CN1583575A - Preparation of super paramagnetic nano particles dispersible in water - Google Patents
Preparation of super paramagnetic nano particles dispersible in water Download PDFInfo
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- CN1583575A CN1583575A CN 200410024894 CN200410024894A CN1583575A CN 1583575 A CN1583575 A CN 1583575A CN 200410024894 CN200410024894 CN 200410024894 CN 200410024894 A CN200410024894 A CN 200410024894A CN 1583575 A CN1583575 A CN 1583575A
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- superparamagnetic nanoparticle
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Abstract
A process for preparing the super-paramagnetic nanoparticles dispersed in water easily includes such steps as mixing the polymer chelating agent with Fe ions, dripping alkali while reacting to generate inn oxide and continuously dripping alkali until pH=9-10.
Description
Technical field
The present invention relates to a kind of in water the easy super paramagnetic nano ionic of dispersive preparation method, be specifically related to a kind of method of utilizing polymeric chelant to synthesize nanoscaled iron oxide particles with superparamagnetism.Be used for biomedical sector.
Background technology
In recent years, magnetic nanoparticle is in bioseparation, the contrast imaging of nucleus magnetic resonance, and the huge applications of aspect such as medicine sustained release is worth, and obtained people and paid attention to greatly.More and more about the research of the preparation of ferric oxide nano particles and application, but ferric oxide nanometer particle is because its high surface energy is assembled easily, and the size distribution that keep nanometer scale is difficulty relatively.The foreign patent technology adopts the method for finishing such as dextran molecule, the product of comparative maturity is just like CLIO, be exactly that crosslinked polymer with bromoacetic acid and polyvinyl alcohol (PVA) is in the superparamagnetic nanoparticle surface, connect again and have amino compound, as quadrol, make the surface that active group-NH2 be arranged, be used for biological exsomatizing and analyzed cellular segregation and MR contrast agent.
Application No. 20030124194, patent name: have the biology of the superparamagnetic nanoparticle of active group amino to connect and and application.〔United?States?Patent?Application，application?number：20030124194，application?name：Amine?functionalizedsuperparamagnetic?nanoparticles?for?the?synthesis?of?bioconjugates?anduses?therefore〕。But this method reactions steps is complicated, the size distribution broad, and also if be applied to drug disposition targeted or other, the stowage of medicine is very limited.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, the preparation method of easy dispersive superparamagnetic nanoparticle in a kind of water is provided.This method is an original position synthetic iron oxide in polymeric chelant, because the dispersiveness of branched chain polymer itself, and hydrophilic radicals such as the carboxyl on surface and hydroxyl, the synthetic superparamagnetic nanoparticle is difficult for assembling and all keeps stable under multiple treatment condition.Prior, can further modify the various bioactive moleculess of connection effectively on the superparamagnetic nanoparticle surface by the active group on surface.Can be applicable to fields such as biomedical separation, drug conveying, medical imaging and treatment.
Superparamagnetic nanoparticle of the present invention is the composite particles of iron oxide particles and polymkeric substance.The polymer molecule that has side chain has improved stability, the dispersiveness and water-soluble of magnetic particle greatly.Simultaneously, can connect various bioactive moleculess on the polymkeric substance, and drug loading in a large number.Preparation method described in the invention is simple, and with low cost, is widely used.
The present invention is achieved by the following technical solutions, at first polymeric chelant and iron ion are mixed, utilize the carboxyl and the iron particle on polymkeric substance Ao mixture surface to form the coordinate bond combination, drip alkali then, under the situation that drips alkali, hydroxyl and iron ion reaction generate ferric oxide, continue to drip alkali between the pH9-10, by the steric hindrance of polymeric chelant, ferric oxide particles stops to continue to increase, and synthesizes the nanoscale, superparamagnetic particle, because reaction is to carry out in position, the polymkeric substance chelating surrounds the surface of particle, again by heated scrub and further modification, promptly obtains the superparamagnetic nanoparticle of functionalization.
In above-mentioned preparation method, the polymkeric substance chelating that adopts is carboxylic acid and the pure polymer mixed polymer that is polymerized, wherein carboxylic acid comprises (at least a in binary acid of C2～C18) and the hydroxycarboxylic acid, alcohol comprises (at least a in the pure and mild sugar alcohol of aliphatic dicarboxylic of C2～C18), its mixed polymer contains carboxyl and hydroxyl, has good dispersiveness in water and multiple organic solvent.
In the preparation of superparamagnetic nanoparticle, can be in synthetic iron oxide, to add this polymeric chelant to carry out original position synthetic; Also can be when synthetic iron oxide, to add monomeric carboxylic acids and alcohol, behind synthetic iron oxide, again the monomeric carboxylic acids of iron oxide surface and alcohol be carried out polyreaction; Also can be behind synthetic iron oxide, directly to add polymeric chelant.
