CN100431614C - Paramagnetic metal coordination compound magnetic resonance imaging contrast medium with narrow-leaved oleaster polyose modification - Google Patents
Paramagnetic metal coordination compound magnetic resonance imaging contrast medium with narrow-leaved oleaster polyose modification Download PDFInfo
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Abstract
A contrast medium for the magnetic resonance (or X-ray CT) imaging of liver with high selectivity and low poison is prepared from the acid byanhydride of EDTA and DTPA and russianolive gum through reaction and then matching with the 2- or 3- valence ions of paramagnetic metal (Mn or Fe) or La- system RE element to obtain a russianolive gum modified paramagnetic metal match.
Description
Technical field
The present invention relates to magnetic resonance imaging contrast, be specifically related to the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose is modified.
Background technology
(magnetic resonance imaging MRI) is present most advanced medical imaging diagnosis technology in nuclear magnetic resonance.Compare with X-ray CT scan art, but this technology has resolution height, the many random layer bedding faults of imaging parameters and human body do not had advantages such as ionization radiation injury.Proton density N (H) and relaxation behavior that the magnetic resonance imaging signal intensity of tissue depends primarily on this tissue comprise longitudinal relaxation time T
1With T2 T
2, when proton density one timing of particular organization, the length of proton relaxation time is the signal intensity of decision tissue just.
In clinical magnetic resonance imaging,, need use contrast agent above 30% diagnosis in order to improve the contrast of signal between diseased region and normal structure.Magnetic resonance imaging contrast is to be used for shortening imaging time, improves a compounds of image contrast and definition, and itself does not produce signal, but can be by influencing the relaxation time T of proton
1Or T
2Increase or reduce signal intensity, improve the image contrast of normal position and disease sites, thereby show the functional status of intracorporeal organ.Therefore the metal complex that can be used as magnetic resonance imaging contrast contains paramagnetic metal such as gadolinium, manganese and ferrum etc. more, these paramagnetic metal ions all have characteristics such as more unpaired electron, high magnetic moment and long electronics relaxation time, and (chemistry is observed Chem.Rev., 1987,87,901).
At present be applied to clinical magnetic resonance imaging contrast ionic contrast agent such as Gd-DTPA (U.S. Pat 4,647,447), Gd-DOTA (medical magnetic resonance magazine Magn.Reson.Med. have been arranged, 1986,3,808), Mn-DPDP (radiology Radiology, 1992,183,167) and nonionic contrast agent such as Gd-DTPA-BMA (U.S. Pat 4,933,411), Gd-HP-DO3A (future drugs Drugs Future, 1992,17,187) etc.They have good imaging effect to brain and central nervous system etc., renal metabolism has limited its application but its extracellular distribution reaches faster, particularly not ideal enough to the radiography effect of more intravital internal organs such as liver, kidney, can not satisfy the optionally requirement of tissue, organ.Therefore, along with continually developing of magnetic resonance contrast agent, the magnetic resonance imaging contrast of future ideality should have stronger relaxivity, good targeting, stability, hypotoxicity and easy discharge property, and cheap.
The various molecular weight that biomacromolecule refers to as main active in the organism reach up to ten thousand or more organic molecule.Common biomacromolecule comprises protein, nucleic acid, lipid, saccharide.Macromoleization is present one of important research direction of magnetic resonance imaging contrast in the world, and small-molecular weight contrast agent and biomacromolecule are linked can prolong its spin correlation time, raising relaxation efficient; Simultaneously, owing to the characteristic of macromole itself, may produce the selectivity or the targeting of tissue, organ and diseased region.In recent years; saccharide is because its unique character; as strongly hydrophilic and have to some tissue and the specificity of organ etc.; design at the MRI contrast agent; caused people's attention in synthetic; and reported with natural amino sugar and diethylenetriamine pentaacetic acid (Diethylenetriaminepentaacetate; DTPA) connect and obtain linear many ammonia multi-carboxylic acid contrast agent (U.S. Pat 5; 330,743), and contain D-galactosyl (Chinese patent CN1; 166; 987, A) and arabinogalactan (SCI, 2002; 23,1837) etc. contrast agent.
