CN101619106A - Polysaccharide macromolecular paramagnetic metal complex and synthesis method and application thereof - Google Patents
Polysaccharide macromolecular paramagnetic metal complex and synthesis method and application thereof Download PDFInfo
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Abstract
The invention relates to a polysaccharide macromolecular paramagnetic metal complex and a synthesis method and an application thereof. Polysaccharide macromolecules are used as carriers, and a ligand compound, the side chains of which contain open-chain or annular polyamino polycarboxylic compounds, acts with paramagnetic metal ions to form the paramagnetic metal complex, wherein the paramagnetic metal ions are positive divalent or trivalent ions of metal elements, the atomic numbers of which are 21-29, 42 and 44 or 57-71. The polysaccharide macromolecular paramagnetic metal complex can be used as a magnetic resonance imaging contrast agent for lymphatic organs, lymphatic vessels, lymphatic systems and cardiovascular systems of people or other mammals.
Description
Technical field
The invention belongs to medicine and pharmacology, technical field of chemistry, a concrete class polysaccharide macromolecular paramagnetic metal complex and the preparation method and use that relate to, be to be carrier with the polysaccharide macromolecular specifically, side chain contains the polysaccharide macromolecular paramagnetic metal complex and the preparation method and use thereof of part open chain or many ammonia of cyclic multi-carboxylic acid compounds and paramagnetic metal ion effect formation.
Background technology
Nuclear magnetic resonance is an advanced medical imaging diagnosis technology, and magnetic resonance imaging contrast is the important component part of this technology, can shorten imaging time, is used for improving image contrast and sharpness.(Chem.Rev.，1987，87，901)。
Retention time is short in vivo for clinical magnetic resonance imaging contrast commonly used such as magnevist Magnevist (Gd-DTPA) now, does not have tissue or organ selectivity or target.At present one of important research direction of magnetic resonance imaging contrast is high molecular and organ, tissue target tropism's a contrast medium (Radiology, 1997,203,297) in the world.Wherein organ target contrast medium can make contrast medium be enriched in specific organ or tissue, and the time length is longer, thereby realizes targeted imaging, improves image contrast and sharpness, and radiography is effective, and dosage is low, and toxicity is little.This class contrast medium is mainly used in the radiography of organ or tissues such as liver, stomach, lung, spleen, tumour.As having entered the close hepatobiliary contrast medium Gd-EOB-DTPA of clinical trial, Gd-BOPTA, Gd-DPDP abroad.
Lymphsystem is the important defence system of human body, also is one and the closely-related netted liquid system of cardiovascular systems.When disease such as infections took place human body, common lymphsystem at first produced reaction, as lymphadenectasis pain etc.Nuclear magnetic resonance is used for the lymphsystem targeting diagnosis, can find minimal disease earlier, improves discriminating, diagnosis and the treatment level of human body diseases.
Macromolecular contrast agent is compared with small molecules MRI contrast medium such as magnevist, and the former molecular dimension is bigger, and it is slower to see through capillary vessel speed, and the speed of rotation of molecule is lower, can improve relaxation rate, reduces dosage, reduces toxicity.And can make contrast medium be enriched in particular organization by polysaccharide, polypeptide, antibody, the equimolecular special biochemical property of VITAMIN, thus realize targeted imaging, improve image contrast and sharpness.The macromolecular contrast agent of foreign study be coupled to small molecules MRI contrast medium natural mostly or the synthetic macromolecular carrier on form, as albumin-Gd-DTPA, polylysine-Gd-DTPA and with the polylysine-Gd-DTPA of poly glycol monomethyl ether modification.
Summary of the invention
Order of the present invention is in order to overcome the shortcoming that existing macromolecular contrast agent exists, one class polysaccharide macromolecular paramagnetic metal complex and preparation method and use thereof is provided, with open chain or many ammonia of cyclic multi-carboxylic acid compounds carry out structure of modification, introduce polysaccharide macromolecular surface amido by the spacer of amido linkage or other type, thus synthetic macromolecule contrast medium part; Then the contrast medium part is cooperated with paramagnetic metal ion, part expectation obtains the relaxation rate height, and good hydrophilic property has the practical macromolecule magnetic resonance imaging contrast agent of new class of target to lymphsystem, cardiovascular systems.
