CN1724076A - Nuclear magnetic resonance imaging contrast medium, and its prepn. method - Google Patents

Nuclear magnetic resonance imaging contrast medium, and its prepn. method Download PDF

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Publication number
CN1724076A
CN1724076A CN 200510031691 CN200510031691A CN1724076A CN 1724076 A CN1724076 A CN 1724076A CN 200510031691 CN200510031691 CN 200510031691 CN 200510031691 A CN200510031691 A CN 200510031691A CN 1724076 A CN1724076 A CN 1724076A
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China
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contrast agent
human serum
serum albumins
particle
preparation
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CN 200510031691
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何捍卫
刘红江
周科朝
王维
容鹏飞
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Central South University
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Central South University
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Abstract

A contrast medium for nuclear magnetic resonance imaging is prepared through the FebO4 nano-particle (1-100 nm)is coated by human serum albumin. Its advantages are low toxin and high biocompatibility and stability.

Description

NMR contrast agent and preparation method thereof
Technical field
The present invention relates to a kind of NMR contrast agent and preparation method thereof.
Background technology
Magnetic resonance imaging is to utilize the resonance of hydrone or the micromolecular proton of rich hydrogen in body fluid or the tissue to come a kind of technology of imaging.It is very responsive to the minim Physicochemical nature difference of Different Organs or tissue.Medically be commonly used to distinguish different tissues and detect the disease that causes that physicochemical properties change, such as tumour, cancer etc.Because the local magnetic field that electron spin produces in some ultra paramagnetic particles can change the magnetic resonance relaxation time T of its contiguous proton 1And T 2, and these particles are higher in the different local accumulative concentration of component of organization, so improve the contrast of NMR (Nuclear Magnetic Resonance)-imaging usually as contrast agent.There are many Superparamagnetic Iron Oxide contrast agent to enter clinical practice, but because magnetic nano-particle has higher toxicity to human body, biocompatibility is poor, make people must adopt the polymer that certain biocompatibility is arranged, as polylactide Acetic acid, hydroxy-, bimol. cyclic ester (PLGA), polylactic acid (PLA), poly-Acetic acid, hydroxy-, bimol. cyclic ester (PGA) etc., come the coated magnetic particle to reduce its toxicity to human body.But these contrast agent and the blood of human body compatibility are unsatisfactory.ZL94195204.5 discloses a kind of contrast agent, and it is formed by structural type polysaccharide or aspartic acid, glutamic acid, the homopolymer of lysine or the ferrum oxide crystal that copolymer coats superparamagnetism.Although the stability and the toxicity of the described contrast agent particle of this patent improve to some extent, also not fine.
Summary of the invention
The purpose of this invention is to provide a kind of NMR contrast agent and preparation method thereof, make biocompatibility and the stability that contrast agent compared with prior art has low toxicity to become reconciled.
For achieving the above object, NMR contrast agent of the present invention is by effective 1 to 100nm the Fe of diagnosis 3O 4Particle, and coat its surperficial human serum albumins formation, the granularity of composite particles is less than 100nm.
The preparation method of NMR contrast agent of the present invention comprises: coat 1 to 100nm the effective Fe of diagnosis with human serum albumins 3O 4Particle obtains granularity less than the composite particles of 100nm.
PH value is controlled at 7 to 8.5 when coating.Preferable range is 7.2 to 8.
When coating, Fe 3O 4With the weight ratio of human serum albumins be 0.1: 1 to 20: 1.Preferable range is 1: 1 to 10: 1.