Oleaster gum polyose (Elaeagnus angustifalial polysaccharide, EAPS) be (the Chinese patent CN1 of the polysaccharide with medical value that the dry product from Elaeangnaceae plant Fructus Elaeagni Angustifoliae stem branch glue juice extracts, 386,764), its molecular weight is big, dissolubility good, and in blood the time of staying long, can be used as the carrier of contrast agent.
Summary of the invention
The objective of the invention is: containing D-galactose end group according to oleaster gum polyose can be by the characteristic such as asialoglycoprotein receptor selectivity identification on mammal liver parenchyma surface, with ethylenediaminetetraacetic acid (Ethylenediaminetetraacetic, EDTA) or diethylenetriamine pentaacetic acid (DTPA) be connected on the oleaster gum polyose molecule with the ester bond form, form EDTA or DTPA macromolecular ligand that oleaster gum polyose is modified, then this part is cooperated with paramagnetic metal ion, can obtain good water solubility, relaxation efficient height has the optionally paramagnetic metal complex magnetic resonance imaging contrast of oleaster gum polyose modification to liver.
The paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose is modified, ethylenediaminetetraacetic acid of modifying with oleaster gum polyose (EDTA) or diethylenetriamine pentaacetic acid (DTPA) macromolecular compound part obtain with the bivalence or the trivalent ion coordination of paramagnetic metal ion manganese, ferrum and lanthanide series rare-earth elements respectively.Have following structure:
Wherein m is 0 or 1, is the EDTA macromolecular ligand that oleaster gum polyose is modified when m=0, is the DTPA macromolecular ligand that oleaster gum polyose is modified when m=1.
N=103～187th, the number of the micromolecule part that connects on each oleaster gum polyose molecule.
M is a paramagnetic metal ion: paramagnetic metal manganese or iron ion; Or the bivalence of lanthanide series rare-earth elements or trivalent ion.
The EDTA that contained oleaster gum polyose is modified in the paramagnetic metal complex magnetic resonance imaging contrast that above-mentioned oleaster gum polyose is modified or the molecular weight of DTPA macromolecular ligand are 10 to 300,000, have following structure:
Wherein m is 0 or 1, is the EDTA macromolecular ligand that oleaster gum polyose is modified when m=0, is the DTPA macromolecular ligand that oleaster gum polyose is modified when m=1.
N=103～187th, the number of the micromolecule part that connects on each oleaster gum polyose molecule.
The paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose is modified, in its building-up process, the EDTA or the DTPA bisgallic acid acid anhydride of the EDTA that synthetic described oleaster gum polyose is modified or the intermediate of DTPA macromolecular ligand are by EDTA or DTPA, in 60 ℃, intramolecular dehydration forms in pyridine and acetic anhydride mixed solution.Its structure is as follows:
Wherein m is 0 or 1, is the EDTA anhydride when m=0, is the DTPA anhydride when m=1.
The step and the condition of the preparation method of the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose is modified are as follows:
(1). the natural oleaster gum polyose that a series of molecular weight are more rudimentary part separates purification with the semipermeable membrane dialysis method and obtains molecular weight and divide 100,000 to 300,000 serial oleaster gum polyose.
(2). with ethylenediaminetetraacetic acid (EDTA) or diethylenetriamine pentaacetic acid (DTPA) 64 ± 2 ℃ of stirring reactions 10～24 hours in acetic anhydride and anhydrous pyridine solution, sucking filtration gets pale brown color insoluble matter, wash with acetic anhydride, the washing of reuse absolute ether, in 50 ℃ of vacuum dryings, obtain the as above high little yellow solid EDTA or the DTPA bisgallic acid acid anhydride of reactivity of structure.
(3). EDTA or DTPA bisgallic acid acid anhydride are dissolved in the anhydrous dimethyl sulfoxide or the solution of dimethyl formamide isopolarity than big solvent of oleaster gum polyose, reaction temperature is generally 20 to 80 ℃, after stirring 24h, the ice-water bath cooling slowly adds distilled water, continue to stir 12h, to deionized water dialysis 5～7 days, change water every day 2～3 times, be evaporated to half of original volume, lyophilizing gets the EDTA or the DTPA macromolecular ligand of the oleaster gum polyose modification of aforesaid structural formula.
