CN105288664A - Asparaginic acid-alanine copolymer modified paramagnetic metal complex, as well as preparation method and application thereof - Google Patents
Asparaginic acid-alanine copolymer modified paramagnetic metal complex, as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a kind of asparatate-alanine copolymer modification paramagnetic metal complexes and the preparation method and application thereof, belong to contrast medium technique field. Solve in the prior art that liver class macromolecular contrast agent biological degradability is low, the technical problem that liver targeting is low and dosage is high. Asparatate of the invention-alanine copolymer modification paramagnetic metal complex, structural formula is shown in formula I, and in formula, a, b, c, d and n are natural number, and meets following relationship: amp; lt; maths num="0001" gt;
lt; /maths gt; lt; maths num="0002" gt;
lt; /maths gt; Nm+ is paramagnetic metal element+2 or+trivalent ion. The asparatate-alanine copolymer modification paramagnetic metal complex can be used as magnetic resonance imaging contrast application, both with good stability, water-soluble and relaxivity, there is fine targeting to liver again, image contrast and clarity are higher, and the lower limit of dosage is every kg weight only 0.001mmol.
Description
Technical field
The invention belongs to contrast medium technique field, be specifically related to paramagnetic metal complex of a kind of aspartic acid-alanine copolymer modification and preparation method thereof and application.
Background technology
Nuclear magnetic resonance ((MagneticResonanceImaging, MRI) technology can carry out imaging in all angles to organism, there is very high temporal resolution and spatial resolution, complete anatomic image clearly can be presented, be widely used in clinical diagnosis.Magnetic resonance imaging contrast is used to the compound shortening imaging time, strengthen radiography, improve image contrast and definition, and the nuclear magnetic resonance of about 50% needs to use magnetic resonance imaging contrast.At present, there are magnevist Magnevist (Gd-DTPA), how its clever Dotarem (Gd-DOTA), gadodiamide Omniscan (Gd-DTPA-BMA) for clinical magnetic resonance imaging contrast, general network is aobvious thinks ProHance (Gd-HPD03A) etc.But these magnetic resonance contrast agents are all micromolecule contrast agent, there is retention time in vivo short, relaxivity is lower, and dosage is comparatively large, and drug injection frequency is higher, does not have the shortcoming of tissue or Organic selection or targeting.
For solving this technical problem, the research of magnetic resonance contrast agent mainly concentrates on raising relaxivity, increases and organizes directionality, improves the aspect such as body internal stability and safety.Find after deliberation, micromolecule contrast agent is connected to the performance that macromole can improve effectively contrast agent.In prior art, the liver class macromolecular contrast agent of foreign study mostly by being formed micromolecule contrast agent Gd-DOTA introducing high polymer main chain or covalent coupling, as albumin-Gd-DOTA etc. on natural polymer, synthetic macromolecular carrier.But it is low that these liver class macromolecular contrast agents have biological degradability, the shortcoming such as the lower and drug dose of liver targeting is higher.
Summary of the invention
The object of the invention is to solve liver class macromolecular contrast agent biological degradability in prior art low, the technical problem that liver targeting is lower and consumption is high, the relaxivity of further raising contrast agent, image contrast, definition and susceptiveness, provide the paramagnetic metal complex that a kind of aspartic acid-alanine copolymer is modified.
In order to solve the problems of the technologies described above, the technical solution used in the present invention is as follows.
The paramagnetic metal complex that aspartic acid-alanine copolymer is modified, structural formula is as follows:
In formula, a, b, c, d and n are natural number, and meet following relation:
N
m+it is paramagnetic metal element+2 or+3 valency ion.
Preferably, described N
m+for Gd
2+, Mn
2+, Dy
2+, Nd
2+, Fe
2+, Ru
2+, Gd
3+, Mn
3+, Dy
3+, Nd
3+, Fe
3+or Ru
3+.
The preparation method of the paramagnetic metal complex that aspartic acid-alanine copolymer is modified, the method comprises the following steps:
(1) by ASPARTIC ACID and ALANINE in molar ratio 10:1 ~ 1:9 mix, the mixture obtained with stir with concentrated phosphoric acid after, 1h ~ 8h is reacted under 24mmHg ~ 200mmHg pressure, reaction temperature controls at 50 DEG C ~ 220 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
Phosphoric acid in described concentrated phosphoric acid and the mass ratio of mixture are 0.1 ~ 1.5:1;
(2) at room temperature aspartic acid-alanine copolymer synthesized in step (1) is dissolved in N, in dinethylformamide solution, dropwise ethylenediamine is added under stirring, stirring at room temperature 1h ~ 5h, ether sedimentation, filters, dialysis, lyophilizing, obtains aminated aspartic acid-alanine copolymer;
The mass ratio of described aspartic acid-alanine copolymer and ethylenediamine is 1:2.8;
(3) at room temperature aminated aspartic acid-alanine copolymer synthesized in step (2) is dissolved in deionized water, regulate pH 7.0 ~ 9.0, the solution obtained is added drop-wise in DOTA mono-N-hydroxy thiosuccinimide active ester (Suflo-DOTA) solution, in stirred at ambient temperature 24-48h, dialysis, concentrated, lyophilizing, obtain the Isosorbide-5-Nitrae that aspartic acid-alanine copolymer is modified, 7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl macromolecular ligand;
The mass ratio of described aminated aspartic acid-alanine copolymer and Suflo-DOTA solution is 1:1;
(4) at ambient temperature by the Isosorbide-5-Nitrae that the aspartic acid of synthesis in step (3)-alanine copolymer is modified, 7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl macromolecular ligand and the reactant aqueous solution containing paramagnetic metal ion, adjust ph is 4.0 ~ 6.5, in stirred at ambient temperature 5h ~ 36h, dialysis, concentrated, lyophilizing, obtains the paramagnetic metal complex that aspartic acid-alanine copolymer is modified;
In the DOTA macromolecular ligand that described aspartic acid-alanine copolymer is modified, the amount of substance of DOTA and the amount of substance of paramagnetic metal ion are than being 1:1.1.
