CN103690971B - A kind of supperparamagnetic particles, preparation method and its usage with rheumatoid arthritis position targeting - Google Patents
A kind of supperparamagnetic particles, preparation method and its usage with rheumatoid arthritis position targeting Download PDFInfo
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Abstract
The present invention utilizes the high-affinity of the macrophage of folic acid and surface expression folacin receptor to develop to realize targeting, provides a kind ofly to make the contrast agent of rheumatoid arthritis video picture by specificity in nuclear magnetic resonance.Method (dicyclohexylcarbodiimide/DMAP method that this magnetic resonance contrast agent adopts chemistry to connect, DCC/DMAP method), the supperparamagnetic particles modify Polyethylene Glycol (PEG)-b-polyacrylic acid (PAA) and folate molecule coupling, obtain particle diameter at the high and magnetic resonance imaging contrast of the rheumatoid arthritis image areas that contrast effect is strong of about 20nm, specificity.
Description
Technical field
The present invention relates to and a kind of there is supperparamagnetic particles of rheumatoid arthritis position targeting and preparation method thereof, also relate to the selectively targeted Superparamagnetism magnetic resonance contrast medium in rheumatoid arthritis position and preparation method thereof containing this supperparamagnetic particles.
Background technology
Nmr imaging technique (MRI) is one of Image Examination be most widely used at present, in clinical MRI detects, the diagnosis of about more than 30% need with magnetic resonance imaging contrast to improve image contrast, the organizational structure originally lacking contrast difference is made to show more clear, thus the better structure of display body inner tissue organ and the character of pathological changes and functional status, greatly can improve the accuracy of diagnosis and early stage property.
MRI contrast agent can be divided into the positive and large class of negative contrast medium two by enhancing type.Opaque contrast medium makes the T1 relaxation time of tissue shorten, and on image, shows signal strengthens, and the chelate of at present conventional paramagnetic contrast medium mainly gadolinium series elements, as Gd-DTAP(Ci Xian Portugal amine), Gd-DTAP-BMA etc.In rheumatoid arthritis imaging, Gd system contrast agent also exists some apparent shortcomings: first, micromolecular Gd system contrast agent poor specificity.After intravenous injection, Gd-DTPA can quick disperse.Except pathological changes joint, also can a certain amount of Gd system of enrichment molecule in natural joint, thus reduce the specificity of Gd molecule radiography, also reduce the contrast of diseased region simultaneously; Secondly, micromolecule contrast agent can very soon remove by kidney, there are some researches show, the signal intensity maximum of Gd contrast agent occurs in 3-5min after contrast agent injection, and the half-life is in vivo at about 30min, all inconvenience is caused to MRI imaging and Real-Time Monitoring; Finally, because Gd element has certain bio-toxicity and micromolecular Ci Xian Portugal amine substance imaging desired concn is higher, thus easily cause infiltration in body to press through height, even may cause the fibrosis of renal tissue.
Comparatively Gd system contrast agent sensitivity is high for superparamagnetic contrast agents, has biocompatibility.The more important thing is, it makes people can to RA(rheumatoid arthritis from cell and molecular level as the special nature that nano-sized materials has) carry out diagnosing more in early days, fast and accurately.By disclosing the cell of RA and molecular mechanism, engulf by macrophage after, SPIO(superparamagnetic iron oxide particles) can better detect in time the synovitis occurred in early stage RA process and macrophages infiltration.The superparamagnetic contrast agents being applied to RA is at present nearly all traditional commercial prod.But, the major defect that traditional commercial prod exists is not good to the targeting ability at RA position, owing to lacking distinctive targeted molecular, commercial prod in vivo mainly identify by reticuloendothelial system, thus be deposited in the abundant tissue of reticuloendothelial cell and organ, thus make the signal of liver, lymph node etc. strengthen.And the contrast agent component often finally entering rheumatoid arthritis position is little.Therefore, utilize sick cell to the specificity of targeting part, the specific magnetic resonance contrast agent of exploitation RA, improves imaging efficiency and signal to noise ratio seems very necessary.