(4). EDTA that the oleaster gum polyose that step (3) is obtained is modified or DTPA macromolecular ligand respectively with paramagnetic metal ion, as manganese or iron ion; Or the bivalence of lanthanide series rare-earth elements or trivalent ion coordination, can obtain the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose is modified.
For the non-vanishing situation of total electrical charge number behind the formation coordination compound, the cation of available physiological compatibility is Na particularly
+, Ca
2+, Cu
2+, Zn
2+, NH
4 +Or its organic derivative such as N-methyl glucoside amine, aminoacid, its institute of hydramine isoequilibrium are electrically charged.
The paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose among the present invention is modified can be made injection.Such as, but injection mat sodium chloride injection, glucose injection, paramagnetic metal complex or its salt that dextrose ﹠ sodium chloride injection or distilled water or other carrier of upward stipulating at the Pharmacopoeia of the People's Republic of China (nineteen ninety version) are modified oleaster gum polyose of the present invention are mixed with the solution that concentration 0.001 arrives 1.0M, particularly preferably be 0.1 to 0.5M solution, and comprise N-methyl glucoside amine with the sour example hydrochloric acid of physiological compatibility or the alkali of physiology intermiscibility, slow blood amine, organic base or ammonia such as aminoacid, sodium hydroxide, sodium carbonate, inorganic bases such as sodium bicarbonate are regulated between pH value to 6.5～8.0.Usually in preparation, add the salt of the physiological compatibility of EDTA that the oleaster gum polyose of EDTA that the oleaster gum polyose of the salt of physiological compatibility of EDTA that EDTA that 0.1～15% the oleaster gum polyose that is equivalent to paramagnetic metal complex amount that oleaster gum polyose modifies modifies or DTPA macromolecular ligand or oleaster gum polyose modify or DTPA macromolecular ligand or calcium, magnesium, copper, zinc modifies or DTPA macromolecule complex or calcium, magnesium, copper, zinc modifies or DTPA macromolecule complex, to guarantee paramagnetic metal ion such as Gd
3+Coordination fully.Also need add the additive that the sodium, calcium salt etc. of antioxidant such as ascorbic acid or ascorbic acid do not influence the preparation preparation, store and use in addition.Another kind of way EDTA or DTPA macromolecular ligand and its salt that to be paramagnetic metal complex that oleaster gum polyose of the present invention is modified modify with 0.1～15% the oleaster gum polyose that is equivalent to paramagnetic metal complex amount that oleaster gum polyose modifies, or calcium, magnesium, copper, the salt of the EDTA that the oleaster gum polyose of zinc is modified or the physiological compatibility of DTPA macromolecule complex or these coordination compounds, the pH regulator agent, other required composition such as antioxidant is mixed with dried solid preparation, be powder pin or injectable powder, be diluted to desired concn with carriers such as sodium chloride injection or distilled water before using.
Contrast agent of the present invention can use according to a conventional method, and this method is to comprising the paramagnetic metal complex that human body or other mammal oleaster gum polyose are modified with diagnosis object, carrying out magnetic resonance imaging analysis then, the nuclear magnetic resonance figure that is enhanced.The dosage of contrast agent of the present invention can because of the molecular weight of paramagnetic complex with bigger variation is arranged as the tissue of diagnosis object or organ and diagnostic device type different.In general, the injection consumption is the every kg body weight 0.001 to 5.0mmol as the human body of diagnosis main body or other mammalian body, preferably every kg body weight 0.05 to 0.5mmol.
The contrast agent that oleaster gum polyose among the present invention is modified is except that being used for magnetic resonance image-forming diagnose, also EDTA that oleaster gum polyose can be modified or DTPA macromolecular ligand and heavy metal ion form heavy metal complex as lead, bismuth, gold etc., be used for X-ray CT, or form the contrast agent of radiometal complex as radiotherapy medicine or γ scintillography with radioactive metal ion.
The present invention compared with the prior art, the technological achievement that has reached:
1. the relaxation efficient of this type of contrast agent is apparently higher than the clinical micromolecule contrast agent (about 2 times) that generally uses.
2. liver had selectivity preferably: behind intravenous injection this type of contrast agent, can obviously improve liver position image contrast (confirmation of SD rat imaging experiment) a little less than clinical dosage (0.1mmolGd/kg).
3. this type of contrast agent has good water-solubility, is easy to be mixed with the intravenous injection of desired concn solution.