Polysaccharide macromolecular paramagnetic metal complex, it has following array structure: with polysaccharide macromolecular as carrier, side chain contains the paramagnetic metal complex of ligand compound open chain or many ammonia of cyclic multi-carboxylic acid compounds and paramagnetic metal ion effect formation, paramagnetic metal ion be ordination number be 21 to 29,42,44 or 57 to 71 metallic element+2 or+3 valency ions, described ligand compound has the chemical structural formula of formula 1
Formula 1
Wherein B is COO
-, CH
2OH, NH
2, CH
2OSO
3 -, CH
2OPO
3 -Or OA; C is NHC (=O) CH
3, OH, CH
3, OCH
3, NH
2, OSO
3 -, NHSO
3 -, OPO
3 -Or OA; D is NHC (=O) CH
3, OH, CH
3, OCH
3, NH
2, OSO
3 -, NHSO
3 -, OPO
3 -Or OA; A is the chemical structural formula with formula 2 or formula 3 representatives:
Formula 2
Formula 3
R wherein
1, R
3, Q is COOH, CO, hydrogen atom, Sauerstoffatom, sulphur atom, NH or N (CR
4R
5) group of X representative; X be hydrogen atom, alkyl ,-(CR
4R
5) m-,-(SR
4R
5) m-,-(OR
4R
5) m-,-(NR
4R
5) m-or-(CR
4R
3) the qCOOH group; R
2, R
4And R
5Represent hydrogen atom, alkyl, aryl or have alkyl, the aryl substituent of one or more hydroxyls, alkoxyl group, amido, aryl or aryloxy; M, n are natural number; P is 2,3 or 4, and r is 0 to 10 integer, and q is 1 or 2;
In polysaccharide macromolecular magnetic resonance imaging contrast molecule, the molar content of A accounts for the 1-99% of the original surperficial primary amine groups of polysaccharide macromolecular respectively, and wherein the summation of the molar content of the molar content of A and polysaccharide macromolecular unreacted surface primary amine groups is 100%.
Described paramagnetic metal ion be preferably Gd, Mn, Cr, Fe, Co, Ni, La, Tc, Dy or Cu metallic element+2 or+3 valency ions.
Described polysaccharide macromolecular molecular weight ranges is 100 to 10
8
A has following structural formula in formula 1 part:
A has following structure in formula 1 part:
A has following structure in formula 1 part:
A has following structure in formula 1 part:
The synthetic method of polysaccharide macromolecular paramagnetic metal complex, it is characterized in that including following steps: the covalent linkage that (1) will contain reactive derivative open chain or many ammonia of cyclic multi-carboxylic acid compounds and polysaccharide macromolecular even forms ligand compound, above-mentioned building-up reactions is carried out in the aqueous solution or organic solvent, and temperature of reaction is-20 ℃ to 120 ℃; (2) will go up the ligand compound that goes on foot formation cooperates with paramagnetic metal ion, paramagnetic metal ion be ordination number be 21 to 29,42,44 or 57 to 71 metallic element+2 or+3 valency ions, form the metal paramagnetic metal complex, described ligand compound cooperates by 1: 1 mol ratio with paramagnetic metal ion, above-mentioned building-up reactions is carried out in the aqueous solution or polar organic solvent, and temperature of reaction is 20 ℃ to 120 ℃.
Press such scheme, described reactive derivative is monocycle acid anhydrides, dicyclo acid anhydrides, mixed acid anhydride, active ester, acyl chlorides or acylbromide.
Press such scheme, the organic solvent described in the step (1) is N, dinethylformamide, the mixed solvent of any one in N,N-dimethylacetamide, methyl-sulphoxide, pyridine, triethylamine, tetrahydrofuran (THF), the dioxane or multiple formation.
Press such scheme, the polar organic solvent described in the step (2) is alcohols, dimethyl formamide, methyl-sulphoxide or pyridine.
Press such scheme, the temperature of reaction that step (1) is suitable is-5 ℃ to 70 ℃.
Press such scheme, the temperature of reaction that step (2) is suitable is 20 ℃ to 80 ℃.
The synthesis reaction temperature of ligand compound depends on the character of reaction raw materials, is generally in-20 ℃ to the 120 ℃ scopes, and suitable temperature of reaction is-5 ℃ to 70 ℃.In reaction process, feed rare gas element such as nitrogen or argon gas and protect, like this to reacting favourable.
In the preparation process in the synthetic above-mentioned ligand compound, the group that does not need in the raw material that needs protection sometimes to react is such as hydroxyl, amido, and available known method is protected, and sloughs protecting group after the reaction again.These methods have description in " blocking group in the organic chemistry " monographs such as (the medium compiling of Zhao Zhi, Science Press, Beijing 1984).