Utilize folacin receptor in the overexpression of tumor and arthritis cell, medicine is combined with folic acid, can targeting diagnosis be realized.And prior art (model rosy clouds, the synthesis of the folic acid-carboxymethyl chitosan-superparamagnetic iron oxide nanoparticle of novel tumor targeting and evaluation, Nanfang Medical Univ, 2010) discloses and folic acid-carboxymethyl chitosan-Superparamagnetic particulates is used for tumor imaging.But existing contrast agent is applicable to lymph or liver target radiography mostly, it is to the scarce capacity of joint targeting radiography, often needs escalated dose to make the amount of contrast agent reach 20mg/kg body weight and just can realize radiography.
Summary of the invention
For current commercialization contrast agent for arthritis position targeting scarce capacity, the restricted present situation of contrast ability, the invention provides a kind of can targeting in the MRI contrast agent at rheumatoid arthritis position.
In order to achieve the above object, present invention employs following technical scheme:
A kind of supperparamagnetic particles with rheumatoid arthritis position targeting, described supperparamagnetic particles comprises the ferroso-ferric oxide that is positioned at core or/and ferric oxide nanoparticles and be coated on the PEG-b-PAA of nanoparticle surface, and PEG-b-PAA surface coupling has folate molecule.
That is, the kernel of described supperparamagnetic particles be ferroso-ferric oxide or/and ferric oxide nanoparticles, nanoparticle surface in conjunction with PEG-b-PAA, PEG-b-PAA surface coupling have folate molecule.Described nanoparticle surface achieves PEG-b-PAA in conjunction with PEG-b-PAA and is coated on nanoparticle surface.
The present invention is by there being the folate molecule coupling of the nanoparticle of PEG-b-PAA and selectively targeted macrophage by finishing, form FA-PEG-b-PAA@SPIO system, obtain the above-mentioned supperparamagnetic particles with rheumatoid arthritis position targeting modified through folate ligand.
Described PEG-b-PAA and polyethylene glycol-acrylic block copolymers, FA is folic acid, and SPIO is super-paramagnetism nano ferric oxide particles.
The following optimal technical scheme as technique scheme, but not as the restriction of technical scheme provided by the invention, by the following technical programs, better can reach and realize technical purpose of the present invention and beneficial effect.
Preferably, on the basis of technical scheme provided by the invention, covalent coupling is carried out by DCC/DMAP method and folate molecule in described PEG-b-PAA surface.
Exemplary a kind of supperparamagnetic particles with rheumatoid arthritis position targeting, the kernel of described supperparamagnetic particles is ferriferrous oxide nano-particle, this particle surface is combined with PEG-b-PAA, and PEG-b-PAA carries out covalent coupling by DCC/DMAP method and folic acid in surface and forms FA-PEG-b-PAA@SPIO system.
The particle diameter of described ferroso-ferric oxide and ferric oxide nanoparticles is 1 ~ 100nm, such as 1 ~ 20nm, 15 ~ 30nm, 45 ~ 60nm, 10 ~ 50nm, 20 ~ 60nm, 30 ~ 65nm, 30 ~ 80nm, 50 ~ 100nm, 45 ~ 95nm or 40 ~ 90nm all independently.
Preferably, the number-average molecular weight of described PEG is the arbitrary integer of 3000 ~ 9000, and the number-average molecular weight of PAA is the arbitrary integer of 200 ~ 10000.The PEG of long-chain-segment can improve circulation time in vivo, avoids removing in body, but long modification can cause the Relaxivity of Superparamagnetic Iron Oxide to weaken, and selects the PEG of molecular weight of the present invention to ensure long circulating and keeps better magnetic property.
Two of object of the present invention is to provide a kind of preparation method as above with the supperparamagnetic particles of rheumatoid arthritis position targeting, and described method comprises the steps:
(1) folic acid is activated;
(2) preparation is by being positioned at the ferroso-ferric oxide of core or/and the suspension of supperparamagnetic particles that forms of ferric oxide nanoparticles and the PEG-b-PAA that is coated on its surface;
(3) the folic acid mixing after the activation that suspension step (2) obtained and step (1) obtain, makes PEG-b-PAA and folic acid generation coupling reaction, obtains the supperparamagnetic particles with rheumatoid arthritis position targeting.
Preferably; step (1) folic acid activation method is: be dissolved in by folic acid in anhydrous DMSO; then the DCC of equivalent is added; folic acid concentration is made to remain on 1-10mmol/L; such as 2mmol/L, 3mmol/L, 4mmol/L, 5mmol/L, 6mmol/L, 7mmol/L, 8mmol/L or 9mmol/L, lucifuge issues life-stylize reaction at protective atmosphere.