4. this type of contrast agent aqueous solution Heat stability is good is suitable for the pressure sintering sterilization.
5. this polysaccharide side chain contains D-galactose end group, can be discerned by the asialoglycoprotein receptor selectivity on liver parenchyma surface.
6. ester bond can slow hydrolysis discharge Gd-DTPA under physiological condition, makes liver obtain imaging window steady in a long-term.
7. people or other mammiferous liver had good selectivity.
Animal imaging experiment: use Brooker company's magnetic resonance imager (30cm coil, 4.7T magnetic field), adopt T
1Weighting multi-disc-many echo-wave imagings mode, repetition time TR:500ms, echo time TE:15ms, scanning area: 5 * 5cm
2, scan matrix: 128 * 256.Get male Sprague Dawley (SD) rat (body weight 170～200g), with after 10% urethane (1.0mL/100g body weight) anesthesia, axle position, test animal abdominal cavity T
1The weighting picture, this contrast agent aqueous solution of intravenous injection (dosage 0.085mmol/kg) back imaging, every 5min sampling observation once, Continuous Observation 90 min.Imaging results shows, a little less than this type of contrast agent of clinical dosage the reinforced effects that the liver magnetic resonance signal produces obviously is better than Gd-DTPA, and the raising of this contrast has demonstrated this type of contrast agent liver selectivity preferably.
Description of drawings
The time dependent reinforced effects of rat kidney signal behind Fig. 1 injection of contrast medium
The time dependent reinforced effects of rat liver signal behind Fig. 2 injection of contrast medium
Fig. 3 injects 200kDa-(Gd-DTPA)
nRat liver axle position T before and after (1: 1)
1The weighting picture
(1) before the injection; (2) injection back 5min; (3) injection back 45min; (4) injection back 80min
Fig. 4 injects 200kDa-(Gd-DTPA)
nRat kidney axle position T before and after (1: 1)
1The weighting picture
(1) before the injection; (2) injection back 15min; (3) injection back 45min; (4) injection back 80min
The specific embodiment
The preparation of ethylenediaminetetraacetic acid gadolinium (Gd-EDTA) coordination compound that 100,000 molecular weight (100kDa) oleaster gum polyose is modified
(1) preparation of ethylenediaminetetraacetic acid bisgallic acid acid anhydride: with 36.0g ethylenediaminetetraacetic acid (EDTA) 64 ± 2 ℃ of stirring reactions 10 hours in 100mL acetic anhydride and 80mL anhydrous pyridine solution.Sucking filtration with acetic anhydride washing, the washing of reuse absolute ether, in 50 ℃ of vacuum dryings, gets the little yellow solid EDTA anhydride of 31.0g.
The preparation of the ethylenediaminetetraacetic acid that (2) 10 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: 0.60g EDTA anhydride is dissolved in the anhydrous DMSO solution of 80mL of 1.00g 100,000 molecular weight (100kDa) oleaster gum polyose, behind the stirring at room 24h, the ice-water bath cooling, slowly add distilled water, continue to stir 12h, to deionized water dialysis 5 days, change water every day 3 times, be evaporated to half of original volume, lyophilizing, the solid product of the ethylenediaminetetraacetic acid modified of 100,000 molecular weight (100kDa) oleaster gum polyose.
The preparation of the ethylenediaminetetraacetic acid Gd coordination compound that (3) 10 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: the product that obtains in the 1.0g reactions steps (2) is dissolved in the 100mL distilled water, adds GdCl
3Pressed powder 0.20g, the stirring at room reaction got clear solution in 5 hours.To deionized water dialysis 7 days, change water every day 3 times, up to T
1＞3000ms is evaporated to half of original volume, lyophilizing, the ethylenediaminetetraacetic acid Gd coordination compound modified of 100,000 molecular weight (100kDa) oleaster gum polyose.
The preparation of ethylenediaminetetraacetic acid manganese (Mn-EDTA) coordination compound that 100,000 molecular weight (100kDa) oleaster gum polyose is modified
(1) preparation of ethylenediaminetetraacetic acid bisgallic acid acid anhydride: with 36.0g ethylenediaminetetraacetic acid (EDTA) 64 ± 2 ℃ of stirring reactions 10 hours in 100mL acetic anhydride and 80mL anhydrous pyridine solution.Sucking filtration with acetic anhydride washing, the washing of reuse absolute ether, in 50 ℃ of vacuum dryings, gets the little yellow solid EDTA anhydride of 31.0g.