Preferably, in described step (3) and step (4), adopt the pH value that potassium hydroxide solution regulates.
The paramagnetic metal complex that above-mentioned aspartic acid-alanine copolymer is modified can be applied as magnetic resonance imaging contrast.
The present invention also provides a kind of magnetic resonance imaging contrast of the paramagnetic metal complex containing above-mentioned aspartic acid-alanine copolymer modification, this magnetic resonance imaging contrast is also containing slow blood amine and solvent, pH value is 6.5 ~ 8.0, and the concentration of the paramagnetic metal complex that aspartic acid-alanine copolymer is modified is 0.001 mol/L ~ 0.5 mol/L;
Described solvent is sodium chloride injection, dextran injection liquid, sodium chloride-dextran injection liquid or distilled water for injection.
Preferably, described magnetic resonance imaging contrast is injection or injectable powder.
Preferably, the consumption of described injection is the every kg body weight 0.001mmol ~ 5.0mmol of mammalian body; More preferably 0.05mmol ~ 0.5mmol.
The preparation method of above-mentioned magnetic resonance imaging contrast is dissolved in sodium chloride injection, dextran injection liquid, sodium chloride-dextran injection liquid or distilled water for injection by the paramagnetic metal complex that aspartic acid-alanine copolymer is modified, regulate pH to 6.5 ~ 8.0 with slow blood amine, make the magnetic resonance imaging contrast that concentration is 0.001 mol/L ~ 0.5 mol/L.
Compared with prior art, beneficial effect of the present invention:
1, the paramagnetic metal complex that aspartic acid provided by the invention-alanine copolymer is modified with aspartic acid-alanine copolymer for carrier, wherein, aspartic acid ensure that paramagnetic metal complex has excellent biocompatibility, water solublity, be easy to degraded in vivo and there is distribution of specific, alanine ensure that paramagnetic metal complex has lipophilic performance; Carrier side chain connects the paramagnetic metal complex of the DOTA part of ring-type, ensure that paramagnetic metal complex of the present invention has the feature of polyamines many carboxylics coordination compound;
The preparation method of the paramagnetic metal complex that 2, aspartic acid provided by the invention-alanine copolymer is modified is easy to operation, and productive rate is high, is applicable to suitability for industrialized production;
3, the paramagnetic metal complex that aspartic acid of the present invention-alanine copolymer is modified is applied as magnetic resonance imaging contrast:
A, there is good water solublity, be easy to be mixed with the intravenous injection of desired concn solution;
B, to have good aqueous stability good, is suitable for pressure sintering sterilization;
C, relaxivity are high, can reach 9.3 ~ 13.6mmol
-1ls
-1, be about 2 times of its spirits many;
D, consumption are few, and the clinical dosage of how its spirit is 0.1 ~ 1mmol/kg body weight, and the lower limit of consumption of the present invention can reach 0.001mmol/kg body weight;
E, toxicity are low, and the highest consumption can reach 5mmol/kg body weight;
F, have targeting and selectivity to people or other mammiferous liver, imaging effect is good, after intravenous injection is a little less than this type of contrast agent of clinical dosage, can significantly improve the image contrast of liver region, definition and susceptiveness;
G, can be enriched in for a long time in tissue or organ, keep stable concentration relatively for a long time, targeting contrast imaging is chronic, and make liver obtain imaging window steady in a long-term, how its spirit can only maintain 30 minutes at most in vivo;
To the early diagnosis level of the disease improving liver organ, there is good result.
Accompanying drawing explanation
Fig. 1 is the time dependent reinforced effects figure of rat liver signal after the magnetic resonance imaging contrast of injection embodiment 16 preparation;
In Fig. 2, A, B, C, D be followed successively by injection embodiment 16 prepare magnetic resonance imaging contrast before and injection 30min, 50min, 70min after rat liver T
1weighting picture figure.
Detailed description of the invention
Invention thought of the present invention is: the present invention is from the technical problem solving the shortcomings such as liver class macromolecular contrast agent in prior art has that biological degradability is low, liver targeting is lower and drug dose is higher, and preparing a kind of take amino acid copolymer as the paramagnetism macromole biocompatibility magnetic resonance imaging contrast of carrier.Amino acid copolymer have good biocompatibility, in vivo low toxicity stablize, biodegradable, easily to be absorbed by body and the advantage of metabolism.Meanwhile, under the effect of sour environment and enzyme in vivo, chemical bond rupture release medicine, can reduce the toxicity of medicine, have amphipathic, can improve medicine dissolution performance, and realize targeting.Therefore, using polyamino acid as carrier, be combined with micromolecular magnetic resonance imaging contrast the macromolecular contrast agent forming biocompatibility, can reach and its time of staying is in vivo reduced to the targeted imaging of liver organ simultaneously, reach the object of drug safety.
