CN101845112B - Preparation method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles - Google Patents
Preparation method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles Download PDFInfo
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Abstract
The present invention relates to a nuclear magnetic resonance imaging contrast agent, in particular to a method of high-flexibility nuclear magnetic resonance imaging contrast agents based on high molecular nanometer particles prepared through fine emulsion polymenrization. The nuclear magnetic resonance imaging contrast agents are prepared from the composition of 1, 4, 7, 10-tetrazo heterocycle dodecane with long-chain alkane and gadolinium (Gd-DOTA for short) or the composition of diethylenetriamine pentaacetic acid and gadolinium (Gd-DTPA for short) for carrying out fine emulsion polymenrization preparation with high molecular monomers. The Gd-DOTA derivatives (Gd-DOTA derivatives for short) with the long-chain alkane and the Gd-DTPA derivatives (Gd- DTPA derivatives for short) with the long-chain alkane respectively have the structures as the first formula and the second formula, wherein the value of n is between 8 and 24.
Description
Technical field
The present invention relates to NMR contrast agent, be specifically related to a kind of method based on the high sensitivity NMR contrast agent of high molecular nanometer particles by mini-emulsion polymerization preparation.
Background technology
NMR (Nuclear Magnetic Resonance)-imaging (MRI) technology has been subjected to unprecedented attention and application in the modern medical diagnosis field, it can avoid offering the high-quality three-dimensional soft-tissue imaging picture of people under the condition of ionizing radiation, is one of modern medicine field major technique of carrying out state of an illness diagnosis.The resulting signal intensity of MRI depends primarily on the proton density of check point and the relaxation rate of water proton, and the proton density and the difference in relaxation time are that the MRI technology can be distinguished human body different tissues and same lesion tissue whether main foundation between the pathological tissues in the human body between the different tissues, in normal structure and this tissue.But, therefore have clinically to surpass 35% MRI and need adopt the method for injecting NMR contrast agent to improve image quality because that the relaxation time of normal structure and pathological tissues exists is certain overlapping.
Being applied to clinical paramagnetic metal complex contrast agent at present mainly contains: Gd-DOTA (Dotarem, many its spirits), Gd-HP-DO3A (ProHance, the apparent think of of general network), Gd-BT-DO3A (Gadovist), Gd-DTPA (Magnevist, magnevist), Gd-DTPA-BMA (Omniscan, Ou Naiying), Gd-DTPA-BMEA (Mallinckrodt), Gd-BOPTA (MultihHance, Mo Disi), Gd-EOB-DTPA (Primovist) and MS-325 (Vasovist) etc.Though that these small molecular core magnetic resonance imaging contrasts possess is stable, low toxicity and good imaging effect, but because relaxation rate is lower, need the more contrast agent of injection at every turn, this has just increased some potential potential safety hazards, and these contrast agent molecules are very fast at the drainage rate of human body, be penetrated into Cytoplasm from blood vessel easily, be unfavorable for blood vessel imaging.Though there are some researches show that micromolecule contrast agent and dendrimer are built binding energy by some chemistry improves its relaxation rate greatly, and prolong its circulation time (J Biol Inorg Chem (2007) 12:406-420) in blood, dendrimer synthesizes and the restriction of purification difficult but its application is subjected to.Also discover, there be (J Biol Inorg Chem (2002) 7:757-769) in the micromolecule contrast agent that has long chain alkane with the micelle state in the aqueous solution of higher concentration, the contrast agent of this moment also has higher relaxation rate, but, because micelle can not stable existence under the lower situation of concentration, this directly causes it not used clinical.Therefore, prepare and a kind ofly have the time of staying of suitable length, and the NMR contrast agent with higher relaxation rate and stability just seems very necessary at human body.
Summary of the invention
The object of the invention is to utilize the mechanism of mini-emulsion polymerization to prepare a kind of area load the high molecular nanometer sphere that contains Gd coordination compound, advantages such as this high molecular nanometer sphere can be used as the contrast agent of NMR (Nuclear Magnetic Resonance)-imaging, and it has, and preparation is simple, the relaxation rate is higher, the time of staying is controlled in stable performance, molecular weight and the body.
