CN1966088B - Magnetic resonance imaging contrast using arabinogalactan as carrier - Google Patents
Magnetic resonance imaging contrast using arabinogalactan as carrier Download PDFInfo
- Publication number
- CN1966088B CN1966088B CN2006101316399A CN200610131639A CN1966088B CN 1966088 B CN1966088 B CN 1966088B CN 2006101316399 A CN2006101316399 A CN 2006101316399A CN 200610131639 A CN200610131639 A CN 200610131639A CN 1966088 B CN1966088 B CN 1966088B
- Authority
- CN
- China
- Prior art keywords
- arabinogalactan
- magnetic resonance
- modified
- dtpa
- resonance imaging
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Abstract
The invention relates to a magnetic resonance image contrast agent which uses arabinogalactan as carrier, wherein its production comprises that: using ethylenediamine tetra acetic acid, diethylene triamine pentacetic acid N-butanimide active ester, ethylenediamine tetra acetic acid, or the anhydrides of diethylene triamine pentacetic, via one short connecting arm to react with amination arabinogalactan; forming amido bond to connect ethylenediamine tetra acetic acid or diethylene triamine pentacetic acid to the arabinogalactan, to match magnetic metal ion as manganese, iron or lanthanide rare-earth element, to obtain complex. The invention has significant liver selectivity and low cute toxin. And the inventive contrast agent can be used in magnetic resonance diagnosis, X-ray CT or Y-flash imaging diagnosis.
Description
Technical field
The present invention relates to a kind of magnetic resonance imaging contrast, being specifically related to the arabinogalactan is the magnetic resonance imaging contrast with liver target of carrier.
Background technology
(magnetic resonance imaging is the great achievement of another universally acknowledged medical science that occurs after X-ray CT MRI), and medical practice has been produced tremendous influence in nuclear magnetic resonance.In clinical imaging,, need use contrast agent above 35% diagnosis in order to improve the contrast of signal between diseased region and normal structure.Magnetic resonance contrast agent is the diagnostic agent that a class can shorten imaging time, raising image contrast and definition, display organization organ dysfunction state.The contrast agent that is used for the clinical magnetic resonance imaging diagnosis at present is mainly the coordination compound of micromolecule gadolinium or manganese: Gd-DTPA (Magnevist, magnevist), Gd-DOTA (Dotarem, many its spirits), Mn-DPDP (Teslascan, safe happy shadow), Gd-DTPA-BMA (Omniscan, Ou Naiying), Gd-HP-DO3A (Prohance, general network shows to be thought), Gd-BOPTA (MultiHance, Mo Disi) etc., these micromolecule contrast agent have good imaging effect to brain and central nervous system etc., renal metabolism has limited its application but its extracellular distribution reaches faster, particularly to more intravital internal organs such as liver, the radiography effect of kidney is not ideal enough, can not satisfy tissue, organ is requirement optionally.Therefore, developing cheap, hypotoxicity, relaxation usefulness is high and particular organization or organ are had the contrast agent of selectivity or targeting, is the developing direction of present magnetic resonance contrast agent.
In recent years, the main flow of contrast agent research and exploitation is to diethylenetriamine pentaacetic acid (Diethylenetriaminepentaacetic acid is hereinafter to be referred as DTPA) and 1 both at home and abroad, 4,7,10-tetraazacyclododecane ten bicyclo--1,4,7,10-tetraacethyl (1,4,7,10-tetraazacyclododecane-N, N ', N ", N
-tetraacetic acid is hereinafter to be referred as DOTA) carry out chemical modification, make various types of contrast agent, wherein macromoleization is a main developing direction.Small-molecular weight contrast agent Gd-DTPA, Gd-DOTA are introduced high polymer main chain or can form macromolecular contrast agent with the macromolecule covalent coupling of natural polymer, synthetic, by prolonging its spin correlation time, improving relaxation efficient; Introduce the group that a certain histoorgan of human body is had affinity according to the characteristics of macromole itself or in macromole, can also strengthen the selectivity and the targeting of tissue, organ.The biomacromolecule carrier that has been used for magnetic resonance imaging contrast research has antibody, serum albumin, polysaccharide, erythrocyte, hormone, polyamino acid etc.Saccharide distributes very extensive as one of four big class biomacromolecules at occurring in nature.Majority is that the drug effect site of carrier is at cell surface with the polysaccharide, therefore this class medicine to whole cell so that to the interference of whole machine body than directly enter cell membrane, intracytoplasmic medicine is much smaller, in this sense, be that the drug side effect of carrier is littler than other drug with the polysaccharide; And in the different cells of organism, exist the receptor of specific polysaccharide, but specific polysaccharide navigates to position specific in the body by the receptor targeting.This targeting can not only further reduce side effect, and can reduce the using dosage of polysaccharide medicine.Saccharide has caused extensive concern: CMD-Gd-DTPA (bioconjugate chemistry, Bioconjugate Chem., 1997.8 as targeting and carrier molecule in the design of MRI contrast agent, in synthetic in recent years; 605-610) [Gd] DTPA-dextran (bioconjugate chemistry; BioconjugateChem., 2004.11,1361-1369), contain D-galactosyl (Chinese patent CN1; 166; 987, A) and arabinogalactan (SCI, 2002; 23,1837) etc. contrast agent.