The paramagnetic metal complex that aspartic acid of the present invention-alanine copolymer is modified, the carrier of this coordination compound is aspartic acid-alanine copolymer, carrier side chain connects 1 of ring-type, 4,7,10-tetraazacyclododecanand-1, the paramagnetic metal complex of 4,7,10-tetraacethyl part;
Structural formula is as follows:
Wherein, aspartic acid-alanine copolymer is obtained by ASPARTIC ACID and ALANINE random copolymerization, and molecular weight is 5000 ~ 400000; The Isosorbide-5-Nitrae of ring-type, 7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, the paramagnetic metal complex of 7,10-tetraacethyl part is by Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl part (DOTA) and paramagnetic metal ion 1:1 coordination in molar ratio obtain; A, b, c, d and n are natural number;
N
m+paramagnetic metal element+2 or+3 valency ion, preferred Gd
2+, Mn
2+, Dy
2+, Nd
2+, Fe
2+, Ru
2+, Gd
3+, Mn
3+, Dy
3+, Nd
3+, Fe
3+or Ru
3+.
The preparation method of the paramagnetic metal complex that above-mentioned aspartic acid-alanine copolymer is modified, the method comprises the following steps:
(1) by ASPARTIC ACID and ALANINE in molar ratio 10:1 ~ 1:9 mix, it is stir in the phosphoric acid solution of 85% that mixture after mixing adds mass fraction, phosphoric acid in phosphoric acid solution and the mass ratio of mixture are 0.1 ~ 1.5:1,1h ~ 8h is reacted under 24mmHg ~ 200mmHg pressure, reaction temperature controls at 50 DEG C ~ 220 DEG C, the preferred reaction time is 5h, reaction temperature is 165 DEG C, after having reacted, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains structural formula following aspartic acid-alanine copolymer:
In formula, m and n is natural number;
(2) at room temperature aspartic acid-alanine copolymer synthesized in step (1) is dissolved in N, in dinethylformamide solution, dropwise add ethylenediamine under stirring, the mass ratio of ethylenediamine and aspartic acid-alanine copolymer is 2.8:1, after being added dropwise to complete, stirring at room temperature 1h ~ 5h, ether sedimentation, filters, dialysis, lyophilizing, obtains aminated aspartic acid-alanine copolymer that structural formula is following;
In formula, a, b, c, d and m are natural number;
(3) at room temperature aminated aspartic acid-alanine copolymer synthesized in step (2) is dissolved in deionized water, regulate pH 7.0 ~ 9.0 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-alanine copolymer and Suflo-DOTA is 1:1, after being added dropwise to complete, stirred at ambient temperature 24h-48h, dialysis, concentrated, lyophilizing, obtain 1 of the following aspartic acid of structural formula-alanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand:
In formula, a, b, c, d and n are natural number;
(4) at ambient temperature the aspartic acid of synthesis in step (3)-alanine copolymer is modified 1, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand and the aqueous solution containing paramagnetic metal ion, 1 of wherein aspartic acid-alanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, in 10-tetraacethyl macromolecular ligand, the amount of substance of DOTA and the amount of substance of paramagnetic metal ion are than being 1:1.1, by potassium hydroxide solution adjust ph to 4.0-6.5, in stirred at ambient temperature 5h ~ 36h, dialysis, concentrated, lyophilizing, obtain the paramagnetic metal complex that the following aspartic acid of structural formula-alanine copolymer is modified,
The paramagnetic metal complex that above-mentioned aspartic acid-alanine copolymer is modified can be applied as magnetic resonance imaging contrast.Embody rule method can be dissolved in sodium chloride injection, dextran injection liquid, sodium chloride-dextran injection liquid or distilled water for injection by the paramagnetic metal complex that aspartic acid-alanine copolymer is modified, regulate pH to 6.5 ~ 8.0 with slow blood amine, make the magnetic resonance imaging contrast that concentration is 0.001 ~ 0.5 mol/L.
Accordingly, the present invention obtains a kind of magnetic resonance imaging contrast of the paramagnetic metal complex containing above-mentioned aspartic acid-alanine copolymer modification, this magnetic resonance imaging contrast is also containing slow blood amine and solvent, pH value is 6.5 ~ 8.0, and the concentration of the paramagnetic metal complex that aspartic acid-alanine copolymer is modified is 0.001 ~ 0.5 mol/L; Wherein, solvent is sodium chloride injection, dextran injection liquid, sodium chloride-dextran injection liquid or distilled water for injection.
Magnetic resonance imaging contrast of the present invention can make injection or injectable powder by the method for routine.Magnetic resonance imaging contrast prepared by the present invention can conventionally use.The consumption of magnetic resonance imaging contrast of the present invention can vary widely because of the kind of paramagnetic metal complex with as the tissue of diagnosis object or the difference of organ and diagnostic device type, general injection consumption is the diagnosis people of main body or every kg body weight mmol0.001 ~ 5.0mmol of other mammalian body, preferred 0.05mmol ~ 0.5mmol.
In the present invention, DOTA is the known chemical substance of chemical field, refers to Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetrabasic carboxylic acid.The speed stirred in the present invention is not particularly limited, and room temperature is (23 ± 2) DEG C.