The preparation of the ethylenediaminetetraacetic acid that (2) 10 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: 0.60g EDTA anhydride is dissolved in the anhydrous DMSO solution of 80mL of 1.00g 100,000 molecular weight (100kDa) oleaster gum polyose, behind the stirring at room 24h, the ice-water bath cooling, slowly add distilled water, continue to stir 12h, to deionized water dialysis 5 days, change water every day 3 times, be evaporated to half of original volume, lyophilizing, the solid product of the ethylenediaminetetraacetic acid modified of 100,000 molecular weight (100kDa) oleaster gum polyose.
The preparation of the ethylenediaminetetraacetic acid manganese complex that (3) 10 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: the product that obtains in the 1.0g reactions steps (2) is dissolved in the 100mL distilled water water, adds MnCl
2Pressed powder 0.10g, the stirring at room reaction got clear solution in 7 hours.To deionized water dialysis 6 days, change water every day 2 times, up to T
1＞3000ms is evaporated to half of original volume, lyophilizing, the ethylenediaminetetraacetic acid manganese complex modified of 100,000 molecular weight (100kDa) oleaster gum polyose.
The preparation of DTPA-Gd (Gd-DTPA) coordination compound that 200,000 molecular weight (200kDa) oleaster gum polyose is modified
(1) preparation of diethylenetriamine pentaacetic acid bisgallic acid acid anhydride: with 59.0g DTPA, 70mL acetic anhydride and the about 100mL anhydrous pyridine 250mL round-bottomed flask of packing into, flask mouth band condensing unit, temperature is controlled at 64 ± 2 ℃, reacts 24 hours.Sucking filtration gets pale brown color insoluble matter, with acetic anhydride washing, the washing of reuse absolute ether, in 50 ℃ of vacuum dryings, gets the little yellow solid DTPA anhydride of 46g.
The preparation of the diethylenetriamine pentaacetic acid that (2) 20 ten thousand molecular weight (200kDa) oleaster gum polyoses are modified: 0.70g DTPA anhydride is dissolved in the anhydrous DMSO solution of 100mL of 1.00g 200,000 molecular weight (200kDa) oleaster gum polyose, behind the stirring at room 24h, the ice-water bath cooling, slowly add distilled water, continue to stir 12h. to deionized water dialysis 5 days, change water every day 3 times, be evaporated to half of original volume, lyophilizing, the lamellar product of the diethylenetriamine pentaacetic acid modified of 200,000 molecular weight (200kDa) oleaster gum polyose.
The preparation of the DTPA-Gd coordination compound that (3) 20 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: the product that obtains in the 1.0g reactions steps (2) is dissolved in the 100mL distilled water, adds GdCl
3Pressed powder 0.20g, the stirring at room reaction got clear solution in 5 hours.To deionized water dialysis 7 days, change water every day 3 times, up to T
1＞3000ms is evaporated to half of original volume, and lyophilizing obtains the DTPA-Gd coordination compound that ten thousand molecular weight (200kDa) oleaster gum polyose is modified.
The preparation of diethylenetriamine pentaacetic acid manganese (Mn-DTPA) coordination compound that 200,000 molecular weight (200kDa) oleaster gum polyose is modified
(1) preparation of diethylenetriamine pentaacetic acid bisgallic acid acid anhydride: with 59.0g DTPA, 70mL acetic anhydride and the about 100mL anhydrous pyridine 250mL round-bottomed flask of packing into, flask mouth band condensing unit, temperature is controlled at 64 ± 2 ℃, reacts 24 hours.Sucking filtration gets pale brown color insoluble matter, with acetic anhydride washing, the washing of reuse absolute ether, in 50 ℃ of vacuum dryings, gets the little yellow solid DTPA anhydride of 46g.