With the synthetic ligand compound, react in water or polar organic solvent with oxide compound, carbonate, acetate, oxyhydroxide or the muriate of the divalence of paramagnetic metal or trivalent ion respectively and make polysaccharide macromolecular paramagnetic metal complex.Temperature of reaction can change according to the differential responses thing, and general range of reaction temperature is 20 ℃-120 ℃, and suitable temperature is 20 ℃-80 ℃.
It is the 0.1-0.5 mol that water miscible paramagnetic metal complex is made concentration usually, and the pH value is 6.5 to 8.0 the aqueous solution.Fat-soluble paramagnetic metal complex is mixed with certain density liposome with biomolecules such as itself and phosphatide usually.For the non-vanishing situation of total charge number behind the formation paramagnetic metal complex, the positively charged ion of available physiological compatibility is Na particularly
+, Ca
2+, Cu
2+, Zn
2+, NH
4+Or organic derivative such as N-methyl glucoside amine, amino acid, morpholine, hydramine or electrically charged with anion ratio such as its institute of chlorion, sulfate radical, phosphate radical or organic acid balance of physiological compatibility, the pH value of regulator solution is in 6.5 to 8.0 scopes.Reaction product can be with ordinary method such as recrystallization, column chromatography, ion-exchange chromatogram purification.
Described polysaccharide macromolecular paramagnetic metal complex is with the magnetic resonance imaging contrast of doing people or other mammiferous lymphoid organs, lymphatic vessel, lymphsystem, cardiovascular systems.
Above-mentioned polysaccharide macromolecular paramagnetic metal complex is used to make a kind of magnetic resonance imaging contrast, this contrast medium is made up of paramagnetic metal complex and at least a pharmaceutical carrier or figuration body, paramagnetic metal complex weight percentage in the contrast medium is 0.1-15%, and pharmaceutical carrier is sodium chloride injection, glucose injection, dextrose ﹠ sodium chloride injection or distilled water; Described figuration body is phosphatide, gelatin, starch or syrup, and the concentration of pharmaceutical carrier or figuration body is the 0.001-5.0 mol.
Press such scheme, described magnetic resonance imaging contrast also adds pH regulator agent, ionogen, sterilizing powder, oxidation inhibitor or stablizer.
Contrast medium among the present invention can be made enterally administering preparation or oral preparation, also can make non-enteral administration preparation such as injection.Wherein injection can be used sodium chloride injection, glucose injection, the carrier that dextrose ﹠ sodium chloride injection or distilled water or other are stipulated on the Pharmacopoeia of the People's Republic of China, paramagnetic metal complex of the present invention is mixed with the solution that concentration is the 0.001-5.0 mol, wherein suitable concentration is the 0.1-0.5 mol, and with the sour example hydrochloric acid of physiological compatibility or the alkali of physiological compatibility: comprise N-methyl glucoside amine, slow blood ammonia, organic bases or ammoniacal liquor such as amino acid, sodium hydroxide, yellow soda ash, mineral alkalis such as sodium bicarbonate are regulated the pH value between 6.5 to 8.0.Usually in contrast medium, add 0.1 to 15% the respective ligand compound that is equivalent to the paramagnetic metal complex amount or salt or calcium, magnesium, copper, the title complex of zinc or the physiological compatibility salt of these title complexs of other physiological compatibilities, to guarantee that paramagnetic metal ion is cooperated fully by ligand compound.Can also add antioxidant such as xitix or its sodium, calcium salt does not in addition influence the additive of preparation, storage and the use of preparation.Another kind of suitable way is that paramagnetic metal ion of the present invention and 0.1% to 15% the respective ligand that is equivalent to said paramagnetic metal complex weight or salt, pH regulator agent, oxidation inhibitor or other required composition of its salt or calcium, magnesium, copper, Zn complex or these title complexs are mixed with dried solid preparation, be pulvis or injectable powder, be diluted to desired concn with distilled water or the injection of chlorine water sodium before using.
Oral preparations can have many forms, such as tablet, pulvis, capsule, powder, syrup, aqua.For example paramagnetic metal complex is mixed with aqua, can adds stablizer, buffer reagent, correctives, oxidation inhibitor, tensio-active agent.
Contrast medium of the present invention can use according to a conventional method, and this method comprises bestows diagnosis object such as human body or other mammalian body paramagnetic metal complex, carries out magnetic resonance imaging analysis then, draws enhanced nuclear magnetic resonance figure.The dosage of contrast medium of the present invention can because of the kind of paramagnetic metal complex with very big variation is arranged as the tissue of diagnosis object or organ and diagnositc equipment type different, generally, the injection consumption preferably 0.05 arrives 0.5mmol for the people of diagnosis main body or every kg body weight 0.001 to 5.0mmol of other mammalian body.Oral dosage is generally every kg body weight 0.01 to 100mmol, preferably 0.5 arrives 20mmol.