Embodiment 1
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA Gd coordination compound:
(1) 20gL-aspartic acid and 5gL-alanine are mixed, the mass fraction that mixture after mixing adds 8g is stir in the phosphoric acid solution of 85%, 5h is reacted under the condition (24mmHg) of decompression, reaction temperature controls at 165 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
(2) at room temperature aspartic acid-alanine copolymer synthesized in (1) is dissolved in N, in dinethylformamide solution, dropwise ethylenediamine is added under stirring, ethylenediamine and aspartic acid-alanine copolymer quality are than being 2.8:1, stirring at room temperature 4h, ether sedimentation, filter, dialysis, lyophilizing, obtains aminated aspartic acid-alanine copolymer;
(3) under room temperature, aminated aspartic acid-alanine copolymer obtained in (2) is dissolved in deionized water, pH is regulated to be 7.5 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-alanine copolymer and Suflo-DOTA is 1:1, in stirred at ambient temperature 36h, dialysis, concentrated, lyophilizing, obtains 1 of aspartic acid-alanine copolymer, 4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl macromolecular ligand;
(4) at ambient temperature aspartic acid-alanine the copolymer obtained in (3) is modified 1, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand and Gadolinium trichloride reactant aqueous solution, be 5.2 with potassium hydroxide solution adjust pH, in the DOTA macromolecular ligand that aspartic acid-alanine copolymer is modified, the amount of substance of DOTA and the amount of substance of gadolinium ion are than being 1:1.1, in stirred at ambient temperature 1 day, dialysis, concentrated, lyophilizing, obtain 1 of aspartic acid-alanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl Gd coordination compound.
Carry out relaxivity detection to the coordination compound that embodiment 1 obtains, the relaxivity of the coordination compound of embodiment 1 in water is 12.8mmol after testing
-1ls
-1.
Embodiment 2
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA Gd coordination compound:
(1) 20gL-aspartic acid and 2gL-alanine are mixed, the mass fraction that mixture after mixing adds 8g is stir in the phosphoric acid solution of 85%, 1h is reacted under the condition (100mmHg) of decompression, reaction temperature controls at 220 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
(2) with step (2) in embodiment 1;
(3) with step (3) in embodiment 1;
(4) with step (4) in embodiment 1.
Carry out relaxivity detection to the coordination compound that embodiment 2 obtains, the relaxivity of the coordination compound of embodiment 2 in water is 10.0mmol after testing
-1ls
-1.
Embodiment 3
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA Gd coordination compound:
(1) 2gL-aspartic acid and 20gL-alanine are mixed, the mass fraction that mixture after mixing adds 8g is stir in the phosphoric acid solution of 85%, 5h is reacted under the condition (200mmHg) of decompression, reaction temperature controls at 50 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
(2) at room temperature aspartic acid-alanine copolymer synthesized in (1) is dissolved in N, in dinethylformamide solution, dropwise ethylenediamine is added under stirring, ethylenediamine and aspartic acid-alanine copolymer quality are than being 2.8:1, stirring at room temperature 5h, ether sedimentation, filter, dialysis, lyophilizing, obtains aminated aspartic acid-alanine copolymer;
(3) with step (3) in embodiment 1
(4) with step (4) in embodiment 1.
Embodiment 4
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA Gd coordination compound:
(1) 20gL-aspartic acid and 40gL-alanine are mixed, the mass fraction that mixture after mixing adds 20g is stir in the phosphoric acid solution of 85%, 8h is reacted under the condition (200mmHg) of decompression, reaction temperature controls at 220 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
(2) with step (2) in embodiment 1;
(3) under room temperature, the aminated aspartic acid-alanine copolymer in (2) is dissolved in deionized water, pH is regulated to be 9.0 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-alanine copolymer and Suflo-DOTA is 1:1, in stirred at ambient temperature 36h, dialysis, concentrated, lyophilizing, obtains 1 of aspartic acid-alanine copolymer, 4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl macromolecular ligand;
(4) with step (4) in embodiment 1.
Embodiment 5
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA Gd coordination compound:
(1) with step (1) in embodiment 1;
(2) at room temperature aspartic acid-alanine copolymer synthesized in (1) is dissolved in N, in dinethylformamide solution, dropwise ethylenediamine is added under stirring, ethylenediamine and aspartic acid-alanine copolymer quality are than being 2.8:1, stirring at room temperature 1h, ether sedimentation, filter, dialysis, lyophilizing, obtains aminated aspartic acid-alanine copolymer;
(3) under room temperature, the aminated aspartic acid-alanine copolymer in (2) is dissolved in deionized water, pH is regulated to be 7.0 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-alanine copolymer and Suflo-DOTA is 1:1, in stirred at ambient temperature 24h, dialysis, concentrated, lyophilizing, obtains 1 of aspartic acid-alanine copolymer, 4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl macromolecular ligand;
(4) with step (4) in embodiment 1.
Carry out relaxivity detection to the coordination compound that embodiment 5 obtains, the relaxivity of the coordination compound of embodiment 5 in water is 10.2mmol after testing
-1ls
-1.
Embodiment 6
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA Gd coordination compound:
(1) with step (1) in embodiment 3;
(2) at room temperature aspartic acid-alanine copolymer synthesized in (1) is dissolved in N, in dinethylformamide solution, dropwise ethylenediamine is added under stirring, ethylenediamine and aspartic acid-alanine copolymer quality are than being 2.8:1, stirring at room temperature 3h, ether sedimentation, filter, dialysis, lyophilizing, obtains aminated aspartic acid-alanine copolymer;
(3) under room temperature, aminated aspartic acid-alanine copolymer obtained in (2) is dissolved in deionized water, pH is regulated to be 8.5 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-alanine copolymer and Suflo-DOTA is 1:1, in stirred at ambient temperature 48h, dialysis, concentrated, lyophilizing, obtains 1 of aspartic acid-alanine copolymer, 4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl macromolecular ligand;
(4) with step (4) in embodiment 1.
