinium ions. The preparation method is as follows: firstly, the hydrophilic polymer and gadolinium The ions undergo a coordination reaction; then add lye to react to obtain organic gadolinium nanoparticles. In the present invention, the free gadolinium ions in the reaction system are exhausted by performing a coordination reaction between the hydrophilic polymer and the gadolinium ion to form particles combined with the hydrophilic polymer and the gadolinium ion; Under the action of liquid, the growth of particles is accelerated, and a good T 1 The organic gadolinium nanoparticles of the imaging effect, the obtained organic gadolinium nanoparticles r at 1.5T 1 ≥30mM ‑1 the s ‑1 , r 2 / r 1 ≤1.3, the obtained organic gadolinium nanoparticles are not easy to dissociate, which overcomes the shortcoming that gadolinium oxide nanoparticles are easy to release toxic gadolinium ions in the acidic environment of endosomes or lysosomes after being phagocytized by cells.

Description

technical field [0001] The invention relates to the technical field of biomedical materials, in particular to an organic gadolinium nanoparticle and its preparation method and application. Background technique [0002] At present, there are mainly two kinds of MRI contrast agents used clinically, namely positive contrast agent (or T 1 -weighted MRI contrast agent) and negative contrast agent (or T 2 - weighted MRI contrast agent). Among them, T 1 -Weighted MRI contrast agents by shortening the proton longitudinal relaxation time (T 1 ) makes T 1 - Increased signal strength on weighted images resulting in brighter images. T 1 Contrast agents are widely used because they produce bright signals. Currently, the most widely used clinical MRI contrast agent is gadolinium chelate-based T 1 contrast agent. Contrast agents approved for clinical use by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency include: Magnevist (Gd-DTPA) (the first MRI con...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K49/12A61K49/18
CPCA61K49/126A61K49/1818
Inventor 沈折玉卢玉蝶卢旋旖
Owner SUZHOU ZHECI PHARM TECH CO LTD