The preparation of the diethylenetriamine pentaacetic acid that (2) 20 ten thousand molecular weight (200kDa) oleaster gum polyoses are modified: 0.70g DTPA anhydride is dissolved in the anhydrous DMSO solution of 100mL of 1.00g 200,000 molecular weight (200kDa) oleaster gum polyose, behind the stirring at room 24h, the ice-water bath cooling, slowly add distilled water, continue to stir 12h. to deionized water dialysis 5 days, change water every day 3 times, be evaporated to half of original volume, lyophilizing, the lamellar product of the diethylenetriamine pentaacetic acid modified of 200,000 molecular weight (200kDa) oleaster gum polyose.
The preparation of the diethylenetriamine pentaacetic acid manganese complex that (3) 20 ten thousand molecular weight (200kDa) oleaster gum polyoses are modified: the product that obtains in the 1.0g reactions steps (2) is dissolved in the 100mL distilled water water, adds MnCl
2Pressed powder 0.10g, the stirring at room reaction got clear solution in 7 hours.To deionized water dialysis 7 days, change water every day 2 times, up to T
1＞3000ms is evaporated to half of original volume, lyophilizing, the diethylenetriamine pentaacetic acid manganese complex modified of 200,000 molecular weight (200kDa) oleaster gum polyose.
Embodiment 5
The preparation of ethylenediaminetetraacetic acid dysprosium (Dy-EDTA) coordination compound that 100,000 molecular weight (100kDa) oleaster gum polyose is modified
(1) preparation of ethylenediaminetetraacetic acid bisgallic acid acid anhydride: with 36.0g ethylenediaminetetraacetic acid (EDTA) 64 ± 2 ℃ of stirring reactions 10 hours in 100mL acetic anhydride and 80mL anhydrous pyridine solution.Sucking filtration with acetic anhydride washing, the washing of reuse absolute ether, in 50 ℃ of vacuum dryings, gets the little yellow solid EDTA anhydride of 31.0g.
The preparation of the ethylenediaminetetraacetic acid that (2) 10 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: 0.60g EDTA anhydride is dissolved in the anhydrous DMSO solution of 80mL of 1.00g 100,000 molecular weight (100kDa) oleaster gum polyose, behind the stirring at room 24h, the ice-water bath cooling, slowly add distilled water, continue to stir 12h, to deionized water dialysis 5 days, change water every day 3 times, be evaporated to half of original volume, lyophilizing, the solid product of the ethylenediaminetetraacetic acid modified of 100,000 molecular weight (100kDa) oleaster gum polyose.
The preparation of the ethylenediaminetetraacetic acid dysprosium coordination compound that (3) 10 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: the product that obtains in the 1.0g reactions steps (2) is dissolved in the 100mL distilled water, adds DyCl
3Pressed powder 0.20g, the stirring at room reaction got clear solution in 5 hours.To deionized water dialysis 7 days, change water every day 3 times, up to T
1＞3000ms is evaporated to half of original volume, lyophilizing, the ethylenediaminetetraacetic acid dysprosium coordination compound modified of 100,000 molecular weight (100kDa) oleaster gum polyose.
Embodiment 6
The preparation of ethylenediaminetetraacetic acid ferrum (Fe-EDTA) coordination compound that 100,000 molecular weight (100kDa) oleaster gum polyose is modified
(1) preparation of ethylenediaminetetraacetic acid bisgallic acid acid anhydride: with 36.0g ethylenediaminetetraacetic acid (EDTA) 64 ± 2 ℃ of stirring reactions 10 hours in 100mL acetic anhydride and 80mL anhydrous pyridine solution.Sucking filtration with acetic anhydride washing, the washing of reuse absolute ether, in 50 ℃ of vacuum dryings, gets the little yellow solid EDTA anhydride of 31.0g.
The preparation of the ethylenediaminetetraacetic acid that (2) 10 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: 0.60g EDTA anhydride is dissolved in the anhydrous DMSO solution of 80mL of 1.00g 100,000 molecular weight (100kDa) oleaster gum polyose, behind the stirring at room 24h, the ice-water bath cooling, slowly add distilled water, continue to stir 12h, to deionized water dialysis 5 days, change water every day 3 times, be evaporated to half of original volume, lyophilizing, the solid product of the ethylenediaminetetraacetic acid modified of 100,000 molecular weight (100kDa) oleaster gum polyose.