Embodiment 7
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA Gd coordination compound:
(1) 2gL-aspartic acid and 20gL-alanine are mixed, the mass fraction that mixture after mixing adds 8g is stir in the phosphoric acid solution of 85%, 5h is reacted under the condition (30mmHg) of decompression, reaction temperature controls at 165 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
(2) with step (2) in embodiment 1;
(3) under room temperature, the aminated aspartic acid-alanine copolymer in (2) is dissolved in deionized water, pH is regulated to be 8.0 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-alanine copolymer and Suflo-DOTA is 1:1, in stirred at ambient temperature 36h, dialysis, concentrated, lyophilizing, obtains 1 of aspartic acid-alanine copolymer, 4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl macromolecular ligand;
(4) with step (4) in embodiment 1.
Carry out relaxivity detection to the coordination compound that embodiment 7 obtains, the relaxivity of the coordination compound of embodiment 7 in water is 13.6mmol after testing
-1ls
-1.
Embodiment 8
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA Gd coordination compound:
(1) 20gL-aspartic acid and 45gL-alanine are mixed, the mass fraction that mixture after mixing adds 25g is stir in the phosphoric acid solution of 85%, 6h is reacted under the condition (150mmHg) of decompression, reaction temperature controls at 180 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
(2) with step (2) in embodiment 1;
(3) under room temperature, the aminated aspartic acid-alanine copolymer in (2) is dissolved in deionized water, pH is regulated to be 7.0 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-alanine copolymer and Suflo-DOTA is 1:1, in stirred at ambient temperature 36h, dialysis, concentrated, lyophilizing, obtains 1 of aspartic acid-alanine copolymer, 4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl macromolecular ligand;
(4) at ambient temperature aspartic acid-alanine the copolymer obtained in (3) is modified 1, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand and Gadolinium trichloride reactant aqueous solution, be 6.5 with potassium hydroxide solution adjust pH, in the DOTA macromolecular ligand that aspartic acid-alanine copolymer is modified, the amount of substance of DOTA and the amount of substance of gadolinium ion are than being 1:1.1, in stirred at ambient temperature 5h, dialysis, concentrated, lyophilizing, obtain 1 of aspartic acid-alanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl Gd coordination compound.
Carry out relaxivity detection to the coordination compound that embodiment 8 obtains, the relaxivity of the coordination compound of embodiment 8 in water is 9.3mmol after testing
-1ls
-1.
Embodiment 9
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA Gd coordination compound:
(1) with step (1) in embodiment 1;
(2) with step (2) in embodiment 2;
(3) under room temperature, the aminated aspartic acid-alanine copolymer in (2) is dissolved in deionized water, pH is regulated to be 8.5 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-alanine copolymer and Suflo-DOTA is 1:1, in stirred at ambient temperature 36h, dialysis, concentrated, lyophilizing, obtains 1 of aspartic acid-alanine copolymer, 4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl macromolecular ligand;
(4) at ambient temperature aspartic acid-alanine the copolymer obtained in (3) is modified 1, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand and Gadolinium trichloride reactant aqueous solution, be 4.0 with potassium hydroxide solution adjust pH, in the DOTA macromolecular ligand that aspartic acid-alanine copolymer is modified, the amount of substance of DOTA and the amount of substance of gadolinium ion are than being 1:1.1, in stirred at ambient temperature 36h, dialysis, concentrated, lyophilizing, obtain 1 of aspartic acid-alanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl Gd coordination compound.
Embodiment 10
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA manganese complex:
(1) 20gL-aspartic acid and 10gL-alanine are mixed, the mass fraction that mixture after mixing adds 10g is stir in the phosphoric acid solution of 85%, 5h is reacted under the condition (24mmHg) of decompression, reaction temperature controls at 165 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
(2) with step (2) in embodiment 1;
(3) with step (3) in embodiment 1;
(4) at ambient temperature aspartic acid-alanine the copolymer obtained in (3) is modified 1, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand and manganese chloride reactant aqueous solution, be 5.2 with potassium hydroxide solution adjust pH, in the DOTA macromolecular ligand that aspartic acid-alanine copolymer is modified, the amount of substance of DOTA and the amount of substance of manganese ion are than being 1:1.1, in stirred at ambient temperature 1 day, dialysis, concentrated, lyophilizing, obtain 1 of aspartic acid-alanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl manganese complex.
Embodiment 11
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA manganese complex:
(1) 20gL-aspartic acid and 10gL-alanine are mixed, the mass fraction that mixture after mixing adds 10g is stir in the phosphoric acid solution of 85%, 5h is reacted under the condition (200mmHg) of decompression, reaction temperature controls at 165 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
(2) at room temperature aspartic acid-alanine copolymer synthesized in (1) is dissolved in N, in dinethylformamide solution, dropwise ethylenediamine is added under stirring, ethylenediamine and aspartic acid-alanine copolymer quality are than being 2.8:1, stirring at room temperature 5h, ether sedimentation, filter, dialysis, lyophilizing, obtains aminated aspartic acid-alanine copolymer;
(3) with step (3) in embodiment 1;
(4) at ambient temperature aspartic acid-alanine the copolymer obtained in (3) is modified 1, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand and manganese chloride reactant aqueous solution, be 5.2 with potassium hydroxide solution adjust pH, in the DOTA macromolecular ligand that aspartic acid-alanine copolymer is modified, the amount of substance of DOTA and the amount of substance of manganese ion are than being 1:1.1, in stirred at ambient temperature 1 day, dialysis, concentrated, lyophilizing, obtain 1 of aspartic acid-alanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl manganese complex.