Described DMSO is dimethyl sulfoxide, and DCC is dicyclohexylcarbodiimide.
Preferably, described protective atmosphere is nitrogen.
Preferably, the time of described priming reaction is 6-18h, such as 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h or 17h.
Preferably, the concentration of step (2) described suspension is 1-10mg/ml, such as 2mg/ml, 3mg/ml, 4mg/ml, 5mg/ml, 6mg/ml, 7mg/ml, 8mg/ml or 9mg/ml, the supperparamagnetic particles of the step (2) namely containing 1-10mg in every ml suspension.
Preferably, the solvent of step (2) described suspension is DMSO.
Preferably, step (2) is described by being positioned at the ferroso-ferric oxide of core or/and the preparation method of supperparamagnetic particles that ferric oxide nanoparticles and the PEG-b-PAA that is coated on its surface form is:
1) be dissolved in tetraethylene glycol (TEG) by ferric acetyl acetonade and PEG-b-PAA, wherein the arbitrary integer of the mass ratio of ferric acetyl acetonade and PEG-b-PAA to be 1:1 ~ 1:2, PEG number-average molecular weight be 3000-9000, PAA number-average molecular weight is the arbitrary integer of 200-10000;
2) stir under inert gas shielding and be heated to 160 ~ 270 DEG C of backflow 3h simultaneously, being warming up to 310 ~ 420 DEG C subsequently, backflow 3h;
3) by step 2) solution that obtains is cooled to room temperature, the ethyl acetate adding 2 ~ 10 times of liquor capacities makes solution flocculation precipitation, then with Magnet, precipitate gathering is separated and repeats 3 times, finally namely the precipitate vacuum drying of acquisition is obtained by being positioned at the ferroso-ferric oxide of core or/and the supperparamagnetic particles that forms of ferric oxide nanoparticles and the PEG-b-PAA that is coated on its surface, i.e. PEG-b-PAA@SPIO particle.
Preferably, step (3) adopts DCC/DMAP method to make PEG-b-PAA and folic acid generation coupling reaction.
Preferably, the addition of described DMAP is 0.1 times of DCC equivalent.
Described DMAP and DMAP.
Preferably, in the folic acid after step (3) activation and suspension, the mass ratio of supperparamagnetic particles is 1:1.
Preferably, the temperature of step (3) described reaction is room temperature, namely 25 DEG C.
Preferably, the time of step (3) described reaction is 6-18h.
DCC/DMAP method and dicyclohexylcarbodiimide/DMAP method.
Exemplary a kind of preparation method as above with the supperparamagnetic particles of rheumatoid arthritis position targeting, described method comprises the steps:
(1 ') folic acid activates: get folic acid and be dissolved in anhydrous DMSO, then add the DCC of equivalent, make folic acid concentration remain on 2mmol/L, lucifuge in a nitrogen atmosphere priming reaction occurs;
(2 ') preparation is by being positioned at the ferroso-ferric oxide of core or/and the suspension of supperparamagnetic particles that forms of ferric oxide nanoparticles and the PEG-b-PAA that is coated on its surface: get supperparamagnetic particles, be scattered in anhydrous DMSO, the concentration keeping suspension is 10mg/mL;
Suspension prepared by step (2 ') adds in the solution that step (1) obtains by (3 '), the mass ratio of the supperparamagnetic particles in suspension and the folic acid after activating is 1:1, and add the DMAP of 0.1 times of DCC equivalent, react 6-18h under room temperature condition, obtain the supperparamagnetic particles with rheumatoid arthritis position targeting.
Wherein (2 ') is described by being positioned at the ferroso-ferric oxide of core or/and the preparation method of supperparamagnetic particles that forms of ferric oxide nanoparticles and the PEG-b-PAA that is coated on its surface is as follows:
1 ') by ferric acetyl acetonade and PEG-b-PAA macromolecule dissolution in tetraethylene glycol (TEG), wherein the mass ratio of ferric acetyl acetonade and PEG-b-PAA is 1:1 ~ 1:2, PEG number-average molecular weight is the arbitrary integer of 3000-9000, and PAA number-average molecular weight is the arbitrary integer of 200-10000.
2 ') stir under inert gas shielding and be heated to 160 ~ 270 DEG C of backflow 3h simultaneously, being warming up to 310 ~ 420 DEG C subsequently, backflow 3h.