Contrast medium part among the present invention also can form heavy metal complex as lead, bismuth, gold etc. with heavy metal ion, be used for ultrasonic imaging or X-ray CT, PET, or form the contrast medium of radiometal complex as radiotherapy medicine or scintillography with radioactive metal ion.
The present invention compared with the prior art, the technique effect that has reached:
Clinical magnetic imaging contrast medium commonly used such as Gadopentetate Meglumine have higher toxicity now, and retention time is short in vivo, accretion rate is fast in vivo, utilization ratio is low, does not have tissue or organ selectivity or target, especially tissue or organ is lacked problems such as selectivity.
The polysaccharide macromolecular paramagnetic metal complex magnetic resonance imaging contrast of present inventor's invention has kept the constructional feature of corresponding many ammonia poly carboxylic acid title complex, thereby have satisfactory stability, a water-soluble and relaxation rate, simultaneously lymphsystem, cardiovascular systems had target, thereby the realization targeted imaging improves image contrast and sharpness.Early diagnosis level to the disease that improves lymphsystem, cardiovascular systems organ or tissue has effect preferably.Compare with the Gadopentetate Meglumine of wide clinical application, this class contrast medium has following advantage:
(1) has the selectivity of lymphsystem, cardiovascular systems.The mouse drug disposition distributes to test and shows, the molecular dimension of target magnetic resonance imaging contrast is bigger, and it is slower to see through capillary vessel speed, and the concentration in lymphsystem, cardiovascular system tissue or organ is higher, thereby the realization targeted imaging improves image contrast and sharpness.
(2) relaxation rate height, imaging effect is good, the susceptibility height, imaging time is long.Compare with Gadopentetate Meglumine, target magnetic resonance imaging contrast relaxation rate height is significantly increased.The picture signal of gained behind the injection target magnetic resonance imaging contrast, sharpness and contrast gradient also obviously improve.Gadopentetate Meglumine can only be kept at most 30 minutes in vivo, and targeted contrast agent can make contrast medium be enriched in tissue or the organ, has than long residence time, was convenient to about 2 hours of long period realization target contrast imaging.
(3) toxicity is low, dosage is little, cost is low.The tissue or the organ target magnetic resonance imaging contrast of the development of this project have lower osmotic pressure and toxicity in vivo, and its toxicity hangs down 50% at least than Gadopentetate Meglumine.Compare with Gadopentetate Meglumine, target magnetic resonance imaging contrast injected dose can reduce half at least.
(4) this class contrast medium is water-soluble fine, is convenient to the wiring solution-forming injection and uses.
(5) this class contrast medium aqueous solution Heat stability is good is suitable for the pressure sintering sterilization.
Description of drawings
After Fig. 1 is subcutaneous injection target polysaccharide macromolecular contrast medium (dosage of 0.0041mmoGdl/kg), New Zealand white rabbit lower limb lymphsystem nuclear magnetic resonance photo;
After Fig. 2 is subcutaneous injection Gadopentetate Meglumine injection liquid (Gd-DTPA, magnevist, the dosage of 0.1mmolGd/kg, Bayer Healthcare's Guangzhou Branch), New Zealand Bai Tu popliteal nest lymphoglandula nuclear magnetic resonance photo;
After Fig. 3 is subcutaneous injection target polysaccharide macromolecular contrast medium (dosage of 0.0041mmoGdl/kg), New Zealand Bai Tu popliteal nest lymphoglandula nuclear magnetic resonance photo;
Fig. 4 for auricular vein injection lymphsystem target polysaccharide macromolecular contrast medium (dosage of 0.0041mmoGdl/kg) after, New Zealand white rabbit lower limb vascular nuclear magnetic resonance photo.