Embodiment 12
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA dysprosium coordination compound:
(1) 20gL-aspartic acid and 2gL-alanine are mixed, the mass fraction that mixture after mixing adds 10g is stir in the phosphoric acid solution of 85%, 8h is reacted under the condition (24mmHg) of decompression, reaction temperature controls at 200 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
(2) with step (2) in embodiment 1;
(3) under room temperature, the aminated aspartic acid-alanine copolymer in (2) is dissolved in deionized water, pH is regulated to be 8.0 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-alanine copolymer and Suflo-DOTA is 1:1, in stirred at ambient temperature 36h, dialysis, concentrated, lyophilizing, obtains 1 of aspartic acid-alanine copolymer, 4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl macromolecular ligand;
(4) at ambient temperature aspartic acid-alanine the copolymer obtained in (3) is modified 1, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand and Dysprosium trichloride reactant aqueous solution, be 5.2 with potassium hydroxide solution adjust pH, in the DOTA macromolecular ligand that aspartic acid-alanine copolymer is modified, the amount of substance of DOTA and the amount of substance of dysprosium ion are than being 1:1.1, in stirred at ambient temperature 1 day, dialysis, concentrated, lyophilizing, obtain 1 of aspartic acid-alanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl dysprosium coordination compound.
Embodiment 13
Aspartic acid-alanine copolymer is by the preparation of ethylene diamine-modified DOTA manganese complex:
(1) 2gL-aspartic acid and 20gL-alanine are mixed, the mass fraction that mixture after mixing adds 8g is stir in the phosphoric acid solution of 85%, 5h is reacted under the condition (30mmHg) of decompression, reaction temperature controls at 165 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
(2) at room temperature aspartic acid-alanine copolymer synthesized in (1) is dissolved in N, in dinethylformamide solution, dropwise ethylenediamine is added under stirring, ethylenediamine and aspartic acid-alanine copolymer quality are than being 2.8:1, stirring at room temperature 4h, ether sedimentation, filter, dialysis, lyophilizing, obtains aminated aspartic acid-alanine copolymer;
(3) under room temperature, the aminated aspartic acid-alanine copolymer in (2) is dissolved in deionized water, pH is regulated to be 7.5 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-alanine copolymer and Suflo-DOTA is 1:1, in stirred at ambient temperature 36h, dialysis, concentrated, lyophilizing, obtains 1 of aspartic acid-alanine copolymer, 4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl macromolecular ligand;
(4) at ambient temperature aspartic acid-alanine the copolymer obtained in (3) is modified 1, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand and manganese chloride reactant aqueous solution, be 5.2 with potassium hydroxide solution adjust pH, in the DOTA macromolecular ligand that aspartic acid-alanine copolymer is modified, the amount of substance of DOTA and the amount of substance of manganese ion are than being 1:1.1, in stirred at ambient temperature 1 day, dialysis, concentrated, lyophilizing, obtain 1 of aspartic acid-alanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl manganese complex.
Embodiment 14
Aspartic acid-phenylalanine copolymer is by the preparation of ethylene diamine-modified DOTA iron complex:
(1) 20gL-aspartic acid and 20gL-phenylalanine are mixed, the mass fraction that mixture after mixing adds 15g is stir in the phosphoric acid solution of 85%, 5h is reacted under the condition (30mmHg) of decompression, reaction temperature controls at 165 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-phenylalanine copolymer;
(2) at room temperature aspartic acid-phenylalanine copolymer synthesized in (1) is dissolved in N, in dinethylformamide solution, dropwise ethylenediamine is added under stirring, ethylenediamine and aspartic acid-phenylalanine copolymer quality are than being 2.8:1, stirring at room temperature 1h, ether sedimentation, filter, dialysis, lyophilizing, obtains aminated aspartic acid-phenylalanine copolymer;
(3) with step (3) in embodiment 1;
(4) at ambient temperature aspartic acid-phenylalanine the copolymer obtained in (3) is modified 1, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand and ferric chloride in aqueous solution react, be 5.2 with potassium hydroxide solution adjust pH, in the DOTA macromolecular ligand that aspartic acid-phenylalanine copolymer is modified, the amount of substance of DOTA and the amount of substance of iron ion are than being 1:1.1, in stirred at ambient temperature 1 day, dialysis, concentrated, lyophilizing, obtain 1 of aspartic acid-phenylalanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl iron complex.