Arabinogalactan (Arabinogalactan, AG) neutral polysaccharide of forming by arabinose and galactose, wooden part content in the fallen leaves pinaster is the abundantest, up to 25%, also contain a certain amount of arabinogalactan in other plant such as corn, Rhizoma Solani tuber osi, Radix Angelicae Sinensis, the Radix Raphani etc., at present existing very sophisticated extractive technique.Characteristics such as arabinogalactan has that molecular weight is big, dissolubility good, and the time of staying is long in blood, and there is the asialoglycoprotein receptor AGPr of specificity identification galactose residue in the hepatic parenchymal cells surface of animal, can be used as the carrier of contrast agent.(SCI 2002,23,1837) DTPA directly links to each other with arabinogalactan by ester bond in previous work, cooperates with gadolinium ion then.This contrast agent has higher relaxation efficient and liver target preferably, but easily take place crosslinked in the building-up process, and hydrolysis easily takes place in the ester bond that forms, thereby causes this contrast agent relaxation efficient to reduce, and existence decomposites free gadolinium and then increases toxic risk.
Summary of the invention
The purpose of this invention is to provide the magnetic resonance imaging contrast that a kind of arabinogalactan is a carrier.This magnetic resonance imaging contrast is to be connected by amido link, ethylenediaminetetraacetic acid (Ethylenediaminetetraacetic acid with the arabinogalactan modification, hereinafter to be referred as EDTA) or the DTPA macromolecular ligand respectively with the bivalence or the trivalent ion of paramagnetic metal ion manganese, ferrum or lanthanide series rare-earth elements, the paramagnetic metal complex that obtains by mol ratio coordination in 1: 1; This paramagnetic metal complex has following structure:
Wherein m=0 or m=1 are the EDTA macromolecular ligand that arabinogalactan is modified when m=0; It when m=1 the DTPA macromolecular ligand that arabinogalactan is modified.
N=18～25th, the number of the micromolecule part that connects on each arabinogalactan molecule.
M is the trivalent ion of paramagnetic metal ion manganese, ferrum or lanthanide series rare-earth elements.The trivalent ion of preferred lanthanide series rare-earth elements is: Gd
3+, Dy
3+Or Nd
3+
R is
CH
2 
i, 2≤i≤6, i is an integer.
EDTA or DTPA macromolecular ligand that described arabinogalactan is modified have following structure:
Wherein m=0 or m=1 are the EDTA macromolecular ligand that arabinogalactan is modified when m=0; It when m=1 the DTPA macromolecular ligand that arabinogalactan is modified.
N=18～25th, the number of the micromolecule part that connects on each arabinogalactan molecule.
R is
CH
2 
i, 2≤i≤6, i is an integer.
Containing D-galactose end group according to arabinogalactan can be by the characteristic such as asialoglycoprotein receptor selectivity identification on mammal liver parenchyma surface, EDTA or DTPA are connected via amido link with the amination arabinogalactan by the linking arm of a weak point, form EDTA or DTPA macromolecular ligand that arabinogalactan 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 arabinogalactan modification to liver.