The coordination compound that DOTA and DTPA and gadolinium form has higher thermodynamics and kinetics stability, and is therefore many clinically with they parts as gadolinium ion.DOTA and DTPA and Gd-DOTA and Gd-DTPA have good water-solubility, and when drawing a long alkane chain on nitrogen-atoms in DOTA or DTPA, whole molecule just has parents' character of hydrophilic and oleophilic, therefore can use as surfactant.When these surfactants carry out mini-emulsion polymerization with some oiliness high polymer monomers, rely on long alkane chain and high molecular hydrophobic-hydrophobic interaction makes it load on the high molecular nanometer sphere surface.Because high molecular nanometer sphere has very big molecular weight, so can reduce the speed of rotation of whole spheroid, has improved the spin correlation time τ of each molecule
RThereby, improved its relaxation rate.In addition, can regulate its drainage rate in human body by controlling high molecular molecular weight.In order to improve the stability of emulsion after the polymerization, the present invention has used mixed surfactant, be about to Gd-DOTA or the derivant of Gd-DTPA and the commercialization surfactant that some have biocompatibility and use jointly, experimental results show that the emulsion of preparing like this is more stable.
A kind of preparation method of the high sensitivity NMR contrast agent based on high molecular nanometer particles, be by having 1 of long chain alkane, 4,7, the coordination compound (being called for short Gd-DTPA) and the high polymer monomer of the coordination compound of 10-tetraazacyclododecanand and gadolinium (being called for short Gd-DOTA) or diethylenetriamine pentaacetic acid and gadolinium carry out the mini-emulsion polymerization preparation; Described Gd-DOTA derivant that has a long chain alkane (being called for short the Gd-DOTA derivant) and the Gd-DTPA derivant (abbreviation Gd-DTPA derivant) that has a long chain alkane have the structure of formula 1 and formula 2 respectively,
Wherein the value of n is 8-24.
Another scheme, the preparation method of contrast agent of the present invention are to carry out mini-emulsion polymerization with high polymer monomer earlier by DOTA that has long alkane chain or DTPA derivant to prepare with the gadolinium coordination again.Described DOTA derivant that has a long chain alkane (being called for short the DOTA derivant) and the DTPA derivant (abbreviation DTPA derivant) that has a long chain alkane have the structure of formula 3 and formula 4 respectively:
Formula 3 formulas 4
Wherein the value of n is 8-24.
The used high polymer monomer of described polymerization is one or more in styrene, divinylbenzene, methyl methacrylate, ethyl methacrylate, metering system tert-butyl acrylate, acrylic acid methyl ester., ethyl acrylate, butyl acrylate, tert-butyl acrylate, the acrylamide.
The surfactant that above-mentioned mini-emulsion polymerization uses is Gd-DOTA derivant or Gd-DTPA derivant and other surfactant mixtures, perhaps is DOTA derivant or DTPA derivant and other surfactant mixtures.
Described other surfactant is in polysorbas20, polysorbate40, polysorbate60, Tween 80, span 20, span 40, sorbester p18, sorbester p17, polyvinyl alcohol, arabic gum, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (the being called for short PEG-PPG-PEG) triblock copolymer any one or a few.
Whole process of preparation has two kinds of schemes, and one comprises following steps:
(1), preparation (J.Org.Chem.1999,64, the 2683-2689 of Gd-DOTA and Gd-DTPA derivant; Synlett, 2006,17,2815-2817).
((2), mini-emulsion polymerization: other surfactant that takes by weighing 10 milligrams-2000 milligrams Gd-DOTA or Gd-DTPA derivant and 5 milligrams-2000 milligrams, the deionized water that adds 5 milliliters-500 milliliters, be stirred to dissolving fully, the mixture that adds 100 milligrams of-5000 milligrams of high polymer monomers, hexadecanol and azodiisobutyronitriles then, stirred 10～60 minutes, ultrasonic again 5～20 minutes, logical nitrogen is after 10～30 minutes, be warming up to 60～90 ℃ rapidly, reacted 5-10 hour, cold filtration, macromolecule emulsion that must be stable.
(3), dialysis removes micromolecule: the emulsion that polymerization is obtained is packed in the aqueous bag filter (the highest see through molecular weight be about 3000), dialyses under deionized water for stirring 3～6 days, and last gained emulsion promptly can be used to test.