Embodiment
Below in conjunction with specific embodiment, technical scheme of the present invention is further described:
Embodiment 1:
1.62g dextran (molecular weight is 20,000) is dissolved in the 100mL methyl-sulphoxide with the 5mL triethylamine, in room temperature, under the magnetic agitation condition, slowly be added dropwise to and contain the 0.98g monobromethane for 1,4,7, the 30ml dimethyl sulfoxide solution of 10-nitrogen heterocyclic dodecane tetraacethyl DOTA, room temperature reaction 4h is raised to 40 ℃ of room temperatures and continues reaction 48h, filters, remove partial solvent under reduced pressure, be cooled to room temperature, debris is poured in the mixed solvent of 600mL dehydrated alcohol-anhydrous diethyl ether dehydrated alcohol in stirring down: the volume ratio of anhydrous diethyl ether is 1: 2, produce light-yellow precipitate, filter, drain, the gained solid is used dissolved in distilled water again, use dehydrated alcohol, also can use the anhydrous diethyl ether reprecipitation, collect light yellow solid, vacuum-drying, obtain the 2.21g solid, productive rate 85%.2.21g the gained solid is dissolved in the 20mL redistilled water, stirs down, adds 0.36g gadolinium sesquioxide Gd
2O
3(gadolinium sesquioxide and gained solid mol ratio are 1: 1), reaction solution is at 40 ℃ of room temperature reaction 1h, regulate pH5 with diluted sodium hydroxide solution, continue to stir 12h, filter, filtrate is precipitated with ethanol/anhydrous diethyl ether (volume ratio is 1/4), vacuum-drying, obtain 2.18g lymphsystem target polysaccharide macromolecular contrast medium, productive rate 85%.
Embodiment 2:
8.08g agar-agar (molecular weight is 40,000) is dissolved in the 200mL methyl-sulphoxide with the 10mL triethylamine, in room temperature, under the magnetic agitation condition, slowly stir to drip down and contain the 60ml dimethyl sulfoxide solution of 3.84g thiocyanic acid phenmethyl-DO3A, room temperature reaction 4h, be raised to 50 ℃ and continue reaction 48h, filter, remove partial solvent under reduced pressure, be cooled to room temperature, debris is poured in the mixed solvent of 1000mL dehydrated alcohol-anhydrous diethyl ether in stirring down, dehydrated alcohol: the volume ratio of anhydrous diethyl ether is 1: 2, produces light-yellow precipitate, filters, drain, the gained solid is used dissolved in distilled water again, uses dehydrated alcohol, also can use the anhydrous diethyl ether reprecipitation, collect light yellow solid, vacuum-drying obtains the 9.54g solid, productive rate 80%.
9.54g the gained solid is dissolved in the 100mL redistilled water, stirs down, adds 1.96g Lanthanum trichloride LaCl
3, reaction solution room temperature reaction 1h regulates pH5 with diluted sodium hydroxide solution, continues to stir 12h, filters, and filtrate is precipitated with ethanol/anhydrous diethyl ether (volume ratio is 1/4), and vacuum-drying obtains 8.63g lymphsystem target polysaccharide macromolecular contrast medium, productive rate 75%.
Embodiment 3:
1.14g hyaluronic acid (molecular weight is 80,000) is dissolved in the 50mL methyl-sulphoxide with the 5mL triethylamine, in room temperature, under the magnetic agitation condition, stir and add the dimethyl sulfoxide solution that content is the single N-hydroxy-succinamide active ester of 1.47g diethylenetriamine pentaacetic acid (DTPA) down in batches, room temperature reaction 4h, be raised to 80 ℃ of room temperatures and continue reaction 48h, filter, remove partial solvent under reduced pressure, be cooled to room temperature, debris is poured in the mixed solvent of 500mL dehydrated alcohol-anhydrous diethyl ether in stirring down, dehydrated alcohol: the volume ratio of anhydrous diethyl ether is 1: 2, produces light-yellow precipitate, filters, drain, the gained solid is used dissolved in distilled water again, uses dehydrated alcohol, also can use the anhydrous diethyl ether reprecipitation, collect light yellow solid, vacuum-drying obtains the 1.83g solid, productive rate 70%.
1.83g the gained solid is dissolved in the 50mL redistilled water, stirs down, adds 0.79g chlorination GdCl
3,, 50 ℃ of reactions of reaction solution 1h regulates pH5 with diluted sodium hydroxide solution, continues to stir 12h, filters, and filtrate is precipitated with ethanol/anhydrous diethyl ether (volume ratio is 1/4), and vacuum-drying obtains 2.25g lymphsystem target polysaccharide macromolecular contrast medium, productive rate 86%.
Embodiment 4:
5.46g chitosan (molecular weight is 200,000) is dissolved in the 100mL methyl-sulphoxide with the 5mL triethylamine, in room temperature, under the magnetic agitation condition, slowly be added dropwise to the 80ml dimethyl sulfoxide solution that contains the single N-hydroxy-succinamide ester of 6.01gDOTA, room temperature reaction 4h, be raised to 100 ℃ and continue reaction 48h, filter, remove partial solvent under reduced pressure, be cooled to room temperature, debris is poured in the mixed solvent of 1200mL dehydrated alcohol-anhydrous diethyl ether in stirring down, dehydrated alcohol: the volume ratio of anhydrous diethyl ether is 1: 2, produces light-yellow precipitate, filters, drain, the gained solid is used dissolved in distilled water again, uses dehydrated alcohol, also can use the anhydrous diethyl ether reprecipitation, collect light yellow solid, vacuum-drying obtains the 7.46g solid, productive rate 65%.