The step and the condition of the preparation method of a kind of magnetic resonance imaging contrast of the present invention are as follows:
A) EDTA or DTPA are dissolved in the mixed solution of acetonitrile and triethylamine, the volume ratio of acetonitrile and triethylamine is 12: 13, be warming up to 55 ℃, after treating that EDTA or DTPA are molten entirely, add N simultaneously, N '-dicyclohexylcarbodiimide (hereinafter to be referred as DCC) and N-hydroxy-succinamide (hereinafter to be referred as HONSu), the mol ratio of EDTA or DTPA and DCC is 1: 1.4, the mol ratio of DCC and HONSu is 1: 1, stirring at room 1.5h, filter the single N-hydroxy-succinamide active ester solution (hereinafter to be referred as EDTA-ONSu solution or DTPA-ONSu solution) of EDTA or DTPA, EDTA-ONSu or DTPA-ONSu structure are as follows:
M=1, the single active ester of DTPA;
M=0, the single active ester of EDTA
B) under 0 ℃ of condition, arabinogalactan is dissolved in the NaOH solution of 6mol/L, add chloroacetic acid then, the mol ratio of monosaccharide is 3.2: 1 in chloroacetic acid and the arabinogalactan, stir 50min, methanol extraction, filtration in 60 ℃, vacuum drying gets carboxymethylated arabinogalactan.It has following structure:
N=26～35th, the number of the micromolecule part that connects on each arabinogalactan molecule.
C) the carboxymethylated arabinogalactan that obtains in the step b) is dissolved in the deionized water; transfer pH=3 with HCl; dropwise add 2-ethyoxyl-1-ethoxy carbonic acyl radical-1; the methanol solution of 2-dihydroquinoline (hereinafter to be referred as EEDQ); stirring state drips ethylenediamine down; the mol ratio of carboxylate radical is 2: 1 in EEDQ and the carboxymethylated arabinogalactan; the mol ratio of carboxylate radical is 10: 1 in ethylenediamine and the carboxymethylated arabinogalactan; stirring at room 4h; methanol extraction; filter, vacuum drying gets the amination arabinogalactan.Its structure is as follows:
N=18～25th, the number of the micromolecule part that connects on each arabinogalactan molecule.
R is
CH
2 
i, 2≤i≤6, i is an integer.
D) the amination arabinogalactan that obtains in the step c) is dissolved in the deionized water, add EDTA-ONSu solution or DTPA-ONSu solution in the step a), mol ratio amino in EDTA-ONSu or DTPA-ONSu and the amination arabinogalactan is 2: 1, transfer pH=10 with NaOH, in stirring at room 24h, acetonitrile is taken out in decompression, adopt the semipermeable membrane dialysis method to separate purification, deionized water dialysis 5～7 days, change water every day 2～3 times, at 55 ℃ of rotary evaporations, lyophilizing gets EDTA or the DTPA macromolecular ligand that arabinogalactan is modified with solution in the osmotic bag.Its structural formula is as follows:
Wherein m is 0 or 1, is the EDTA macromolecular ligand that arabinogalactan is modified when m=0, is the DTPA macromolecular ligand that arabinogalactan is modified when m=1.
N=18～25th, the number of the micromolecule part that connects on each arabinogalactan molecule.
R is
CH
2 i, 2≤i≤6, i is an integer.
E) EDTA that the arabinogalactan that obtains in the step d) is modified or DTPA macromolecular ligand respectively with the bivalence or the trivalent ion coordination of manganese, ferrum or lanthanide series rare-earth elements, can obtain the magnetic resonance imaging contrast that arabinogalactan is a carrier.
For the bivalence that guarantees EDTA that arabinogalactan is modified or DTPA macromolecular ligand and manganese, ferrum or lanthanide series rare-earth elements or trivalent ion by mol ratio coordination in 1: 1, can add bivalence or trivalent ion above manganese, ferrum or the lanthanide series rare-earth elements of proportional quantity 20%, dialysis is removed the bivalence or the trivalent ion of Excessive Manganese, ferrum or lanthanide series rare-earth elements then, obtains the paramagnetic metal complex magnetic resonance imaging contrast that arabinogalactan 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 NH
4 +Organic derivative: N-methyl glucoside amine, aminoacid or hydramine come balance its institute electrically charged.