Resulting superparamagnetic nanoparticle, particle diameter is 5nm～500nm, the aqueous solution and can with the organic solvent of water immiscible phase such as ethanol, acetone and other organic solvent in good dispersiveness is arranged, polymer active group such as carboxyl and hydroxyl are contained in the surface, repeatedly cleaning, after ultrafiltration and concentration or the drying, disperse median size and the no considerable change of size distribution size once more; The ferric oxide nanometer particle that wherein contains is Fe
2O
3, Fe
3O
4, iron carbonyl and composition thereof, its single primary particle particle diameter is not more than 30nm, evacuates the mode of gathering with single primary particle or 2-5 primary particle and exist in nanoparticle.
Further, can be in superparamagnetic nanoparticle drug loading.Medicine can be wrapped in the polymkeric substance by the common method in this area, or the method that connects by chemistry is combined on the polymkeric substance.Medicine can be micromolecular compound medicine, middle pharmaceutically active ingredient, albumen, polypeptide, nucleic acid drug etc.
Simultaneously, can also connect the biomolecules that antibody, part, cytokine, polypeptide etc. have the targeting characteristic on the superparamagnetic nanoparticle surface.Method is slightly: take by weighing the exsiccant superparamagnetic nanoparticle, adding the solvent supersonic ripple handled 5～10 minutes, get the partial confounding suspension, it is an amount of perhaps directly to get the superparamagnetic nanoparticle suspension for preparing, add an amount of linking agent such as N, N-carbonyl diurethane miaow pyridine (CDI), carbon imide (EDC), N-maloyl imines etc. stirred 10 minutes～2 hours.Active group carboxyl on the polymkeric substance is activated, isolate carboxyl activatory ferric oxide, suspendible again then.Add medicine or protein polypeptide solution, stirred 1～24 hour, separate, clean several times, get final product.
The superparamagnetic nanoparticle that the present invention is prepared can be used as the contrast medium of biomedical imaging, realizes the imaging to intravital specific biological molecules; Also can be used as the targeted carrier of medicine, under the effect of externally-applied magnetic field, realize the directed conveying of medicine.
The superparamagnetic nanoparticle for preparing is characterized: the superparamagnetic nanoparticle of preparation is placed on carries out drying in 105 ℃ of loft drier and be prepared into Powdered, carry out X-ray diffraction analysis, with the ferric oxide standard control, prove ferric oxide particles, and estimation ferric oxide crystalline particle diameter is about 9.2nm-18.2nm from collection of illustrative plates; This superparamagnetic nanoparticle very easily disperses in the aqueous solution, uses transmission electron microscope observation, being evenly distributed of ferric oxide particles, and particle diameter is about 14nm; Scan in the aqueous solution with atomic force microscope, particle distribution is even, good dispersity.Ferric oxide particles is 2～3 monomer aggregation with individual particle or part, is present in the water, and grain diameter measurement is 10nm; Use dynamic laser scattering method (PCS) measure the size distribution of magnetic particle (ZETASIZER 3000HSa, MALVERN), nano particle diameter is evenly distributed, more than 90% about 30nm.As a comparison, do not have the ferric oxide particles for preparing under the polymeric chelant situation, then assemble serious, easy precipitation in water.
The present invention has substantive distinguishing features and marked improvement, the present invention uses the dendritic alkyd of branch as sequestrant, this polymkeric substance has active group, can the chelated iron ion, when synthetic, iron ion original position under the encirclement of this polymkeric substance is synthetic, so particle diameter is little and be evenly distributed, be difficult for reuniting, need do not add or the modification activities group after the preparation, and can keep particle satisfactory stability and water dispersible at particle surface.Synthetic method and technology are simple, are easy to industrialization.Further, the synthetic superparamagnetic nanoparticle, both had super paramagnetic characteristic, can reprint medicine again, and connect various biomolecules by the active group on the polymkeric substance side chain, at aspects such as MRI molecules influence radiography, biomolecule detection and targeted drug conveyings, has excellent application value.
Embodiment
Content in conjunction with the inventive method provides following examples, and technical solution of the present invention is done further to understand.