(4), the relaxation rate is measured: relaxation rate and imaging effect are measured with Siemens's Trio 3T MR imaging apparatus, earlier the contrast agent emulsion is diluted to the solution of some variable concentrations, be contained in 1.5 milliliters the centrifuge tube, on the 3T magnetic resonance imager, adopt the inversion recovery method to carry out imaging operation, can calculate the spin spinrelaxation (T of each concentration solution by the brightness of image
1), pass through formula again:
c.r
1+1/T
W＝1/T
1
Calculate the T under each concentration
1(wherein c is a gadolinium concentrations, T
WSpin spinrelaxation for hydrone), obtain the relaxation rate r of contrast agent at last by computer fitting
1Wherein the gadolinium concentrations utilization is composed direct-reading plasma emission spectroscopy (ICP-AES) entirely and is measured.
It two may further comprise the steps:
(1), preparation (J.Org.Chem.1999,64, the 2683-2689 of DOTA and DTPA derivant; Synlett, 2006,17,2815-2817).
(2), mini-emulsion polymerization: DOTA or DTPA derivant and 5 milligrams of-2000 milligrams of other surfactants of taking by weighing 10 milligrams-2000 milligrams, the deionized water that adds 5 milliliters-500 milliliters, be stirred to dissolving fully, the mixture that adds 100 milligrams of-5000 milligrams of high polymer monomers, hexadecanol and azodiisobutyronitriles then, stirred 10～40 minutes, ultrasonic again 5～20 minutes, logical nitrogen is after 10～30 minutes, be warming up to 60～90 ℃ rapidly, reacted 5～10 hours, cold filtration, macromolecule emulsion that must be stable.
(3), carry out coordination with gadolinium: get emulsion after a certain amount of polymerization, PH is transferred to 5～9 with hydrochloric acid and sodium hydroxide, slowly drip the Gadolinium trichloride aqueous solution then, drip the back and reacted 24 hours down for 20～50 ℃.
(4), micromolecule is removed in dialysis: the emulsion after the coordination is packed in the aqueous bag filter (the highest see through molecular weight be about 3000), under deionized water for stirring, dialysed 3～6 days, remove unnecessary gadolinium ion and other small molecular weight material, last gained emulsion promptly can be used for test.
(5), the relaxation rate is measured: relaxation rate and imaging effect are measured with Siemens's Trio 3T MR imaging apparatus, earlier the contrast agent emulsion is diluted to the solution of some variable concentrations, be contained in 1.5 milliliters the centrifuge tube, on the 3T magnetic resonance imager, adopt the inversion recovery method to carry out imaging operation, can calculate the spin spinrelaxation (T of each concentration solution by the brightness of image
1), pass through formula again:
c.r
1+1/T
W＝1/T
1
Calculate the T under each concentration
1(wherein c is a gadolinium concentrations, T
WSpin spinrelaxation for hydrone), obtain the relaxation rate r of contrast agent at last by computer fitting
1Wherein the gadolinium concentrations utilization is composed direct-reading plasma emission spectroscopy (ICP-AES) entirely and is measured.
The macromolecule that obtains by the tem observation mini-emulsion polymerization be the diameter of contrast agent of carrier between 20～50 nanometers, present uniformity and stability preferably.Nuclear magnetic resonance experiment records Gd-DOTA series is that the contrast agent relaxation rate of carrier is 11.1mMS with the macromolecule
-1, than clinical practice value (4.2mMS
-1) improved and will use up twice; Gd-DTPA series be that the contrast agent relaxation rate of carrier is 6.6mMS with the macromolecule
-1, than clinical practice value (4.3mMS
-1) improve above 50%.
Description of drawings
Fig. 1 is the TEM figure of the macromolecule NMR contrast agent that obtains according to embodiment 3 mini-emulsion polymerizations.
Fig. 2 is the SEM figure of the macromolecule NMR contrast agent that obtains according to embodiment 3 mini-emulsion polymerizations.
The macromolecule NMR contrast agent spin spinrelaxation (T of Fig. 3 for obtaining according to embodiment 3
1) inverse with the variation diagram of gadolinium concentration.