The paramagnetic metal complex magnetic resonance imaging contrast that arabinogalactan among the present invention is modified can be made injection.Such as, injection can be used sodium chloride injection, glucose injection, the solution that the paramagnetic metal complex that dextrose ﹠ sodium chloride injection or distilled water or other are gone up regulation at the Pharmacopoeia of the People's Republic of China (nineteen ninety version) carrier is modified arabinogalactan of the present invention or its salt are mixed with concentration 0.001-1.0mol/L, particularly preferably be the solution of 0.1-0.5mol/L, 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 arabinogalactan of EDTA that the arabinogalactan of the salt of physiological compatibility of EDTA that EDTA that 0.1～15% the arabinogalactan that is equivalent to paramagnetic metal complex quality that arabinogalactan modifies modifies or DTPA macromolecular ligand or arabinogalactan 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 that paramagnetic metal ion is 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 arabinogalactan of the present invention is modified modify with 0.1～15% the arabinogalactan that is equivalent to paramagnetic metal complex quality that arabinogalactan modifies, or calcium, magnesium, copper, the salt of the EDTA that the arabinogalactan 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 arabinogalactan 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 as the human body of diagnosis main body or every kg body weight 0.001～5.0mmol of other mammalian body, preferably every kg body weight 0.05～0.5mmol.
Beneficial effect of the present invention:
1. the relaxation efficient of this type of contrast agent is about 2 times of micromolecule contrast agent apparently higher than the clinical micromolecule contrast agent that generally uses.
2. this type of contrast agent has good water-solubility, is easy to be mixed with the intravenous injection of desired concn solution.
3. liver had selectivity preferably: behind intravenous injection this type of contrast agent, can obviously improve liver position image contrast (confirmation of Wistar rat imaging experiment) a little less than clinical dosage (0.1mmolGd/kg).
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. this type of contrast agent can keep stable concentration in vivo relatively for a long time, makes liver obtain imaging window steady in a long-term.
7. people or other mammiferous liver had good selectivity.
The animal imaging experiment: use Brooker company magnetic resonance imager, the 30cm coil, T is adopted in 4.7T magnetic field
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.Get the Wistar rat of male body weight 190～210g, press 1.0mL/100g body weight anesthesia with 10% urethane after, axle position, test animal abdominal cavity T
1The weighting picture is pressed imaging after the above-mentioned contrast agent solution of 0.093mmol/kg body weight dosage intravenous injection, every 3min sampling observation once, and more than the Continuous Observation 90min.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 keeps good reinforced effects (as Fig. 2) in the whole experimental stage always.The raising of this contrast has demonstrated the good liver selectivity of this type of contrast agent.
Description of drawings
Fig. 1 injects the time dependent reinforced effects of contrast agent (hereinafter to be referred as Gd-DTPA-CMAGA) back rat kidney signal of the DTPA-Gd coordination compound of arabinogalactan modification
The time dependent reinforced effects of rat liver signal behind Fig. 2 injection of contrast medium Gd-DTPA-CMAGA
Fig. 3 be before the injection of contrast medium Gd-DTPA-CMAGA and 20min after rat axle position kidney T
1The weighting picture
Fig. 4 be before the injection of contrast medium Gd-DTPA-CMAGA and 20min after rat liver axle position T
1The weighting picture
The specific embodiment
Embodiment 1
Arabinogalactan is by the preparation of ethylene diamine-modified DTPA-Gd coordination compound (Gd-DTPA-CMAGA) magnetic resonance imaging contrast
A) 1g DTPA is dissolved in the mixed solution of 4.8ml acetonitrile and 5.4ml triethylamine, is warming up to 55 ℃, treat DTPA complete molten after, add 0.371g DCC and 0.207g HONSu simultaneously, stirring at room 1.5h, filter DTPA-ONSu solution.
B) under 0 ℃ of condition, the 6g arabinogalactan is dissolved in the NaOH solution of 50ml 6mol/L, add the 12.3g chloroacetic acid then, in 60 ℃ of stirring 50min, methanol extraction filters, and vacuum drying gets carboxymethylated arabinogalactan.
C) the carboxymethylated arabinogalactan of 6g is dissolved in the deionized water, transfers pH=3, dropwise add the methanol solution of 9.3g EEDQ with 1mol/LHCl, be added dropwise to 12.5ml ethylenediamine, stirring at room 4h, methanol extraction under the stirring state, washing, vacuum drying gets the amination arabinogalactan.
D) the amination arabinogalactan among the 1g c is dissolved in the 25ml deionized water, add the DTPA-ONSu solution among the 10ml step a, transfer pH=10 with 6mol/L NaOH, in stirring at room 24h, acetonitrile is taken out in decompression, dialysed 5 days, with solution in the osmotic bag at 55 ℃ of rotary evaporations to small size, lyophilizing gets the DTPA macromolecular ligand (hereinafter to be referred as DTPA-CMAGA) that arabinogalactan is modified.