7.46g the gained solid is dissolved in the 200mL redistilled water, stirs down, adds 2.80g Dysprosium trichloride DyCl
2,, 100 ℃ of reactions of reaction solution 1h regulates pH5 with diluted sodium hydroxide solution, continues to stir 12h, filters, and filtrate is precipitated with ethanol/anhydrous diethyl ether (volume ratio is 1/4), and vacuum-drying obtains 9.23g lymphsystem target polysaccharide macromolecular contrast medium, productive rate 90%.
Embodiment 5:
7.08g chondroitin sulfate (molecular weight is 500,000) is dissolved in the 250mL methyl-sulphoxide with the 15mL triethylamine, in room temperature, under the magnetic agitation condition, slowly be added dropwise to the 150ml dimethyl sulfoxide solution that contains 13.5g thiocyanic acid phenmethyl-diethylenetriamine pentaacetic acid, 0 ℃ of reaction 4h, be raised to room temperature and continue reaction 48h, filter, remove partial solvent under reduced pressure, be cooled to room temperature, debris is poured in the mixed solvent of 2000mL dehydrated alcohol-anhydrous diethyl ether in stirring down, dehydrated alcohol: the volume ratio of anhydrous diethyl ether is 1: 2, produces light-yellow precipitate, filters, drain, the gained solid is used dissolved in distilled water again, uses dehydrated alcohol, also can use the anhydrous diethyl ether reprecipitation, collect light yellow solid, vacuum-drying obtains the 13.37g solid, productive rate 65%.
13.37g the gained solid is dissolved in the 200mL redistilled water, stirs down, adds 3.18g iron(ic) chloride FeCl
2, reaction solution-5 ℃ reaction 1h regulates pH5 with diluted sodium hydroxide solution, continues to stir 12h, filters, and filtrate is precipitated with ethanol/anhydrous diethyl ether (volume ratio is 1/4), and vacuum-drying obtains 12.41g lymphsystem target polysaccharide macromolecular contrast medium, productive rate 75%.
Embodiment 6:
29.82g heparin (molecular weight is 1,000,000) is dissolved in the 300mL methyl-sulphoxide with the 20mL triethylamine, in room temperature, under the magnetic agitation condition, slowly be added dropwise to the 200ml dimethyl sulfoxide solution of the single isobutyl ester that contains the 20.21g diethylenetriamine pentaacetic acid,-20 ℃ of reaction 4h, be raised to room temperature and continue reaction 48h, filter, remove partial solvent under reduced pressure, be cooled to room temperature, debris is poured in the mixed solvent of 2500mL dehydrated alcohol-anhydrous diethyl ether in stirring down, dehydrated alcohol: the volume ratio of anhydrous diethyl ether is 1: 2, produces light-yellow precipitate, filters, drain, the gained solid is used dissolved in distilled water again, uses dehydrated alcohol, also can use the anhydrous diethyl ether reprecipitation, collect light yellow solid, vacuum-drying obtains the 30.02g solid, productive rate 60%.
30.02g the gained solid is dissolved in the 200mL redistilled water, stirs down, adds 5.67g Manganous chloride tetrahydrate MnCl
2, 0 ℃ of reaction of reaction solution 1h regulates pH5 with diluted sodium hydroxide solution, continues to stir 12h, filters, and filtrate is precipitated with ethanol/anhydrous diethyl ether (volume ratio is 1/4), and vacuum-drying obtains 25.0g lymphsystem target polysaccharide macromolecular contrast medium, productive rate 70%.
Embodiment 7:
The lymphsystem target polysaccharide macromolecular contrast medium of getting 0.1 mole embodiment 1 is dissolved in the conventional sodium chloride injection, with regulating the pH value to 6.5-8.0, makes magnetic resonance imaging contrast.
Embodiment 8:
The lymphsystem target polysaccharide macromolecular contrast medium of getting 0.1 mole embodiment 2 is dissolved in the conventional glucose injection, with regulating the pH value to 6.5-8.0, makes 0.001 mol magnetic resonance imaging contrast.
Embodiment 9:
The lymphsystem target polysaccharide macromolecular contrast medium of getting 0.3 mole embodiment 3 is dissolved in conventional sodium-chlor-glucose injection, with regulating the pH value to 6.5-8.0, makes 0.01 mol magnetic resonance imaging contrast.