Human serum albumins is to have a kind of protein the abundantest in the blood plasma, can and interior many endogenous, the allogenic materials of human body combine, be convenient in blood, carry.It also is to keep the colloid osmotic pressure of serum balance and the various amino acid needed sources of organizing are provided.Its major function is to carry various fatty acids, metabolite and noxious substance such as tranquillizer, anesthetis etc.Therefore, with human serum albumins coated magnetic Fe 3O 4Particle has good biocompatibility and biological degradability, i.e. lower toxicity.Fe through the human serum albumins coating 3O 4The reunion characteristic of particle changes little with the pH value, this illustrates that contrast preparation dispersion stabilization of the present invention is good, is conducive to carry in blood of human body.And composite particles is less than 100nm, and easily penetration cell wall and being absorbed strengthens the effect of radiography.
The control pH value can make NMR contrast agent of the present invention be suitable for the requirement of human plasma biocompatibility 7 to 8.5 in the coating process of preparation, and not perishable.
In the coating process of preparation, control Fe 3O 4The weight ratio of particle and human serum albumins is 0.1: 1 to 20: 1, can make human serum albumins fully coat Fe 3O 4Particle prevents the coating particles reunion, has increased dispersed and stable.
200 days no deposited phenomenons of the colloid sample that makes under these conditions, recording its specific saturation magnetization is 33.5emu/g.This sample is expelled in the adult rat body of 80 regular grade about body weight 200g, when dosage is less than or equal to 5umol/kg, rat is had no adverse effects; When progressively increasing to 10umol/kg with dosage, the rat heart beating is obviously accelerated; When dosage increases to 20umol/kg, the rat phenomenon that has a convulsion; When dosage increased to 40umol/kg, the tic phenomenon increased the weight of, but recovered normal behind the 3min at the most.After 1 week all white mouse hair color gloss of participating in test as before, Normal-weight increases.More than experiment shows that NMR contrast agent of the present invention is not only better stable, and toxicity is lower.
The specific embodiment
Embodiment 1 (a) takes by weighing 0.006mol FeCl 24H 2O, 0.009mol FeCl 36H 2O and 0.1g citric acid are dissolved in the 75ml ultrasonic degas deionized water; Under 60 ℃, stirring and logical nitrogen protection effect, slowly drip 2mol/L NaOH solution and make pH reach 11, reaction 60min.Magnetic separates Fe 3O 4Particle also cleans ultrasonic being scattered in the 200ml secondary deionized water 5 times with secondary deionized water.(b) with the nanometer Fe for preparing 3O 4Colloidal solution transfers to Fe 3O 4Content is 0.001g/ml, measures this solution 100ml and carries out ultrasonic dispersion 10min; Adjust pH to 7 with 1% NaOH solution simultaneously, ultrasonic dispersion 5min again obtains the Fe of 10nm to 50nm 3O 4Colloidal solution.Simultaneously under the action condition, get the human serum albumins that 5ml concentration is 0.2g/ml in 40 ℃, the ultrasonic dispersion of clearance-type and mechanical agitation, inject nanometer Fe 3O 4In the colloidal solution, make Fe 3O 4With the weight ratio of human serum albumins be 0.1: 1.Coat and obtain the NMR contrast agent that the composite particles particle diameter is 40nm to 80nm after 1 hour.
Embodiment 2 (a) takes by weighing 0.006mol FeCl 24H 2O, 0.009mol FeCl 36H 2O and 0.1g citric acid are dissolved in the 75ml ultrasonic degas deionized water; Under 60 ℃, stirring and logical nitrogen protection effect, slowly drip 2mol/L NaOH solution and make pH reach 11.5, reaction 60min.Magnetic separates Fe 3O 4Particle also cleans ultrasonic being scattered in the 200ml secondary deionized water 5 times with secondary deionized water.(b) with the nanometer Fe for preparing 3O 4Colloidal solution transfers to Fe 3O 4Content is 0.001g/ml, measures this solution 100ml and carries out ultrasonic dispersion 10min; Adjust pH to 7.4 with 1% NaOH solution simultaneously, ultrasonic dispersion 5min again obtains the Fe of 10nm to 40nm 3O 4Colloidal solution.Simultaneously under the action condition, get the human serum albumins that 0.0625ml concentration is 0.2g/ml in 50 ℃, the ultrasonic dispersion of clearance-type and mechanical agitation, inject nanometer Fe 3O 4In the colloidal solution, make Fe 3O 4With the weight ratio of human serum albumins be 8: 1.Coat and obtain the NMR contrast agent that the composite particles particle diameter is 20nm to 60nm after 1 hour.