E) DTPA-CMAGA among the 0.5g d is dissolved in the 10ml deionized water, adds 3ml0.2mol/L GdCl
3Solution (surpassing proportional quantity 20%) is 5.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets the Gd-DTPA-CMAGA magnetic resonance imaging contrast.
Embodiment 2
Arabinogalactan is by the preparation of the magnetic resonance imaging contrast of ethylene diamine-modified diethylenetriamine pentaacetic acid manganese complex
A) with step a) in the example 1.
B) with step b) in the example 1.
C) with step c) in the example 1.
D) with step d) in the example 1.
E) the DTPA macromolecular ligand that arabinogalactan among the 0.5g d is modified is dissolved in the 10ml deionized water, adds 3ml 0.2mol/L MnCl
2Solution (surpassing proportional quantity 20%) is 5.7 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets arabinogalactan by ethylene diamine-modified diethylenetriamine pentaacetic acid manganese complex magnetic resonance imaging contrast.
Embodiment 3
Arabinogalactan is by the preparation of the magnetic resonance imaging contrast of ethylene diamine-modified ethylenediaminetetraacetic acid Gd coordination compound
A) 0.743g EDTA is dissolved in the mixed solution of 4.8ml acetonitrile and 5.4ml triethylamine, is warming up to 55 ℃, treat EDTA complete molten after, add 0.371g DCC and 0.207gHONSu simultaneously, stirring at room 1.5h, filter EDTA-ONSu solution.
B) with step b) in the example 1.
C) with step c) in the example 1.
D) the amination arabinogalactan among the 1g c is dissolved in the 25ml deionized water, add the EDTA-ONSu solution among the 10ml step a, transfer pH=10 with 6mol/L NaOH, in stirring at room 24h, acetonitrile is taken out in decompression, dialysed 5 days, with solution in the osmotic bag at 55 ℃ of rotary evaporations to small size, lyophilizing gets the EDTA macromolecular ligand that arabinogalactan is modified..
E) the EDTA macromolecular ligand that arabinogalactan among the 0.5g d is modified is dissolved in the 10ml deionized water, adds 3ml 0.2mol/L GdCl
3Solution (surpassing proportional quantity 20%) is 5.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets arabinogalactan by ethylene diamine-modified ethylenediaminetetraacetic acid Gd coordination compound magnetic resonance imaging contrast.
Embodiment 4
Arabinogalactan is by the preparation of the magnetic resonance imaging contrast of ethylene diamine-modified ethylenediaminetetraacetic acid manganese complex
A) with step a) in the example 3.
B) with step b) in the example 1.
C) with step c) in the example 1.
D) with step d) in the example 3.
E) the EDTA macromolecular ligand that arabinogalactan among the 0.5g d is modified is dissolved in the 10ml deionized water, adds 3ml 0.2mol/L MnCl
2Solution (surpassing proportional quantity 20%) is 5.7 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets arabinogalactan by ethylene diamine-modified ethylenediaminetetraacetic acid manganese complex.
Embodiment 5
Arabinogalactan is by the preparation of the DTPA-Gd coordination compound of hexamethylene diamine modification
A) with step a) in the example 1.
B) with step b) in the example 1.
C) the carboxymethylated arabinogalactan of 6g is dissolved in the deionized water, transfers pH=3, dropwise add the methanol solution of 9.3g EEDQ with 1mol/LHCl, be added dropwise to 15ml hexamethylene diamine, stirring at room 4h, methanol extraction under the stirring state, methanol wash, vacuum drying get the amination arabinogalactan.
D) the amination arabinogalactan among the 1g c is dissolved in the 25ml deionized water, add the DTPA-ONSu solution among the 10ml step a, transfer pH=10 with 6mol/L NaOH, in stirring at room 24h, acetonitrile is taken out in decompression, dialysed 5 days, with solution in the osmotic bag at 55 ℃ of rotary evaporations to small size, lyophilizing gets the DTPA macromolecular ligand that arabinogalactan is modified.
E) the DTPA macromolecular ligand that arabinogalactan among the 0.5g d is modified is dissolved in the 10ml deionized water, adds 3ml 0.2mol/L GdCl
3Solution (surpassing proportional quantity 20%) is 5.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets the DTPA-Gd coordination compound magnetic resonance imaging contrast that arabinogalactan is modified by hexamethylene diamine.