Embodiment 10:
The lymphsystem target polysaccharide macromolecular contrast medium of getting 0.4 mole embodiment 4 is dissolved in the distilled water for injection, with regulating the pH value to 6.5-8.0, makes 0.1 mol magnetic resonance imaging contrast.
Embodiment 11:
The lymphsystem target polysaccharide macromolecular contrast medium of getting 0.5 mole embodiment 5 is dissolved in the conventional glucose injection, with regulating the pH value to 6.5-8.0, makes 1.0 mol magnetic resonance imaging contrasts.
Embodiment 12:
The lymphsystem target polysaccharide macromolecular contrast medium of getting 2.0 moles embodiment 6 is dissolved in the conventional sodium chloride injection, regulates the pH value to 6.5-8.0, makes 5.0 mol magnetic resonance imaging contrasts.
The present invention relates to a class polysaccharide macromolecular paramagnetic metal complex had carried out lymphsystem and blood vessel in the white rabbit body nuclear magnetic resonance experiment.This experiment is magnetic resonance imaging contrast with the polysaccharide macromolecular among the embodiment 3 as the paramagnetic metal complex of carrier.Method and result that it is concrete are as follows:
1.1 big white mouse nuclear magnetic resonance experiment
Animal imaging experiment: use Siemens (SIEMENS) whole body nuclear magnetic resonance imaging instrument: 30cm Helmholtz coil, 50cm aperture, Magnetom Tiro Tim 3.0T magnetic field, scanning sequence and parameter: all scanning sequences are spin echo (spinecho, SE) sequence.Comprise T1WI (TR/TE=539/14ms, secondary acquisition), fat suppression T1WI (T1WI FS, TR/TE=539/14ms, secondary acquisition), PDWI (TR/TE=2234/14ms, secondary acquisition).Based on the transverse axis bit scan, add crown position and sagittal plain scanning in case of necessity.FOV=180mm, matrix are 256*256, bed thickness=3mm, and the interlamellar spacing factor is 0.1.
New Zealand white rabbit intravenous injection vetanarcol 30mg.kg
-1After the anesthesia, again behind the tissue space injection or the auricular vein injection of contrast medium aqueous solution, shank and the popliteal nest lymphoglandula of white rabbit carried out imaging.The result shows, use this class contrast medium and use same dose Gadopentetate Meglumine injection liquid (Gd-DTPA, magnevist, 0.1mmolGd/kg dosage, Bayer Healthcare's Guangzhou Branch) compares, the former obviously strengthens the radiography of lymphsystem, cardiovascular systems etc., and sharpness and contrast gradient improve.
1.2 nuclear magnetic resonance experiment conclusion
From two groups of photos more as can be seen, behind the subcutaneous injection lymphsystem target polysaccharide macromolecular contrast medium (dosage of 0.0041mmoGdl/kg), New Zealand white rabbit De popliteal nest lymphoglandula (thigh inside the knee) and the lymph house steward's that links to each other Yu popliteal nest lymphoglandula picture signal obviously is better than injecting the picture signal of Gd-DTPA (0.1mmol/kg) back gained, and sharpness and contrast gradient also obviously improve.And in blood vessel, have the long residence time (about 2 hours), can be so that the lymphadenography imaging of long period, the Plasma Concentration that in lymphoglandula, keeps relative stability in the long period, radiography is effective, and dosage is low.
The result shows, as Fig. 2-shown in Figure 3, compares with Gd-DTPA, the relaxation rate of lymphsystem target paramagnetic metal complex is significantly improved, and can be absorbed by the lymphsystem selectivity, and lymphoglandula and vasculolymphatic nuclear magnetic resonance are respond well, the contrast gradient height, sharpness is good.And dosage is few, and toxicity is low, and imaging time is long.
In addition, behind auricular vein injection lymphsystem target paramagnetic metal complex, blood vessel to shank carries out imaging, owing to the less molecular contrast agents of its volume obvious increase is arranged as macromolecular contrast medium, so can in blood vessel, keep a metastable concentration within a certain period of time, thereby also be used as blood pond contrast medium.This class polysaccharide macromolecular contrast medium angiographic imaging has reinforced effects preferably, and in blood vessel, have the long residence time (about 2 hours), can be so that the liver contrast imaging of long period, the Plasma Concentration that in blood vessel, keeps relative stability in the long period, radiography is effective, dosage is low, as shown in Figure 4.