Fig. 4 is the macromolecule NMR contrast agent imaging effect that obtains according to embodiment 3 variation diagram with gadolinium concentration.
Fig. 5 is the TEM figure of the macromolecule NMR contrast agent that obtains according to embodiment 10 mini-emulsion polymerizations.
Fig. 6 is the SEM figure of the macromolecule NMR contrast agent that obtains according to embodiment 10 mini-emulsion polymerizations.
The macromolecule NMR contrast agent spin spinrelaxation (T of Fig. 7 for obtaining according to embodiment 10
1) inverse with the variation diagram of gadolinium concentration.
Fig. 8 is the macromolecule NMR contrast agent imaging effect that obtains according to embodiment 10 variation diagram with gadolinium concentration.
The specific embodiment
Below in conjunction with specific embodiment the present invention is further described.
40% the glyoxal water solution of the trivinyl tetramine of the preparation of DOTA derivant: 10g and 10g is in acetonitrile, ice bath reaction 2 hours, the Bromofume and the 40g potassium carbonate that add the 4-10 milliliter then, 60～80 ℃ were reacted 24 hours down, and cold filtration precipitates with normal hexane with a small amount of dichloromethane dissolving back, solution is spin-dried for, cross post and purify, products therefrom and 1.5 normal iodohexadecanes reacted in 60 ℃ toluene 4～6 days, removed and desolvated, wash with ether, add 10 normal oxammonium hydrochloride .s, in ethanol, refluxed 2 hours, remove and desolvate, add sodium hydrate aqueous solution, with chloroform extraction three times, remove chloroform after, with the salt Acid precipitation, to be deposited in recrystallization in the ethanol, alkalization again, extraction, drying, products therefrom were reacted 4-10 hour with bromoacetic acid in 40～100 ℃ aqueous solution, and PH keeps between 8～11, after the reaction PH is transferred to neutrality, cooling is left standstill, and the adularescent solid is separated out, and is the derivant (formula 3) of DOTA.
The preparation of the derivant of Gd-DOTA: the derivant of getting the DOTA of 200mg is dissolved in the 5ml water, PH transfers to 5-8, add 1.2 normal Gadolinium trichlorides, 20～100 ℃ were reacted 24 hours down, again PH is transferred to about 9, use filtering with microporous membrane, cross ion exchange resin, remove aqueous solvent, promptly get derivant (formula 1) with Gd-DOTA.
Embodiment 3
Took by weighing a certain amount of Gd-DOTA and polysorbate60 in 1: 2～4: 1 according to mole; the deionized water that adds 5～20 milliliters; the dissolving back adds the styrene of 0.1～0.4g fully; 0.1 the divinylbenzene of～0.2g; 2～20 milligrams hexadecanol; 2～20 milligrams AIBN; 60～90 ℃ of following reactions of nitrogen protection 6～10 hours; filter back dialysis 3～6 days; the gained emulsion dispersion is even; the diameter of emulsion particle is 20～50 nanometers (as Fig. 1); the solution of preparation variable concentrations; adopting magnetic resonance imager to carry out the relaxation rate measures; spin spinrelaxation and gadolinium ion concentration are good linear relationship (as Fig. 2), finally calculate transverse relaxation speed r
1=8.9mMS
-1, along with the decline of gadolinium ion concentration, the brightness of imaging also presents downward trend (as Fig. 3) thereupon.
Took by weighing a certain amount of Gd-DOTA and Tween 80 in 1: 2～4: 1 according to mole; the deionized water that adds 5～20 milliliters; the dissolving back adds the styrene of 0.1～0.4g fully; 0.1 the divinylbenzene of～0.2g; 2～20 milligrams hexadecanol; 2～20 milligrams AIBN; 60～90 ℃ of nitrogen protections were reacted 6～10 hours down; filter back dialysis 3～6 days; the gained emulsion dispersion is even; the diameter of emulsion particle is 20～100 nanometers; the solution of preparation variable concentrations; adopting magnetic resonance imager to carry out relaxation rate measures; spin spinrelaxation and gadolinium ion concentration are good linear relationship, finally calculate transverse relaxation speed r
1=7～11mMS
-1, along with the decline of gadolinium ion concentration, the brightness of imaging also presents downward trend thereupon.