Embodiment 6
Arabinogalactan is by the preparation of the magnetic resonance imaging contrast of the diethylenetriamine pentaacetic acid manganese complex of hexamethylene diamine modification
A) with step a) in the example 1.
B) with step b) in the example 1.
C) with step c) in the example 5.
D) with step d) in the example 5.
E) the DTPA macromolecular ligand that arabinogalactan among the 0.5g d is modified is dissolved in the 10ml deionized water, adds 3ml 0.2mol/L MnCl
2Solution (surpassing proportional quantity 20%) is 5.7 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets the diethylenetriamine pentaacetic acid manganese complex magnetic resonance imaging contrast that arabinogalactan is modified by hexamethylene diamine.
Embodiment 7
Arabinogalactan is by the preparation of the magnetic resonance imaging contrast of the ethylenediaminetetraacetic acid Gd coordination compound of hexamethylene diamine modification
A) with step a) in the example 3.
B) with step b) in the example 1.
C) with step c) in the example 5.
D) the amination arabinogalactan among the 1g c is dissolved in the 25ml deionized water, add the EDTA-ONSu solution among the 10ml step a, transfer pH=10 with 6mol/L NaOH, in stirring at room 24h, acetonitrile is taken out in decompression, dialysed 5 days, with solution in the osmotic bag at 55 ℃ of rotary evaporations to small size, lyophilizing gets the EDTA macromolecular ligand that arabinogalactan is modified.
E) the EDTA macromolecular ligand that arabinogalactan among the 0.5g d is modified is dissolved in the 10ml deionized water, adds 3ml 0.2mol/L GdCl
3Solution (surpassing proportional quantity 20%) is 5.5 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets the ethylenediaminetetraacetic acid Gd coordination compound that arabinogalactan is modified by hexamethylene diamine.
Embodiment 8
Arabinogalactan is by the preparation of the magnetic resonance imaging contrast of the ethylenediaminetetraacetic acid manganese complex of hexamethylene diamine modification
A) with step a) in the example 3.
B) with step b) in the example 1.
C) with step c) in the example 5.
D) with step d) in the example 7.
E) the EDTA macromolecular ligand that arabinogalactan among the 0.5g d is modified is dissolved in the 10ml deionized water, adds 3ml 0.2mol/L MnCl
2Solution (surpassing proportional quantity 20%) is 5.7 with 1mol/L NaOH adjust pH, in stirred overnight at room temperature, and dialysis, the outer aqueous solution of exchange bag filter is until its longitudinal relaxation time T
1Greater than 3000ms, lyophilizing gets the ethylenediaminetetraacetic acid manganese complex magnetic resonance imaging contrast that arabinogalactan is modified by hexamethylene diamine.
The paramagnetic metal complex magnetic resonance imaging contrast usage that arabinogalactan is modified is as follows:
Embodiment 9
The Gd-DTPA-CMAGA that takes by weighing among the 0.2946g 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 adds 0.001g DTPA-CMAGA in preparation, obtains the injection of contrast agent Gd-DTPA-CMAGA.Get the Wistar rat of male 190～210g body weight, press 1.0mL/100g body weight anesthesia with 10% urethane after, press the above-mentioned contrast agent solution of 0.093mmol/kg body weight dosage intravenous injection after, axle position, test animal abdominal cavity T
1The weighting picture, every 3min 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 (2)
1. magnetic resonance imaging contrast that arabinogalactan is a carrier, it is characterized in that: this magnetic resonance imaging contrast is to be connected by amido link, ethylenediaminetetraacetic acid of modifying with arabinogalactan or diethylenetriamine pentaacetic acid macromolecular ligand respectively with the bivalence or the trivalent ion of paramagnetic metal ion manganese, ferrum or lanthanide series rare-earth elements, the paramagnetic metal complex that obtains by mol ratio coordination in 1: 1;
This paramagnetic metal complex has following structure:
Wherein m=0 or m=1 are the ethylenediaminetetraacetic acid macromolecular ligand that arabinogalactan is modified when m=0; It when m=1 the diethylenetriamine pentaacetic acid macromolecular ligand that arabinogalactan is modified;
N=18～25th, the number of the micromolecule part that connects on each arabinogalactan molecule;
M is the bivalence or the trivalent ion of paramagnetic metal ion manganese, ferrum or lanthanide series rare-earth elements,
R is
2≤i≤6, i is an integer;
Ethylenediaminetetraacetic acid or diethylenetriamine pentaacetic acid macromolecular ligand that described arabinogalactan is modified have following structure:
Wherein m=0 or m=1 are the ethylenediaminetetraacetic acid macromolecular ligand that arabinogalactan is modified when m=0; It when m=1 the diethylenetriamine pentaacetic acid macromolecular ligand that arabinogalactan is modified;
N=18～25th, the number of the micromolecule part that connects on each arabinogalactan molecule;
R is
2≤i≤6, i is an integer.