Claims (9)
1, polysaccharide macromolecular paramagnetic metal complex, it has following array structure: with polysaccharide macromolecular as carrier, side chain contains the paramagnetic metal complex of ligand compound open chain or many ammonia of cyclic multi-carboxylic acid compounds and paramagnetic metal ion effect formation, paramagnetic metal ion be ordination number be 21 to 29,42,44 or 57 to 71 metallic element+2 or+3 valency ions, described ligand compound has the chemical structural formula of formula 1
Wherein B is COO
-, CH
2OH, NH
2, CH
2OSO
3 -, CH
2OPO
3 -Or OA; C is NHC (=O) CH
3, OH, CH
3, OCH
3, NH
2, OSO
3 -, NHSO
3 -, OPO
3 -Or OA; D is NHC (=O) CH
3, OH, CH
3, OCH
3, NH
2, OSO
3 -, NHSO
3 -, OPO
3 -Or OA; A is the chemical structural formula with formula 2 or formula 3 representatives:
R wherein
1, R
3, Q is COOH, CO, hydrogen atom, Sauerstoffatom, sulphur atom, NH or N (CR
4R
5) group of X representative; X be hydrogen atom, alkyl ,-(CR
4R
5) m-,-(SR
4R
5) m-,-(OR
4R
5) m-,-(NR
4R
5) m-or-(CR
4R
3) the qCOOH group; R
2, R
4And R
5Represent hydrogen atom, alkyl, aryl or have alkyl, the aryl substituent of one or more hydroxyls, alkoxyl group, amido, aryl or aryloxy; M, n are natural number; P is 2,3 or 4, and r is 0 to 10 integer, and q is 1 or 2;
In polysaccharide macromolecular magnetic resonance imaging contrast molecule, the molar content of A accounts for the 1-99% of the original surperficial primary amine groups of polysaccharide macromolecular respectively, and wherein the summation of the molar content of the molar content of A and polysaccharide macromolecular unreacted surface primary amine groups is 100%.
2, by the described polysaccharide macromolecular paramagnetic metal complex of claim 1, it is characterized in that described paramagnetic metal ion be Gd, Mn, Cr, Fe, Co, Ni, La, Tc, Dy or Cu metallic element+2 or+3 valency ions.
3, by the described polysaccharide macromolecular paramagnetic metal complex of claim 1, it is characterized in that described polysaccharide macromolecular molecular weight ranges is 100 to 10
8
4, by the described polysaccharide macromolecular paramagnetic metal complex of claim 1, it is characterized in that A has following structural formula in formula 1 part:
5, by the described polysaccharide macromolecular paramagnetic metal complex of claim 1, it is characterized in that A has following structure in formula 1 part:
6, by the described polysaccharide macromolecular paramagnetic metal complex of claim 1, it is characterized in that A has following structure in formula 1 part:
7, by the described polysaccharide macromolecular paramagnetic metal complex of claim 1, it is characterized in that A has following structure in formula 1 part:
8, the synthetic method of the described polysaccharide macromolecular paramagnetic metal complex of claim 1, it is characterized in that including following steps: the covalent linkage that (1) will contain reactive derivative open chain or many ammonia of cyclic multi-carboxylic acid compounds and polysaccharide macromolecular even forms ligand compound, above-mentioned building-up reactions is carried out in the aqueous solution or organic solvent, and temperature of reaction is-20 ℃ to 120 ℃; (2) will go up the ligand compound that goes on foot formation cooperates with paramagnetic metal ion, paramagnetic metal ion be ordination number be 21 to 29,42,44 or 57 to 71 metallic element+2 or+3 valency ions, form the metal paramagnetic metal complex, described ligand compound cooperates by 1: 1 mol ratio with paramagnetic metal ion, above-mentioned building-up reactions is carried out in the aqueous solution or polar organic solvent, temperature of reaction is 20 ℃ to 120 ℃, and described reactive derivative is monocycle acid anhydrides, dicyclo acid anhydrides, mixed acid anhydride, active ester, acyl chlorides or acylbromide.
9, the any described polysaccharide macromolecular paramagnetic metal complex of claim 1-7 is used to make a kind of to people or other mammiferous lymphoid organs, lymphatic vessel, lymphsystem, the magnetic resonance imaging contrast of cardiovascular systems, it is characterized in that this magnetic resonance imaging contrast is made up of polysaccharide macromolecular paramagnetic metal complex and at least a pharmaceutical carrier or figuration body, polysaccharide macromolecular paramagnetic metal complex weight percentage in the magnetic resonance imaging contrast is 0.1-15%, and described pharmaceutical carrier is a sodium chloride injection, glucose injection, dextrose ﹠ sodium chloride injection or distilled water; Described figuration body is phosphatide, gelatin, starch or syrup, and the concentration of pharmaceutical carrier or figuration body is the 0.001-5.0 mol.
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