Embodiment 1
Take by weighing polyalcohols acid polymer in 2.13 grams, add 5ml ethanol and 45ml water, ultrasonic 10 minutes, add 0.743 gram FeCl
3.6H
2O and 0.382 gram FeCl
2.4H
2O.Ultrasonic 5 minutes, feed N
2, dripping NaOH, the magnetic agitation knob is threaded to the about 1800rpm of maximum, about 75 ℃ of heating, the online detection of pH is treated pH between 9～10.45 about 50 minutes, stops to add NaOH and heating.Recording median size with PCS after after the centrifugation is about 5nm.Measuring the ferric oxide particles particle diameter through transmission electron microscope is 3nm.In nanoparticle, mainly exist in single primary particle mode.Present method synthetic superparamagnetic nanoparticle is compared with additive method, and it is little to have a particle diameter, and the characteristics that are evenly distributed do not have obviously and assemble, and have good dispersibility and stability in water.
Embodiment 2
Take by weighing the high polyalcohols acid polymer of 4.8 grams, add 20ml water, add 1.235 gram FeCl
3.6H
2O feeds N
2, ultrasonic 30 minutes.Take by weighing 0.612 gram FeCl
2.4H
2O adds in the threeway bottle, ultrasonic 10 minutes.Feed N
2, electric power stirs 1093rpm, drips NaOH1～2 droplet/second (3.149 gram NaOH+130ml water), till being added drop-wise to the reaction solution color and becoming black.Continuation was 75 ℃ of heating 30 minutes.After treating centrifugation, it is about 500nm that PCS records median size, and measuring the ferric oxide particles particle diameter through transmission electron microscope is 30nm, mainly evacuates the mode of gathering with 5 primary particles and exist in nanoparticle.Size distribution is even, does not have obviously and assembles, and has good dispersibility and stability in water.
Embodiment 3
Take by weighing the oligomeric alkyd of 1.022 grams, add 5ml ethanol and 45ml water, ultrasonic 10 minutes, add 0.823 gram FeCl
3.6H
2O and 0.392 gram FeCl
2.4H
2O.Ultrasonic 5 minutes, feed N
2Drip NaOH, the magnetic agitation knob is threaded to the about 1800rpm of maximum, about 75 ℃ of heating, the online detection of pH treats that pH is between 9～10, stop to add NaOH and continue heating 50-100 minute, after the centrifugation, it is about 200nm that PCS records median size, and it is about 18nm that transmission electron microscope is measured the ferric oxide particles particle diameter; Mainly evacuating the mode of gathering with 2 primary particles in nanoparticle exists.Size distribution is even, does not have obviously and assembles, and has good dispersibility and stability in water.
Embodiment 4
Connect the medicine selagine on the superparamagnetic nanoparticle surface: get an amount of exsiccant superparamagnetic nanoparticle, preparation tetrahydrofuran (THF) suspension adds an amount of N, the tetrahydrofuran solution of N-carbonyl diurethane miaow pyridine (CDI), magnetic agitation 60 minutes.Isolate carboxyl activatory ferric oxide then, miscible again in tetrahydrofuran (THF), add the tetrahydrofuran solution of selagine then, magnetic agitation was spent the night 12 hours.Separated product and about 9 times with solvent cleaning.Soluble in water and dilution several times are preserved to be measured with it.Ultraviolet spectrometry spectrum and capillary electrophoresis detect all show selagine chemistry be connected in the superparamagnetic nanoparticle surface.When adopting homemade superparamagnetic nanoparticle to connect,, be evenly distributed, increased the contact area with selagine greatly, improved the efficient and the homogeneity that is connected product of ligation because nano particle diameter is little.Simultaneously, the superparamagnetic nanoparticle that has connected selagine still has good dispersibility and stability.
Embodiment 5
Connect integrin alpha on the superparamagnetic nanoparticle surface
5β v specific binding polypeptide GV3: 1-ethyl-3-of 100 milligrams (3-dimethyl propyl) carbodiimide hydrochlorides (EDC) and 500mgN-maloyl imines (NHS) are dissolved in pH6.In (N-morphine quinoline) ethyl sulfonic acid (MES) solution of 0, add an amount of superparamagnetic nanoparticle solution, magnetic agitation 60 minutes.Isolate carboxyl activatory ferric oxide then, add the MES solution of 5 milligrams of GV3 then, 20 degrees centigrade were reacted separated product 2 hours.With buffer solution for cleaning 5 times, dilution, detecting in the endotheliocyte model has tangible absorption enhancement.When adopting homemade superparamagnetic nanoparticle to carry out the biomolecules connection, the reaction conditions gentleness helps keeping biological activity; Reaction efficiency height, reaction evenly connect product and still have good dispersibility and stability.Simultaneously, because the superparamagnetic nanoparticle that is connected with polypeptide can increase the contact area of targeted polypeptide and cell surface greatly still at nanoscale when cell experiment.Effect obviously is better than the ferric oxide particles-peptide modified thing of the micro-meter scale of employing at present.