2. a kind of arabinogalactan as claimed in claim 1 is the magnetic resonance imaging contrast of carrier, it is characterized in that, described M is the trivalent ion of lanthanide series rare-earth elements, and it is: Gd
3+, Dy
3+Or Nd
3+
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006101316399A CN1966088B (en) | 2006-11-16 | 2006-11-16 | Magnetic resonance imaging contrast using arabinogalactan as carrier |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006101316399A CN1966088B (en) | 2006-11-16 | 2006-11-16 | Magnetic resonance imaging contrast using arabinogalactan as carrier |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1966088A CN1966088A (en) | 2007-05-23 |
| CN1966088B true CN1966088B (en) | 2010-09-29 |
Family
ID=38075181
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006101316399A Expired - Fee Related CN1966088B (en) | 2006-11-16 | 2006-11-16 | Magnetic resonance imaging contrast using arabinogalactan as carrier |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1966088B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105343900A (en) * | 2015-09-16 | 2016-02-24 | 中国海洋大学 | Lymph targeted nuclear magnetic resonance imaging contrast agent with brown algal polysaccharide serving as carrier and preparation method and application of lymph targeted nuclear magnetic resonance imaging contrast agent with brown algal polysaccharide serving as carrier |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8999157B2 (en) * | 2007-07-09 | 2015-04-07 | Ge Healthcare Bio-Sciences Ab | Method for preparation of a biomolecule adsorbent |
| CN101642579B (en) * | 2009-08-14 | 2013-10-23 | 江苏大学 | Chitosan modified paramagnetic metal ion magnetic resonance imaging contrast agent preparation method |
| US9944722B2 (en) | 2010-06-01 | 2018-04-17 | Ge Healthcare Bioprocess R&D Ab | Chelator and use thereof |
| CN102336838B (en) * | 2011-06-27 | 2013-03-20 | 中国科学院长春应用化学研究所 | Paramagnetic metal complex and synthetic method and application thereof |
| CN106474473A (en) * | 2016-10-12 | 2017-03-08 | 湖北工业大学 | A kind of Fe modified based on gadolinium3O4The preparation of the photo-thermal diagnosis agent of@PDA nano material |
| CN107149685A (en) * | 2017-04-17 | 2017-09-12 | 南开大学 | A kind of water-soluble Mn2+The preparation method of the silicon nano of functionalization |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5141739A (en) * | 1986-07-03 | 1992-08-25 | Advanced Magnetics, Inc. | Delivery of x-ray contrast agents using receptor mediated endocytosis |
| 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 |
-
2006
- 2006-11-16 CN CN2006101316399A patent/CN1966088B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5141739A (en) * | 1986-07-03 | 1992-08-25 | Advanced Magnetics, Inc. | Delivery of x-ray contrast agents using receptor mediated endocytosis |
| 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 |
Non-Patent Citations (8)
| Title |
|---|
| 俞开潮，等.用于磁共振成像对比增强的造影剂研究进展.波谱学杂志21 4.2004,21(4),第505-525页. |
| 俞开潮等.用于磁共振成像对比增强的造影剂研究进展.波谱学杂志21 4.2004,21(4),第505-525页. * |
| 傅雁军，等.肝靶向性磁共振成像造影剂-含D半乳糖基的DTPA双酰胺钆配合物的研究.高等学校化学学报18 7.1997,18(7),第1072-1079页. |
| 傅雁军等.肝靶向性磁共振成像造影剂-含D半乳糖基的DTPA双酰胺钆配合物的研究.高等学校化学学报18 7.1997,18(7),第1072-1079页. * |
| 孙国英, 等.以阿拉伯半乳聚糖为载体的磁共振成像造影剂的研究.高等学校化学学报23 10.2002,23(10),第1837页第23-24行，第1838页第31行. |
| 孙国英等.以阿拉伯半乳聚糖为载体的磁共振成像造影剂的研究.高等学校化学学报23 10.2002,23(10),第1837页第23-24行,第1838页第31行. * |
| 林红霞，陈骐.磁共振成像造影剂的研究进展.沈阳药科大学学报19 2.2002,19(2),第138-142页. |
| 林红霞,陈骐.磁共振成像造影剂的研究进展.沈阳药科大学学报19 2.2002,19(2),第138-142页. * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105343900A (en) * | 2015-09-16 | 2016-02-24 | 中国海洋大学 | Lymph targeted nuclear magnetic resonance imaging contrast agent with brown algal polysaccharide serving as carrier and preparation method and application of lymph targeted nuclear magnetic resonance imaging contrast agent with brown algal polysaccharide serving as carrier |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1966088A (en) | 2007-05-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1966088B (en) | Magnetic resonance imaging contrast using arabinogalactan as carrier | |