The preparation of the ethylenediaminetetraacetic acid manganese complex that (3) 10 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: the product that obtains in the 1.0g reactions steps (2) is dissolved in the 100mL distilled water water, adds FeCl
3Pressed powder 0.15g, the stirring at room reaction got clear solution in 7 hours.To deionized water dialysis 6 days, change water every day 2 times, up to T
1＞3000ms is evaporated to half of original volume, lyophilizing, the ethylenediaminetetraacetic acid iron complex modified of 100,000 molecular weight (100kDa) oleaster gum polyose.
Embodiment 7
The preparation of ethylenediaminetetraacetic acid neodymium (Nd-EDTA) coordination compound that 200,000 molecular weight (100kDa) oleaster gum polyose is modified
(1) preparation of ethylenediaminetetraacetic acid bisgallic acid acid anhydride: with 36.0g ethylenediaminetetraacetic acid (EDTA) 64 ± 2 ℃ of stirring reactions 10 hours in 100mL acetic anhydride and 80mL anhydrous pyridine solution.Sucking filtration with acetic anhydride washing, the washing of reuse absolute ether, in 50 ℃ of vacuum dryings, gets the little yellow solid EDTA anhydride of 31.0g.
The preparation of the ethylenediaminetetraacetic acid that (2) 20 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: 0.60g EDTA anhydride is dissolved in the anhydrous DMSO solution of 80mL of 1.00g 100,000 molecular weight (100kDa) oleaster gum polyose, behind the stirring at room 24h, the ice-water bath cooling, slowly add distilled water, continue to stir 12h, to deionized water dialysis 5 days, change water every day 3 times, be evaporated to half of original volume, lyophilizing, the solid product of the ethylenediaminetetraacetic acid modified of 100,000 molecular weight (100kDa) oleaster gum polyose.
The preparation of the ethylenediaminetetraacetic acid neodymium coordination compound that (3) 20 ten thousand molecular weight (100kDa) oleaster gum polyoses are modified: the product that obtains in the 1.0g reactions steps (2) is dissolved in the 100mL distilled water, adds NdCl
3Pressed powder 0.20g, the stirring at room reaction got clear solution in 5 hours.To deionized water dialysis 7 days, change water every day 3 times, up to T
1＞3000ms is evaporated to half of original volume, lyophilizing, the ethylenediaminetetraacetic acid neodymium coordination compound modified of 100,000 molecular weight (100kDa) oleaster gum polyose.
The paramagnetic metal complex magnetic resonance imaging contrast usage that oleaster gum polyose is modified is as follows:
The ethylenediaminetetraacetic acid Gd coordination compound that takes by weighing 100,000 molecular weight (100kDa) the oleaster gum polyose modification that makes among the 0.1134g embodiment 1 is dissolved in the 15mL sodium chloride injection, be mixed with the solution that concentration is 10mmol/L, regulating pH value with slow blood amine is 6.5, and in preparation, add the ethylenediaminetetraacetic acid that 0.001g 100,000 molecular weight (100kDa) oleaster gum polyose is modified, obtain the contrast-medium injection liquid of the ethylenediaminetetraacetic acid Gd coordination compound of 100,000 molecular weight (100kDa) oleaster gum polyose modification.Get the SD rat of male 170～200g body weight, press 1.0mL/100g body weight anesthesia with 10% urethane after, press the above-mentioned contrast agent solution of 0.094mmol/kg body weight dosage intravenous injection after, axle position, test animal abdominal cavity T
1The weighting picture, every 5min sampling observation once, more than the Continuous Observation 90min.Obtain the axle position T of this contrast agent liver and kidney
1The weighting picture.
Embodiment 9
The ethylenediaminetetraacetic acid Gd coordination compound that takes by weighing 200,000 molecular weight (200kDa) the oleaster gum polyose modification that makes among the 0.1258g embodiment 1 is dissolved in the 15mL sodium chloride injection, be mixed with the solution that concentration is 10mmol/L, regulating pH value with slow blood amine is 6.5, and in preparation, add the ethylenediaminetetraacetic acid that 0.001g 200,000 molecular weight (200kDa) oleaster gum polyose is modified, obtain the contrast-medium injection liquid of the ethylenediaminetetraacetic acid Gd coordination compound of 200,000 molecular weight (200kDa) oleaster gum polyose modification.Add sodium ascorbate, obtain the ethylenediaminetetraacetic acid Gd coordination compound contrast agent solid preparation that 200,000 molecular weight (200kDa) oleaster gum polyose is modified, be diluted to 10mmol/L with sodium chloride injection before using with the freeze dryer lyophilizing.Get the SD rat of male 170～200g body weight, press 1.0mL/100g body weight anesthesia with 10% urethane after, press the above-mentioned contrast agent solution of 0.096mmol/kg body weight dosage intravenous injection after, axle position, test animal abdominal cavity T
1The weighting picture, every 5min sampling observation once, more than the Continuous Observation 90min.Obtain the axle position T of this contrast agent kidney and liver
1Weighting picture such as Fig. 3 and 4.