Embodiment 3 (a) takes by weighing 0.006mol FeCl 24H 2O, 0.009mol FeCl 36H 2O and 0.1g citric acid are dissolved in the 75ml ultrasonic degas deionized water; Under 60 ℃, stirring and logical nitrogen protection effect, slowly drip 2mol/L NaOH solution and make pH reach 12, reaction 60min.Magnetic separates Fe 3O 4Particle also cleans ultrasonic being scattered in the 200ml secondary deionized water 5 times with secondary deionized water.(b) with the nanometer Fe for preparing 3O 4Colloidal solution transfers to Fe 3O 4Content is 0.001g/ml, measures this solution 100ml and carries out ultrasonic dispersion 10min; Adjust pH to 8 with 1% NaOH solution simultaneously, ultrasonic dispersion 5min again obtains the Fe of 10nm to 30nm 3O 4Colloidal solution.Simultaneously under the action condition, get the human serum albumins that 0.025ml concentration is 0.2g/ml in 45 ℃, the ultrasonic dispersion of clearance-type and mechanical agitation, inject nanometer Fe 3O 4In the colloidal solution, make Fe 3O 4With the weight ratio of human serum albumins be 20: 1.Coat and obtain the NMR contrast agent that the composite particles particle diameter is 50nm to 95nm after 1 hour.
Embodiment 4 (a) takes by weighing 0.006mol FeCl 24H 2O, 0.009mol FeCl 36H 2O and 0.1g citric acid are dissolved in the 75ml ultrasonic degas deionized water; Under 50 ℃, stirring and logical nitrogen protection effect, slowly drip 2mol/L NaOH solution and make pH reach 11.8, reaction 60min.Magnetic separates Fe 3O 4Particle also cleans ultrasonic being scattered in the 200ml secondary deionized water 5 times with secondary deionized water.(b) with the nanometer Fe for preparing 3O 4Colloidal solution transfers to Fe 3O 4Content is 0.001g/ml, measures this solution 100ml and carries out ultrasonic dispersion 10min; Adjust pH to 8.5 with 1% NaOH solution simultaneously, ultrasonic dispersion 5min again obtains the Fe of 20nm to 50nm 3O 4Colloidal solution.Simultaneously under the action condition, get the human serum albumins that 0.5ml concentration is 0.2g/ml in 30 ℃, the ultrasonic dispersion of clearance-type and mechanical agitation, inject nanometer Fe 3O 4In the colloidal solution, make Fe 3O 4With the weight ratio of human serum albumins be 1: 1.Coat and obtain the NMR contrast agent that the composite particles particle diameter is 30nm to 70nm after 1 hour.
Embodiment 5 (a) takes by weighing 0.006mol FeCl 24H 2O, 0.009mol FeCl 36H 2O and 0.1g citric acid are dissolved in the 75ml ultrasonic degas deionized water; Under 60 ℃, stirring and logical nitrogen protection effect, slowly drip 2mol/L NaOH solution and make pH reach 11.4, reaction 50min.Magnetic separates Fe 3O 4Particle also cleans ultrasonic being scattered in the 200ml secondary deionized water 5 times with secondary deionized water.(b) with the nanometer Fe for preparing 3O 4Colloidal solution transfers to Fe 3O 4Content is 0.001g/ml, measures this solution 100ml and carries out ultrasonic dispersion 10min; Adjust pH to 7.2 with 1% NaOH solution simultaneously, ultrasonic dispersion 5min again obtains the Fe of 25nm to 60nm 3O 4Colloidal solution.Simultaneously under the action condition, get the human serum albumins that 0.05ml concentration is 0.2g/ml in 35 ℃, the ultrasonic dispersion of clearance-type and mechanical agitation, inject nanometer Fe 3O 4In the colloidal solution, make Fe 3O 4With the weight ratio of human serum albumins be 10: 1.Coat and obtain the NMR contrast agent that the composite particles particle diameter is 40nm to 80nm after 1 hour.