| US5801228A (en) | Polymeric contrast agents for medical imaging | |
| JP2894879B2 (en) | Diagnostic contrast agent | |
| EP0430863B1 (en) | Complexe builders bonded to sterwise prepared polymers, their complexes and conjugates, process for their preparation and pharmaceutical agents containing the same | |
| CN101569751B (en) | Tumor-targeted nonionic dendritic macromolecule magnetic resonance imaging contrast agent | |
| NZ227750A (en) | Paramagnetic chelated compounds useful as contrast agents for diagnosis, detoxification, therapy or radiotherapy; process for preparation | |
| CN102336838B (en) | Paramagnetic metal complex and synthetic method and application thereof | |
| CN102803270B (en) | Gadolinium complex, method for preparing same, and MRI contrast agent comprising same | |
| DE3701665A1 (en) | POLYMER COMPLEXES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THEM | |
| CN1325286A (en) | Manganese compositions and methods for MRI | |
| WO2009157561A1 (en) | Polymer/metal complex composite having mri contrast ability and mri contrasting and/or antitumor composition using the same | |
| CN104069515B (en) | Paramagnetic metal complex modified by aspartic acid-leucine copolymer as well as preparation and application of paramagnetic metal complex | |
| KR100343313B1 (en) | Diagnostic imaging agent | |
| CN100431614C (en) | Paramagnetic metal coordination compound magnetic resonance imaging contrast medium with narrow-leaved oleaster polyose modification | |
| CN102727911B (en) | Diamino polyethylene glycol modified paramagnetic metal complex magnetic resonance imaging contrast agent | |
| US20180272010A1 (en) | Lymph targeting nuclear magnetic contrast agent using brown algae polysaccharide as carrier and preparation method and use thereof | |
| CN101002950B (en) | Magnetic resonace imaging contrast medium with glycyrrhizic acid as carrier | |
| CN104083778B (en) | Paramagnetic metal complex that aspartic acid-phenylalanine copolymer is modified and its preparation method and application | |
| NZ236267A (en) | 10-(2'-hydroxy-3'-polyoxaalkyl)-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane | |
| CN1166987A (en) | Magnetic resonance imaging contrast medium of paramagnetism metal compound containing D-galactose group | |
| CN109602920B (en) | Dendritic molecular image probe and preparation method thereof | |
| CN102961763B (en) | Paramagnetism metal complex magnetic resonance imaging contrast agent containing asparaginic acid-glucan and preparation method of contrast agent | |
| JPH0525059A (en) | Nuclear magnetic resonance contrast medium | |
| CN102188722A (en) | Ferrous iron-containing magnetic resonance imaging contrast agent | |
| CN105343902A (en) | Paramagnetic metal complex using aspartic acid-valine copolymer as carrier, preparation method of paramagnetic metal complex and magnetic resonance imaging contrast agent |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: CHANGZHOU INSTITUTE OF ENERGY STORAGE MATERIALS + Free format text: FORMER OWNER: CHANGCHUN INST. OF APPLIED CHEMISTRY, CHINESE ACADEMY OF SCIENCES Effective date: 20130916 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 130022 CHANGCHUN, JILIN PROVINCE TO: 213000 CHANGZHOU, JIANGSU PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20130916 Address after: Changzhou City, Jiangsu province Hehai road 213000 No. 9 Patentee after: Changzhou Institute of Energy Storage Materials & Devices Address before: 130022 Changchun people's street, Jilin, No. 5625 Patentee before: Changchun Institue of Applied Chemistry, Chinese Academy of Sciences |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100929 Termination date: 20181116 |