Took by weighing a certain amount of Gd-DOTA and polyvinyl alcohol in 1: 2～4: 1 according to mole; the deionized water that adds 5～20 milliliters; the dissolving back adds the styrene of 0.1～0.4g, the divinylbenzene of 0.1～0.2g, the hexadecanol of 2～20mg, the AIBN of 2～20mg fully; 60～90 ℃ of nitrogen protections were reacted 6～10 hours down; filter back dialysis 3～6 days; get the translucent emulsion of stable and uniform, test performance is close with embodiment 1.
Took by weighing a certain amount of Gd-DOTA and PEG-PPG-PEG in 1: 2～4: 1 according to mole; the deionized water that adds 5～20 milliliters; the dissolving back adds the styrene of 0.1～0.4g, the divinylbenzene of 0.1～0.2g, the hexadecanol of 2～20mg, the AIBN of 2～20mg fully; 60～90 ℃ of nitrogen protections were reacted 6～10 hours down; filter back dialysis 3～6 days; get the translucent emulsion of stable and uniform, test performance is close with embodiment 1.
Embodiment 7
Took by weighing a certain amount of Gd-DOTA and polysorbate60 in 1: 2～4: 1 according to mole; the deionized water that adds 5～20 milliliters; the dissolving back adds the methyl methacrylate of 0.1～0.4g, the divinylbenzene of 0.1～0.2g, 4～20 milligrams acrylamide, 2～20 milligrams hexadecanol, 2～20 milligrams AIBN fully; 60～90 ℃ of nitrogen protections were reacted 6～10 hours down; filter back dialysis 3～6 days; get uniform and stable emulsion, test performance is close with embodiment 1.
The preparation of DTPA derivant: get Diethylenetriamine 10g and bromohexadecane 3g and in ethanol, reacted 6 hours under 90 ℃, stop to heat the back and continue to stir 15～20 hours.Revolve to steam to remove and desolvate, obtain faint yellow crude product, take off a layer organic facies, revolve to steam to remove and desolvate vacuum drying with dichloromethane and saturated sodium-chloride extraction.The aqueous solution of gained solid and bromoacetic acid reacted 6 hours under 90 ℃ in oxolane, and dropping sodium solution keeps between the pH 8～12 simultaneously.Add HCl and regulate pH to about 1～3, revolve to steam to remove and desolvate, solid is washed with ice ethanol, sucking filtration, solid water-soluble again (pH=8), and adding HCl, to regulate pH extremely about 1～3, leaves standstill, and the adularescent solid is separated out, and is DTPA derivant (formula 4).
Embodiment 9
The preparation of the derivant of Gd-DTPA: the derivant of getting the DTPA of 200mg is dissolved in the 5ml water, PH transfers to 5-8, add 1.2 normal Gadolinium trichlorides, 20～100 ℃ were reacted 24 hours down, retell PH and transfer to about 9, use filtering with microporous membrane, cross ion exchange resin, remove aqueous solvent, promptly get derivant (formula 2) with Gd-DTPA.
Took by weighing a certain amount of Gd-DTPA and polysorbate60 in 1: 2～5: 1 according to mole; the deionized water that adds 5～20 milliliters; the dissolving back adds the styrene of 0.1～0.4g fully; 0.01 the divinylbenzene of～0.02g; 2～20 milligrams hexadecanol; 2～20 milligrams AIBN; 40～100 ℃ of nitrogen protections were reacted 6～10 hours down; filter back dialysis 3～6 days; the gained emulsion dispersion is even; the solution of preparation variable concentrations; adopting magnetic resonance imager to carry out relaxation rate measures; spin spinrelaxation and gadolinium ion concentration are good linear relationship (as Fig. 2), finally calculate transverse relaxation speed r
1=6～9mM
-1S
-1
Embodiment 11
Took by weighing a certain amount of Gd-DTPA and Tween 80 in 1: 2～5: 1 according to mole; the deionized water that adds 5～20 milliliters; the dissolving back adds the styrene of 0.1～0.4g, the divinylbenzene of 0.01～0.02g, 2～20 milligrams hexadecanol, 2～20 milligrams AIBN fully; 40～100 ℃ of nitrogen protections were reacted 6～10 hours down; filter back dialysis 3～6 days; the gained emulsion dispersion is even, and test performance is close with embodiment 10.