Claims (9)
1. the paramagnetic metal complex magnetic resonance imaging contrast modified of oleaster gum polyose, be the coordination compound that the ethylenediaminetetraacetic acid (EDTA) modified with oleaster gum polyose or diethylenetriamine pentaacetic acid (DTPA) macromolecular ligand obtain with the paramagnetic metal ion coordination respectively, it has following structure:
Wherein m is 0 or 1, is the EDTA macromolecular ligand that oleaster gum polyose is modified when m=0, is the DTPA macromolecular ligand that oleaster gum polyose is modified when m=1;
N=103～187th, the number of the micromolecule part that connects on each oleaster gum polyose molecule;
M is a paramagnetic metal ion: paramagnetic metal manganese or iron ion; Or the bivalence of lanthanide series rare-earth elements or trivalent ion.
2. the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose as claimed in claim 1 is modified is characterized in that, EDTA or DTPA macromolecular ligand that described oleaster gum polyose is modified, and its structure is as follows:
Wherein m is 0 or 1, is the EDTA macromolecular ligand that oleaster gum polyose is modified when m=0, is the DTPA macromolecular ligand that oleaster gum polyose is modified when m=1;
N=103～187th, the number of the micromolecule part that connects on each oleaster gum polyose molecule.
3. the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose as claimed in claim 2 is modified is characterized in that, the EDTA that described oleaster gum polyose is modified or the molecular weight of DTPA macromolecular ligand are 10 to 300,000.
4. the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose as claimed in claim 1 is modified is characterized in that, the EDTA that synthetic described oleaster gum polyose is modified or the intermediate E DTA or the DTPA bisgallic acid acid anhydride structure of DTPA macromolecular ligand are as follows:
Wherein m is 0 or 1, is the EDTA anhydride when m=0, is the DTPA anhydride when m=1.
5. the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose as claimed in claim 1 is modified is characterized in that described paramagnetic metal ion is Mn
2+
6. the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose as claimed in claim 1 is modified is characterized in that described paramagnetic metal ion is Fe
3+
7. the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose as claimed in claim 1 is modified is characterized in that described paramagnetic metal ion is Gd
3+
8. the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose as claimed in claim 1 is modified is characterized in that described paramagnetic metal ion is Dy
3+
9. the paramagnetic metal complex magnetic resonance imaging contrast that oleaster gum polyose as claimed in claim 1 is modified is characterized in that described paramagnetic metal ion is Nd
3+
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| CN101619106B (en) * | 2009-08-17 | 2012-07-04 | 武汉工程大学 | Polysaccharide macromolecular paramagnetic metal complex and synthesis method and application thereof |
| CN105622773B (en) * | 2016-02-22 | 2017-08-22 | 中国科学院新疆理化技术研究所 | A kind of preparation method of oleaster gum polyose |
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| US5330743A (en) * | 1992-11-12 | 1994-07-19 | Magnetic Research, Inc. | Aminosaccharide contrast agents for magnetic resonance images |
| CN1166987A (en) * | 1997-06-18 | 1997-12-10 | 武汉大学 | Magnetic resonance imaging contrast medium of paramagnetism metal compound containing D-galactose group |
| CN1586279A (en) * | 2004-09-10 | 2005-03-02 | 中国科学院新疆理化技术研究所 | Method for preparing Russion olive glue powder |
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| US5330743A (en) * | 1992-11-12 | 1994-07-19 | Magnetic Research, Inc. | Aminosaccharide contrast agents for magnetic resonance images |
| CN1166987A (en) * | 1997-06-18 | 1997-12-10 | 武汉大学 | Magnetic resonance imaging contrast medium of paramagnetism metal compound containing D-galactose group |
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