Embodiment 15
Aspartic acid-phenylalanine copolymer is by the preparation of ethylene diamine-modified DOTA ruthenium complex:
(1) with step (1) in embodiment 3;
(2) at room temperature aspartic acid-phenylalanine copolymer synthesized in (1) is dissolved in N, in dinethylformamide solution, dropwise ethylenediamine is added under stirring, ethylenediamine and aspartic acid-phenylalanine copolymer quality are than being 2.8:1, stirring at room temperature 1h, ether sedimentation, filter, dialysis, lyophilizing, obtains aminated aspartic acid-phenylalanine copolymer;
(3) under room temperature, aminated aspartic acid-phenylalanine copolymer obtained in (2) is dissolved in deionized water, pH is regulated to be 7.0 with potassium hydroxide solution, the solution obtained is added drop-wise in Suflo-DOTA solution, the mass ratio of aminated aspartic acid-phenylalanine copolymer and Suflo-DOTA is 1:1, in stirred at ambient temperature 36h, dialysis, concentrated, lyophilizing, obtains 1 of aspartic acid-phenylalanine copolymer modification, 4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl macromolecular ligand;
(4) at ambient temperature aspartic acid-phenylalanine the copolymer obtained in (3) is modified 1, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl macromolecular ligand and ruthenium chloride aqueous solution react, be 5.2 with potassium hydroxide solution adjust pH, in the DOTA macromolecular ligand that aspartic acid-phenylalanine copolymer is modified, the amount of substance of DOTA and the amount of substance of ruthenium ion are than being 1:1.1, in stirred at ambient temperature 1 day, dialysis, concentrated, lyophilizing, obtain 1 of aspartic acid-phenylalanine copolymer modification, 4, 7, 10-tetraazacyclododecanand-1, 4, 7, 10-tetraacethyl ruthenium complex.
Embodiment 16
The paramagnetic metal complex modified of aspartic acid-alanine copolymer is as the application of magnetic resonance imaging contrast: get that aspartic acid-alanine copolymer of the embodiment 1 of 0.1g modifies 1,4,7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, 7,10-tetraacethyl Gd coordination compound, be dissolved in conventional sodium chloride injection, be 6.5 by slow blood amine adjust ph, make 0.001 mol/L magnetic resonance imaging contrast.
Fig. 1 is the time dependent reinforced effects figure of rat liver signal after the magnetic resonance imaging contrast prepared of injection the present embodiment.This figure illustrates that the magnetic resonance imaging contrast imaging effect of complex preparation of the present invention is good, and susceptiveness is high, and imaging time is long.Compared with its spirits many, the picture signal of gained after injection targeting MRI contrast agents, definition and contrast also significantly improve.Its spirits many can only maintain 30min at most in vivo, and targeted contrast agent can make contrast agent be enriched in tissue or organ, and targeting contrast imaging is chronic.
Get the Wistar rat of male 110-130g body weight, after pressing the anesthesia of 1.0mL/100g body weight with 10% urethane, after the magnetic resonance imaging contrast by 0.1mmol/kg body weight dose intravenous injection embodiment 16, test animal abdominal cavity T
1weighting picture, every 10min sampling observation once, more than Continuous Observation 120min (uses Brooker company magnetic resonance imager, 30cm coil, 4.7T magnetic field, adopts T
1weighting multi-disc-many echo-wave imagings mode, repetition time TR:300ms, echo time TE:13.6ms, scanning area: 5.5 × 5.5cm
2, scan matrix: 128 × 128).
In Fig. 2, a, b, c, d be followed successively by injection embodiment 16 prepare magnetic resonance imaging contrast before and injection 30min, 50min, 70min after rat liver T
1weighting picture figure.As can be seen from Figure 2, under Isodose, magnetic resonance imaging contrast is better than the Gd-DOTA under Isodose to the increase successful that liver magnetic resonance signal produces.The raising of this contrast, shows the liver selective that this type of contrast agent is good.
Embodiment 17
The paramagnetic metal complex modified of aspartic acid-alanine copolymer is as the application of magnetic resonance imaging contrast: get that aspartic acid-alanine copolymer of the embodiment 3 of 0.1g modifies 1,4,7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl Gd coordination compound is dissolved in conventional dextran injection liquid, be 8.0 by slow blood amine adjust ph, make 0.01 mol/L magnetic resonance imaging contrast.
Embodiment 18
The paramagnetic metal complex modified of aspartic acid-alanine copolymer is as the application of magnetic resonance imaging contrast: get that aspartic acid-alanine copolymer of the embodiment 7 of 0.1g modifies 1,4,7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl Gd coordination compound is dissolved in conventional sodium chloride-dextran injection liquid, be 6.5 by slow blood amine adjust ph, make 0.1 mol/L magnetic resonance imaging contrast.
Embodiment 19
The paramagnetic metal complex modified of aspartic acid-alanine copolymer is as the application of magnetic resonance imaging contrast: get that aspartic acid-alanine copolymer of the embodiment 10 of 0.1g modifies 1,4,7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl manganese complex is dissolved in conventional dextran injection liquid, be 8.0 by slow blood amine adjust ph, make 0.01 mol/L magnetic resonance imaging contrast.
Embodiment 20
The paramagnetic metal complex modified of aspartic acid-alanine copolymer is as the application of magnetic resonance imaging contrast: get that aspartic acid-alanine copolymer of the embodiment 11 of 0.1g modifies 1,4,7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl manganese complex is dissolved in conventional sodium chloride-dextran injection liquid, be 6.5 by slow blood amine adjust ph, make 0.5 mol/L magnetic resonance imaging contrast.
Claims (10)
1. the paramagnetic metal complex that aspartic acid-alanine copolymer is modified, it is characterized in that, structural formula is as follows:
In formula, a, b, c, d and n are natural number, and meet following relation:
N
m+it is paramagnetic metal element+2 or+3 valency ion.
2. the paramagnetic metal complex that aspartic acid according to claim 1-alanine copolymer is modified, is characterized in that, described N
m+for Gd
2+, Mn
2+, Dy
2+, Nd
2+, Fe
2+, Ru
2+, Gd
3+, Mn
3+, Dy
3+, Nd
3+, Fe
3+or Ru
3+.