Embodiment 6 (a) takes by weighing 0.006mol FeCl 24H 2O, 0.009mol FeCl 36H 2O and 0.1g citric acid are dissolved in the 75ml ultrasonic degas deionized water; Under 60 ℃, stirring and logical nitrogen protection effect, slowly drip 2mol/L NaOH solution and make pH reach 11.7, reaction 60min.Magnetic separates Fe 3O 4Particle also cleans ultrasonic being scattered in the 200ml secondary deionized water 5 times with secondary deionized water.(b) with the nanometer Fe for preparing 3O 4Colloidal solution transfers to Fe 3O 4Content is 0.001g/ml, measures this solution 100ml and carries out ultrasonic dispersion 10min; Adjust pH to 7.6 with 1% NaOH solution simultaneously, ultrasonic dispersion 5min again obtains the Fe of 10nm to 50nm 3O 4Colloidal solution.Simultaneously under the action condition, get the human serum albumins that 0.1ml concentration is 0.2g/ml in 25 ℃, the ultrasonic dispersion of clearance-type and mechanical agitation, inject nanometer Fe 3O 4In the colloidal solution, make Fe 3O 4With the weight ratio of human serum albumins be 5: 1.Coat and obtain the NMR contrast agent that the composite particles particle diameter is 46nm to 82nm after 1 hour.
Embodiment 7 (a) takes by weighing 0.006mol FeCl 24H 2O, 0.009mol FeCl 36H 2O and 0.1g citric acid are dissolved in the 75ml ultrasonic degas deionized water; Under 60 ℃, stirring and logical nitrogen protection effect, slowly drip 2mol/L NaOH solution and make pH reach 11.5, reaction 60min.Magnetic separates Fe 3O 4Particle also cleans ultrasonic being scattered in the 200ml secondary deionized water 5 times with secondary deionized water.(b) with the nanometer Fe for preparing 3O 4Colloidal solution transfers to Fe 3O 4Content is 0.001g/ml, measures this solution 100ml and carries out ultrasonic dispersion 10min; Adjust pH to 7.4 with 1% NaOH solution simultaneously, ultrasonic dispersion 5min again obtains the Fe of 10nm to 40nm 3O 4Colloidal solution.Simultaneously under the action condition, get the human serum albumins that 0.0667ml concentration is 0.2g/ml in 50 ℃, the ultrasonic dispersion of clearance-type and mechanical agitation, inject nanometer Fe 3O 4In the colloidal solution, make Fe 3O 4With the weight ratio of human serum albumins be 7.5: 1.Coat and obtain the NMR contrast agent that the composite particles particle diameter is 20nm to 60nm after 1 hour.
Embodiment 8 (a) takes by weighing 0.006mol FeCl 24H 2O, 0.009mol FeCl 36H 2O and 0.1g citric acid are dissolved in the 75ml ultrasonic degas deionized water; Under 50 ℃, stirring and logical nitrogen protection effect, slowly drip 2mol/L NaOH solution and make pH reach 11.8, reaction 60min.Magnetic separates Fe 3O 4Particle also cleans ultrasonic being scattered in the 200ml secondary deionized water 5 times with secondary deionized water.(b) with the nanometer Fe for preparing 3O 4Colloidal solution transfers to Fe 3O 4Content is 0.001g/ml, measures this solution 100ml and carries out ultrasonic dispersion 10min; Adjust pH to 8.5 with 1% NaOH solution simultaneously, ultrasonic dispersion 5min again obtains the Fe of 20nm to 50nm 3O 4Colloidal solution.Simultaneously under the action condition, get the human serum albumins that 0.0588ml concentration is 0.2g/ml in 30 ℃, the ultrasonic dispersion of clearance-type and mechanical agitation, inject nanometer Fe 3O 4In the colloidal solution, make Fe 3O 4With the weight ratio of human serum albumins be 8.5: 1.Coat and obtain the NMR contrast agent that the composite particles particle diameter is 30nm to 70nm after 1 hour.
Dosage is respectively the sample reagent difference intravenous injection of 2.5umol/kg, 5umol/kg, 10umol/kg, 20umol/kg, 40umol/kg in several rat bodies, make the NMR (Nuclear Magnetic Resonance)-imaging scanning of its liver behind the 30min of SIEMENS 1.5T superconduction MR system, the unenhanced T1 phase of the MRI of the rat liver that obtains, MRI strengthen the T1 phase, the unenhanced T2 of MRI strengthens T2 distribution image mutually with MRI mutually.NMR contrast agent of the present invention has the more big development of good development effect and dosage more obvious to liver by analyzing as can be known.
In addition, by experiment as can be known NMR contrast agent of the present invention also spleen and lymph are had good development effect.
The present invention can summarize with other concrete forms without prejudice to spirit of the present invention or principal character.In the implication suitable with claims of the present invention and any change in the scope, all should think within protection domain of the present invention.