Took by weighing a certain amount of Gd-DTPA arabic gum in 1: 2～5: 1 according to mole; the deionized water that adds 5～20 milliliters; the dissolving back adds the styrene of 0.1～0.4g, the divinylbenzene of 0.01～0.02g, 2～20 milligrams hexadecanol, 2～20 milligrams AIBN fully; 40～100 ℃ of nitrogen protections were reacted 6～10 hours down; filter back dialysis 3～6 days; the gained emulsion dispersion is even, and test performance is close with embodiment 10.
Embodiment 13
Took by weighing a certain amount of Gd-DTPA and polyvinyl alcohol in 1: 2～5: 1 according to mole; the deionized water that adds 5～20 milliliters; the dissolving back adds the methyl methacrylate of 0.1～0.4g, the divinylbenzene of 0.01～0.02g, 4～20 milligrams acrylamide, 2～20 milligrams hexadecanol, 2～20 milligrams AIBN fully; 40～100 ℃ of nitrogen protections were reacted 6～10 hours down; filter back dialysis 3～6 days; the gained emulsion dispersion is even, and test performance is close with embodiment 10.
Took by weighing a certain amount of Gd-DTPA and polysorbate60 in 1: 2～5: 1 according to mole; the deionized water that adds 5～20 milliliters; the dissolving back adds the methyl methacrylate of 0.1～0.4g, the divinylbenzene of 0.01～0.02g, 4～20 milligrams acrylamide, 2～20 milligrams hexadecanol, 2～20 milligrams AIBN fully; 40～100 ℃ of nitrogen protections were reacted 6～10 hours down; filter back dialysis 3～6 days; the gained emulsion dispersion is even, and test performance is close with embodiment 10.
Claims (4)
1. the preparation method based on the high sensitivity NMR contrast agent of high molecular nanometer particles is characterized in that, derivant and high polymer monomer that Gd-DOTA or Gd-DTPA have long chain alkane carry out the mini-emulsion polymerization preparation; Described Gd-DOTA derivant or Gd-DTPA derivant have the structure of formula 1 and formula 2 respectively:
Formula 1 formula 2
Wherein the value of n is 8-24;
The used high polymer monomer of described polymerization is one or more in styrene, divinylbenzene, methyl methacrylate, acrylic acid methyl ester., ethyl acrylate, butyl acrylate, methacrylic acid, the acrylamide;
The surfactant that described mini-emulsion polymerization uses is Gd-DTPA derivant and other surfactant mixtures shown in Gd-DOTA derivant shown in the formula 1 or the formula 2;
Described other surfactant is in soil temperature 20, soil temperature 40, soil temperature 60, soil temperature 80, span 20, span 40, sorbester p18, sorbester p17, polyvinyl alcohol, arabic gum, polyethylene glycol-expoxy propane-Polyethylene Glycol (the being called for short PEG-PPG-PEG) triblock copolymer any one or a few.
2. the preparation method based on the high sensitivity NMR contrast agent of high molecular nanometer particles is characterized in that, the derivant that DOTA or DTPA have a long alkane chain is earlier carried out mini-emulsion polymerization with high polymer monomer and prepared with the gadolinium coordination; Described DOTA derivant or DTPA derivant have the structure of formula 3 and formula 4 respectively:
Formula 3 formulas 4
Wherein the value of n is 8-24;
The used high polymer monomer of described polymerization is one or more in styrene, divinylbenzene, methyl methacrylate, acrylic acid methyl ester., ethyl acrylate, butyl acrylate, methacrylic acid, the acrylamide;
The surfactant that described mini-emulsion polymerization uses is Gd-DTPA derivant and other surfactant mixtures shown in Gd-DOTA derivant shown in the formula 1 or the formula 2;
Described other surfactant is in soil temperature 20, soil temperature 40, soil temperature 60, soil temperature 80, span 20, span 40, sorbester p18, sorbester p17, polyvinyl alcohol, arabic gum, polyethylene glycol-expoxy propane-Polyethylene Glycol (the being called for short PEG-PPG-PEG) triblock copolymer any one or a few.