3 ') by step 2 ') solution that obtains is cooled to room temperature, the ethyl acetate adding 2 ~ 10 times of liquor capacities makes solution flocculation precipitation, then with Magnet, precipitate gathering be separated and repeat 3 times, finally namely the precipitate vacuum drying of acquisition being obtained supperparamagnetic particles.
Three of object of the present invention is to provide a kind of selectively targeted in the Superparamagnetism magnetic resonance contrast medium at rheumatoid arthritis position, and described contrast agent comprises the supperparamagnetic particles as above with rheumatoid arthritis position targeting.
The particle diameter of described contrast agent is 20nm.
Four of object of the present invention is the preparation method providing a kind of selectively targeted Superparamagnetism magnetic resonance contrast medium in rheumatoid arthritis position as above, and described method comprises the steps:
The supperparamagnetic particles as above with rheumatoid arthritis position targeting is scattered in buffer solution and forms stable dispersion, selectively targeted in the Superparamagnetism magnetic resonance contrast medium at rheumatoid arthritis position.
Preferably, described buffer solution is phosphate buffer solution (PBS).
The preparation method of exemplary a kind of selectively targeted Superparamagnetism magnetic resonance contrast medium in rheumatoid arthritis position as above, described method comprises the steps:
(1 ') folic acid activates: get folic acid and be dissolved in anhydrous DMSO, then add the DCC of equivalent, make folic acid concentration remain on 1-10mmol/L, lucifuge in a nitrogen atmosphere priming reaction occurs;
(2 ') preparation is by being positioned at the ferroso-ferric oxide of core or/and the suspension of supperparamagnetic particles that forms of ferric oxide nanoparticles and the PEG-b-PAA that is coated on its surface: get supperparamagnetic particles, be scattered in anhydrous DMSO, the concentration keeping suspension is 10mg/mL;
Suspension prepared by step (2 ') adds in the solution that step (1) obtains by (3 '), the mass ratio of the supperparamagnetic particles in suspension and the folic acid after activating is 1:1, and add the DMAP of 0.1 times of DCC equivalent, react 6-18h under room temperature condition, obtain the supperparamagnetic particles with rheumatoid arthritis position targeting;
(4) the above-mentioned supperparamagnetic particles with rheumatoid arthritis position targeting is scattered in PBS, obtains selectively targeted in the Superparamagnetism magnetic resonance contrast medium at rheumatoid arthritis position.
Wherein (2 ') is described by being positioned at the ferroso-ferric oxide of core or/and the preparation method of supperparamagnetic particles that forms of ferric oxide nanoparticles and the PEG-b-PAA that is coated on its surface is as follows:
1 ') ferric acetyl acetonade and PEG-b-PAA are dissolved in tetraethylene glycol (TEG), wherein the mass ratio of ferric acetyl acetonade and PEG-b-PAA is 1:1 ~ 1:2, PEG number-average molecular weight is the arbitrary integer of 3000-9000, and PAA number-average molecular weight is the arbitrary integer of 200-10000.
2 ') stir under inert gas shielding and be heated to 160 ~ 270 DEG C of backflow 3h simultaneously, being warming up to 310 ~ 420 DEG C subsequently, backflow 3h.
3 ') by step 2 ') solution that obtains is cooled to room temperature, the ethyl acetate adding 2 ~ 10 times of liquor capacities makes solution flocculation precipitation, then with Magnet, precipitate gathering be separated and repeat 3 times, finally namely the precipitate vacuum drying of acquisition being obtained supperparamagnetic particles.
Compared with the prior art, the present invention has following beneficial effect:
The present invention utilizes the high-affinity of the macrophage of folic acid and surface expression folacin receptor to develop to realize targeting, provides a kind ofly to make the contrast agent of rheumatoid arthritis video picture by specificity in nuclear magnetic resonance.The important symbol that folacin receptor is activated as macrophage and being widely used on the macrophage targeting of inflammation part.Because the imaging of SPIO at RA position depends on the phagocytosis of macrophage for SPIO to a great extent, thus pass through SPIO and folate molecule (folic acid, FA) link together, the targeting ability of SPIO contrast agent be will greatly improve, thus imaging capability and the signal to noise ratio of rheumatoid arthritis position MRI promoted.
Described contrast agent specificity is high and contrast effect strong, and the consumption of contrast agent is little, and dosage is the radiography that 4mg/kg body weight can realize to arthritis position.