3. the preparation method of the paramagnetic metal complex that aspartic acid-alanine copolymer is modified, it is characterized in that, the method comprises the following steps:
(1) by ASPARTIC ACID and ALANINE in molar ratio 10:1 ~ 1:9 mix, the mixture obtained with stir with concentrated phosphoric acid after, 1h ~ 8h is reacted under 24mmHg ~ 200mmHg pressure, reaction temperature controls at 50 DEG C ~ 220 DEG C, deionized water precipitates, and filters, washing, drying under reduced pressure, obtains aspartic acid-alanine copolymer;
Phosphoric acid in described concentrated phosphoric acid and the mass ratio of mixture are 0.1 ~ 1.5:1;
(2) at room temperature aspartic acid-alanine copolymer synthesized in step (1) is dissolved in N, in dinethylformamide solution, dropwise ethylenediamine is added under stirring, stirring at room temperature 1h ~ 5h, ether sedimentation, filters, dialysis, lyophilizing, obtains aminated aspartic acid-alanine copolymer;
The mass ratio of described aspartic acid-alanine copolymer and ethylenediamine is 1:2.8;
(3) be at room temperature dissolved in deionized water by aminated aspartic acid-alanine copolymer synthesized in step (2), regulate pH 7.0 ~ 9.0, the solution obtained is added drop-wise in DOTA mono-N-hydroxy thiosuccinimide active ester solution, in stirred at ambient temperature 24h-48h, dialysis, concentrated, lyophilizing, obtain the Isosorbide-5-Nitrae that aspartic acid-alanine copolymer is modified, 7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl macromolecular ligand;
The mass ratio of described aminated aspartic acid-alanine copolymer and DOTA mono-N-hydroxy thiosuccinimide active ester is 1:1;
(4) at ambient temperature by the Isosorbide-5-Nitrae that the aspartic acid of synthesis in step (3)-alanine copolymer is modified, 7,10-tetraazacyclododecanand-1,4,7,10-tetraacethyl macromolecular ligand and the reactant aqueous solution containing paramagnetic metal ion, adjust ph is 4.0 ~ 6.5, in stirred at ambient temperature 5h ~ 36h, dialysis, concentrated, lyophilizing, obtains the paramagnetic metal complex that aspartic acid-alanine copolymer is modified;
In the DOTA macromolecular ligand that described aspartic acid-alanine copolymer is modified, the amount of substance of DOTA and the amount of substance of paramagnetic metal ion are than being 1:1.1.
4. the preparation method of the paramagnetic metal complex that aspartic acid-alanine copolymer is modified, is characterized in that, in described step (3) and step (4), adopts the pH value of potassium hydroxide solution adjustment.
5. the paramagnetic metal complex that the aspartic acid described in claim 1 or 2-alanine copolymer is modified can be applied as magnetic resonance imaging contrast.
6. the magnetic resonance imaging contrast of the paramagnetic metal complex containing the aspartic acid described in claim 1 or 2-alanine copolymer modification, it is characterized in that, this magnetic resonance imaging contrast is also containing slow blood amine and solvent, pH value is 6.5 ~ 8.0, and the concentration of the paramagnetic metal complex that aspartic acid-alanine copolymer is modified is 0.001 mol/L ~ 0.5 mol/L;
Described solvent is sodium chloride injection, dextran injection liquid, sodium chloride-dextran injection liquid or distilled water for injection.
7. magnetic resonance imaging contrast according to claim 6, is characterized in that, described magnetic resonance imaging contrast is injection or injectable powder.
8. magnetic resonance imaging contrast according to claim 6, is characterized in that, the consumption of described injection is the every kg body weight 0.001mmol ~ 5.0mmol of mammalian body.
9. magnetic resonance imaging contrast according to claim 8, is characterized in that, the consumption of described injection is the every kg body weight 0.05mmol ~ 5.0mmol of mammalian body.
10. the preparation method of magnetic resonance imaging contrast according to claim 6, it is characterized in that, the paramagnetic metal complex that aspartic acid-alanine copolymer is modified is dissolved in sodium chloride injection, dextran injection liquid, sodium chloride-dextran injection liquid or distilled water for injection, regulate pH to 6.5 ~ 8.0 with slow blood amine, make the magnetic resonance imaging contrast that concentration is 0.001 mol/L ~ 0.5 mol/L.
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| CN105963720A (en) * | 2016-06-24 | 2016-09-28 | 中国科学院长春应用化学研究所 | Aspartate-leucine copolymer modified paramagnetism metal complex as well as preparation method and application thereof |
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| WO2006029560A1 (en) * | 2004-09-14 | 2006-03-23 | The University Of Hong Kong | Paramagnetic complexes with pendant crown compounds showing improved targeting-specificity as mri contrast agents |
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| CN104069515A (en) * | 2014-06-27 | 2014-10-01 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex modified by aspartic acid-leucine copolymer as well as preparation and application of paramagnetic metal complex |
| CN104083778A (en) * | 2014-06-27 | 2014-10-08 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex modified by asparaginic acid-phenylalanine copolymer, preparation method and application of paramagnetic metal complex |
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| WO2006029560A1 (en) * | 2004-09-14 | 2006-03-23 | The University Of Hong Kong | Paramagnetic complexes with pendant crown compounds showing improved targeting-specificity as mri contrast agents |
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