3. the preparation method of contrast agent according to claim 1 is characterized in that, comprises following steps:
(1), the preparation of Gd-DOTA or Gd-DTPA derivant;
(2), mini-emulsion polymerization: take by weighing the Gd-DOTA of 10 milligrams-2 grams or other surfactant of Gd-DTPA derivant and 5 milligrams-2 grams, the deionized water that adds 5 milliliters-500 milliliters, be stirred to dissolving fully, add the mixture of 100 milligrams-5 grams high polymer monomer, hexadecanol and azodiisobutyronitriles then, stirred 10～60 minutes, ultrasonic again 5～20 minutes, logical nitrogen was warming up to 60～90 ℃ rapidly after 10～30 minutes, reacted 5～10 hours, cold filtration, macromolecule emulsion that must be stable; (3), micromolecule is removed in dialysis: the emulsion that polymerization the is obtained the highest molecular weight that sees through of packing into is in 3000 the aqueous bag filter, dialysed under deionized water for stirring 3～6 days, the gained emulsion promptly is based on the high sensitivity NMR contrast agent of high molecular nanometer particles.
4. the preparation method of contrast agent according to claim 2 is characterized in that, comprises following steps:
(1), the preparation of DOTA or DTPA derivant;
(2), mini-emulsion polymerization: DOTA or DTPA derivant and 5 milligrams-2 other surfactants of gram of taking by weighing 10 milligrams-2 grams, the deionized water that adds 5 milliliters-500 milliliters, be stirred to dissolving fully, add the mixture of 100 milligrams-5 grams high polymer monomer, hexadecanol and azodiisobutyronitriles then, stirred 10～40 minutes, ultrasonic again 5～20 minutes, logical nitrogen was warming up to 60～90 ℃ rapidly after 10～30 minutes, reacted 5～10 hours, cold filtration, macromolecule emulsion that must be stable;
(3), carry out coordination: get emulsion after 2 milliliters-50 milliliters the polymerization, PH is transferred to 5～9 with hydrochloric acid and sodium hydroxide, slowly drip the Gadolinium trichloride aqueous solution then, drip the back and reacted 24 hours down for 20～50 ℃ with gadolinium;
(4), micromolecule is removed in dialysis: with the highest molecular weight that sees through of packing into of the emulsion after the coordination is in 3000 the aqueous bag filter, under deionized water for stirring, dialysed 3～6 days, remove gadolinium ion and other small molecular weight material of unnecessary (not coordination), the gained emulsion promptly is based on the high sensitivity NMR contrast agent of high molecular nanometer particles.
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| EP0883610B1 (en) * | 1996-02-26 | 2000-07-12 | Schering Aktiengesellschaft | Process for preparing 1,4,7,10-tetraazacyclododecane and its derivatives |
| CN1333695A (en) * | 1998-12-23 | 2002-01-30 | 伯拉考成像股份公司 | Blood pool agents for nulcear magnetic resonance diagnostics |
| EP0708761B1 (en) * | 1994-05-11 | 2002-08-14 | BRACCO International B.V. | Enhanced relaxivity monomeric and multimeric compounds |
-
2010
- 2010-06-02 CN CN2010101907272A patent/CN101845112B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0708761B1 (en) * | 1994-05-11 | 2002-08-14 | BRACCO International B.V. | Enhanced relaxivity monomeric and multimeric compounds |
| EP0883610B1 (en) * | 1996-02-26 | 2000-07-12 | Schering Aktiengesellschaft | Process for preparing 1,4,7,10-tetraazacyclododecane and its derivatives |
| CN1333695A (en) * | 1998-12-23 | 2002-01-30 | 伯拉考成像股份公司 | Blood pool agents for nulcear magnetic resonance diagnostics |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102908634A (en) * | 2012-11-14 | 2013-02-06 | 华东理工大学 | Double-strand quaternary ammonium type nuclear magnetic resonance imaging contrast agent and preparation method thereof |
| CN102908634B (en) * | 2012-11-14 | 2015-07-01 | 华东理工大学 | Double-strand quaternary ammonium type nuclear magnetic resonance imaging contrast agent and preparation method thereof |
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| CN101845112A (en) | 2010-09-29 |
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