Accompanying drawing explanation
Fig. 1 is FA-PEG-b-PAA@SPIO and PEG-b-PAA@SPIO uv-spectrogram.
Fig. 2 is FA-PEG-b-PAA@SPIO and PEG-b-PAA@SPIO Fourier infared spectrum.
Detailed description of the invention
Technical scheme of the present invention is further illustrated by detailed description of the invention below in conjunction with accompanying drawing.
Embodiment 1
(1) activate folic acid: get 0.45g folic acid and 0.21g DCC is dissolved in the anhydrous DMSO of 10.6mL, lucifuge leads to nitrogen reaction 6h;
(2) prepare supperparamagnetic particles suspension: get supperparamagnetic particles 90mg, be scattered in the anhydrous DMSO of 9mL, maintenance final concentration is 1mg/mL;
(3) suspension prepared by step (2) is added in the solution that step (1) acquires, and add the DMAP of 12.9mg, under room temperature condition, react 6h;
(4) be separated: the rear 5000rpm/min of reaction centrifugal 30min acquisition product is laid equal stress on and is scattered in PBS, namely obtains required contrast agent.
Wherein the preparation method of (2) described supperparamagnetic particles is as follows: using the ferric acetyl acetonade (Fe (acca) as 1400mg
3) and the PEG550-b-PAA1000 of 1g be dissolved in 2,2'-ethylenedioxybis(ethanol)., agitating solution under inert gas shielding, is heated to 160 DEG C simultaneously, backflow, then heated solution c to 320 DEG C, backflow.Solution after refluxing adds the ethyl acetate of liquor capacity 2 ~ 10 times after being cooled to room temperature, after solution flocculation precipitation, assemble sediment separate out with Magnet, finally namely the precipitate vacuum drying of acquisition is obtained PEG-b-PAA@SPIO particle.
Embodiment 2
(1) activate folic acid: get 4.5g folic acid and 2.1g DCC is dissolved in the anhydrous DMSO of 10.6mL, lucifuge leads to nitrogen reaction 6h;
(2) prepare supperparamagnetic particles suspension: get supperparamagnetic particles 900mg, be scattered in the anhydrous DMSO of 9mL, maintenance final concentration is 10mg/mL;
(3) suspension prepared by step (2) is added in the solution that step (1) acquires, and add the DMAP of 129mg, under room temperature condition, react 6h;
(4) be separated: the rear 5000rpm/min of reaction centrifugal 30min acquisition product is laid equal stress on and is scattered in PBS, namely obtains required contrast agent.
Wherein the preparation method of (2) described supperparamagnetic particles is as follows: using the ferric acetyl acetonade (Fe (acca) as 1400mg
3) and the PEG550-b-PAA1000 of 1g be dissolved in 2,2'-ethylenedioxybis(ethanol)., agitating solution under inert gas shielding, is heated to 160 DEG C simultaneously, backflow, then heated solution c to 320 DEG C, backflow.Solution after refluxing adds the ethyl acetate of liquor capacity 2 ~ 10 times after being cooled to room temperature, after solution flocculation precipitation, assemble sediment separate out with Magnet, finally namely the precipitate vacuum drying of acquisition is obtained PEG-b-PAA@SPIO particle.
Embodiment 3
(1) activate folic acid: get 4.5g folic acid and 2.1g DCC is dissolved in the anhydrous DMSO of 10.6mL, lucifuge leads to nitrogen reaction 18h;
(2) prepare supperparamagnetic particles suspension: get supperparamagnetic particles 900mg, be scattered in the anhydrous DMSO of 9mL, maintenance final concentration is 10mg/mL;
(3) suspension prepared by step (2) is added in the solution that step (1) acquires, and add the DMAP of 129mg, under room temperature condition, react 18h;
(4) be separated: the rear 5000rpm/min of reaction centrifugal 30min acquisition product is laid equal stress on and is scattered in PBS, namely obtains required contrast agent.
Wherein the preparation method of (2) described supperparamagnetic particles is as follows: using the ferric acetyl acetonade (Fe (acca) as 1400mg
3) and the PEG550-b-PAA1000 of 1g be dissolved in 2,2'-ethylenedioxybis(ethanol)., agitating solution under inert gas shielding, is heated to 160 DEG C simultaneously, backflow, then heated solution c to 320 DEG C, backflow.Solution after refluxing adds the ethyl acetate of liquor capacity 2 ~ 10 times after being cooled to room temperature, after solution flocculation precipitation, assemble sediment separate out with Magnet, finally namely the precipitate vacuum drying of acquisition is obtained PEG-b-PAA@SPIO particle.