Claims (7)

1. a NMR contrast agent contains composite particulate material, it is characterized in that: particle is by effective 1 to 100nm the Fe of diagnosis 3O 4Particle, and coat its surperficial human serum albumins formation, the granularity of composite particles is less than 100nm.
2. the preparation method of a NMR contrast agent is characterized in that: coat 1 to 100nm the effective Fe of diagnosis with human serum albumins 3O 4Particle obtains granularity less than the composite particles of 100nm.
3. according to the preparation method of the NMR contrast agent of claim 2, it is characterized in that: pH value is controlled at 7 to 8.5 when coating.
4. according to the preparation method of the NMR contrast agent of claim 2, it is characterized in that: pH value is controlled at 7.2 to 8 when coating.
5. according to the preparation method of arbitrary NMR contrast agent of claim 2 to 4, it is characterized in that: Fe when coating 3O 4With the weight ratio of human serum albumins be 0.1: 1 to 20: 1.
6. according to the preparation method of arbitrary NMR contrast agent of claim 2 to 4, it is characterized in that: Fe when coating 3O 4With the weight ratio of human serum albumins be 1: 1 to 10: 1.
7. according to the NMR contrast agent of claim 1, can be used for the enhancing contrast imaging of liver or spleen or the lymph of human body or non-human body with the colloidal solution of its preparation.
CN 200510031691 2005-06-10 2005-06-10 Nuclear magnetic resonance imaging contrast medium, and its prepn. method Pending CN1724076A (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009129649A1 (en) * 2008-04-22 2009-10-29 Industrial Technology Research Institute Biocompatible polymer and magnetic nanoparticle with biocompatibility
CN101474414B (en) * 2009-02-06 2010-09-15 上海师范大学 Preparation and application of polymer-coated magnetic nanoparticle contrast agent
CN102657881A (en) * 2012-05-16 2012-09-12 上海师范大学 Fe3O4 nano-magnetic resonance contrast medium material and preparation method thereof
CN101167662B (en) * 2006-10-25 2012-12-19 美国西门子医疗解决公司 System for lymph node imaging by cooperation of CT and MR
CN103201211A (en) * 2010-08-31 2013-07-10 韩华石油化学株式会社 Iron oxide nanocapsule, method of manufacturing the same, and mri contrast agent using the same
CN105288666A (en) * 2015-11-03 2016-02-03 中国科学院高能物理研究所 Magnetic nano-particles coated with water-soluble protein and preparation method of magnetic nano-particles
CN105617408A (en) * 2016-02-02 2016-06-01 天津医科大学 Albumin magnetic nanoparticles for magnetic resonance imaging (MRI) and preparation method thereof

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101167662B (en) * 2006-10-25 2012-12-19 美国西门子医疗解决公司 System for lymph node imaging by cooperation of CT and MR
WO2009129649A1 (en) * 2008-04-22 2009-10-29 Industrial Technology Research Institute Biocompatible polymer and magnetic nanoparticle with biocompatibility
US8741615B2 (en) 2008-04-22 2014-06-03 Industrial Technology Research Institute Magnetic nanoparticle with biocompatibility
CN101474414B (en) * 2009-02-06 2010-09-15 上海师范大学 Preparation and application of polymer-coated magnetic nanoparticle contrast agent
CN103201211A (en) * 2010-08-31 2013-07-10 韩华石油化学株式会社 Iron oxide nanocapsule, method of manufacturing the same, and mri contrast agent using the same
CN103201211B (en) * 2010-08-31 2014-08-06 韩华石油化学株式会社 Iron oxide nanocapsule, method of manufacturing the same, and mri contrast agent using the same
CN102657881A (en) * 2012-05-16 2012-09-12 上海师范大学 Fe3O4 nano-magnetic resonance contrast medium material and preparation method thereof
CN102657881B (en) * 2012-05-16 2013-11-27 上海师范大学 Preparation method of Fe3O4 nano-magnetic resonance contrast medium material
CN105288666A (en) * 2015-11-03 2016-02-03 中国科学院高能物理研究所 Magnetic nano-particles coated with water-soluble protein and preparation method of magnetic nano-particles
CN105288666B (en) * 2015-11-03 2018-10-12 中国科学院高能物理研究所 A kind of magnetic nanoparticle and preparation method thereof of water-solubility protein cladding
CN105617408A (en) * 2016-02-02 2016-06-01 天津医科大学 Albumin magnetic nanoparticles for magnetic resonance imaging (MRI) and preparation method thereof
CN105617408B (en) * 2016-02-02 2019-01-11 天津医科大学 Albumin magnetic nano particle and preparation method thereof for MRI contrast imaging

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