Applicant states, the present invention illustrates method detailed of the present invention by above-described embodiment, but the present invention is not limited to above-mentioned method detailed, does not namely mean that the present invention must rely on above-mentioned method detailed and could implement.Person of ordinary skill in the field should understand, any improvement in the present invention, to equivalence replacement and the interpolation of auxiliary element, the concrete way choice etc. of each raw material of product of the present invention, all drops within protection scope of the present invention and open scope.
Claims (6)
1. one kind selectively targeted in the Superparamagnetism magnetic resonance contrast medium at rheumatoid arthritis position, described contrast agent comprises the supperparamagnetic particles with rheumatoid arthritis position targeting, described supperparamagnetic particles comprises the ferroso-ferric oxide that is positioned at core or/and ferric oxide nanoparticles and be coated on the PEG-b-PAA of nanoparticle surface, and PEG-b-PAA surface coupling has folate molecule; Wherein, covalent coupling is carried out by DCC/DMAP method and folate molecule in PEG-b-PAA surface.
2. contrast agent as claimed in claim 1, it is characterized in that, the number-average molecular weight of described PEG is the arbitrary integer of 3000 ~ 9000, and the number-average molecular weight of PAA is the arbitrary integer of 200 ~ 10000.
3. contrast agent as claimed in claim 1 or 2, it is characterized in that, the particle diameter of described ferroso-ferric oxide and ferric oxide nanoparticles is 1 ~ 100nm all independently.
4. contrast agent as claimed in claim 1 or 2, it is characterized in that, the particle diameter of described contrast agent is 20nm.
5. the preparation method of the selectively targeted Superparamagnetism magnetic resonance contrast medium in rheumatoid arthritis position as described in one of claim 1-4, wherein, the described preparation method with the supperparamagnetic particles of rheumatoid arthritis position targeting comprises the steps:
(1 ') folic acid activates: get folic acid and be dissolved in anhydrous DMSO, then add the DCC of equivalent, make folic acid concentration remain on 2mmol/L, lucifuge in a nitrogen atmosphere priming reaction occurs;
(2 ') preparation is by being positioned at the ferroso-ferric oxide of core or/and the suspension of supperparamagnetic particles that forms of ferric oxide nanoparticles and the PEG-b-PAA that is coated on its surface: get supperparamagnetic particles, be scattered in anhydrous DMSO, the concentration keeping suspension is 10mg/mL;
Suspension prepared by step (2 ') adds in the solution that step (1 ') obtains by (3 '), the mass ratio of the supperparamagnetic particles in suspension and the folic acid after activating is 1:1, and add the DMAP of 0.1 times of DCC equivalent, react 6-18h under room temperature condition, obtain the supperparamagnetic particles with rheumatoid arthritis position targeting;
Wherein (2 ') is described by being positioned at the ferroso-ferric oxide of core or/and the preparation method of supperparamagnetic particles that forms of ferric oxide nanoparticles and the PEG-b-PAA that is coated on its surface is as follows:
1 ') ferric acetyl acetonade and PEG-b-PAA are dissolved in tetraethylene glycol (TEG), wherein the mass ratio of ferric acetyl acetonade and PEG-b-PAA is 1:1 ~ 1:2, PEG number-average molecular weight is the arbitrary integer of 3000-9000, and PAA number-average molecular weight is the arbitrary integer of 200-10000;
2 ') stir under inert gas shielding and be heated to 160 ~ 270 DEG C of backflow 3h simultaneously, being warming up to 310 ~ 420 DEG C subsequently, backflow 3h;
3 ') by step 2 ') solution that obtains is cooled to room temperature, the ethyl acetate adding 2 ~ 10 times of liquor capacities makes solution flocculation precipitation, then with Magnet, precipitate gathering be separated and repeat 3 times, finally namely the precipitate vacuum drying of acquisition being obtained supperparamagnetic particles;
The supperparamagnetic particles with rheumatoid arthritis position targeting is scattered in buffer solution and forms stable dispersion, obtain selectively targeted in the Superparamagnetism magnetic resonance contrast medium at rheumatoid arthritis position.
6. method as claimed in claim 5, it is characterized in that, the time of described priming reaction is 6-18h.
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