Claims (6)
1, the preparation method of easy dispersive superparamagnetic nanoparticle in a kind of water, it is characterized in that, at first polymeric chelant and iron ion are mixed, utilize the carboxyl and the iron particle on polymeric chelant surface to form the coordinate bond combination, drip alkali then, under the situation that drips alkali, hydroxyl and iron ion reaction generate ferric oxide, continue to drip alkali between the pH9-10, steric hindrance by polymeric chelant, ferric oxide particles stops to continue to increase, synthesize the nanoscale, superparamagnetic particle, because reaction is to carry out in position, polymeric chelant surrounds the surface of particle, by heated scrub and further modification, promptly obtain the superparamagnetic nanoparticle of functionalization again.
2, the preparation method of easy dispersive superparamagnetic nanoparticle in the water as claimed in claim 1, it is characterized in that, the polymeric chelant that adopts is carboxylic acid and the pure polymer mixed polymer that is polymerized, wherein carboxylic acid comprises at least a in C2～C18 binary acid and the hydroxycarboxylic acid, alcohol comprises at least a in C2～pure and mild sugar alcohol of C18 aliphatic dicarboxylic, its mixed polymer contains carboxyl and hydroxyl, has good dispersiveness in water and multiple organic solvent.
3, the preparation method of easy dispersive superparamagnetic nanoparticle in the water as claimed in claim 1 or 2, it is characterized in that, adding this polymeric chelant in synthetic iron oxide, to carry out original position synthetic, or when synthetic iron oxide, add monomeric carboxylic acids with pure, behind synthetic iron oxide, again the monomeric carboxylic acids of iron oxide surface and alcohol are carried out polyreaction, or behind synthetic iron oxide, directly add polymeric chelant.
4, the preparation method of easy dispersive superparamagnetic nanoparticle in the water as claimed in claim 1, it is characterized in that, resulting superparamagnetic nanoparticle, the median size that adopts the photon correlation light-intensity method to record is 5nm～500nm, aqueous solution and can with the miscible organic solvent of water such as ethanol, acetone in good dispersiveness is arranged, repeatedly cleaning, after ultrafiltration and concentration or the drying, disperse once more, median size and size distribution are stable, and the polymer active group is contained on the surface.
5, as the preparation method of easy dispersive superparamagnetic nanoparticle in claim 1 or the 4 described water, it is characterized in that the ferric oxide particles that comprises in the described superparamagnetic nanoparticle is Fe
2O
3, Fe
3O
4, iron carbonyl and composition thereof, the particle diameter that its single primary ferric oxide particles records with transmission electron microscope is limited to or equals 30nm, evacuates the mode of gathering with single primary particle or 2-5 primary particle and exist in nanoparticle.
6, as the easy preparation method of dispersive superparamagnetic nanoparticle in claim 1 or the 4 described water, it is characterized in that, drug loading in superparamagnetic nanoparticle, pharmaceutical pack is wrapped in the polymkeric substance, or be combined on the polymkeric substance by the method that chemistry connects, medicine is micromolecular compound medicine, middle pharmaceutically active ingredient, albumen, polypeptide, nucleic acid class biotechnology medicine; Perhaps connect antibody, part, cytokine, polypeptide this type of has the biomolecules of targeting characteristic on superparamagnetic nanoparticle surface, and method is: take by weighing the exsiccant superparamagnetic nanoparticle, add solvent, get the partial confounding suspension behind the ultra-sonic dispersion; Or the superparamagnetic nanoparticle solution of directly getting after the separation and purification is an amount of, add an amount of linking agent such as N, the pyridine of N-carbonyl diurethane miaow, 1-ethyl-3-(3-dimethyl propyl) carbodiimide hydrochloride, N-maloyl imines, active group carboxyl on the polymkeric substance is activated, isolate the superparamagnetic nanoparticle that carboxyl has been activated then, add this type of targeted molecular solution of medicine or protein polypeptide again, question response finishes the back to be separated, clean, promptly finish.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010130206A1 (en) | 2009-05-12 | 2010-11-18 | 无锡纳奥新材料科技有限公司 | Composite nanogranules from polymer/inorganic nanoparticles, preparation method thereof and use of the same |
| CN101008643B (en) * | 2006-01-23 | 2013-03-27 | 中国人民解放军军事医学科学院生物医学分析中心 | Metal chelated nanometer magnetic beads and preparation method and application therefor |
| WO2016078576A1 (en) * | 2014-11-19 | 2016-05-26 | 正大天晴药业集团股份有限公司 | Method for preparing modified superparamagnetic ferric oxide |
-
2004
- 2004-06-03 CN CN 200410024894 patent/CN1277751C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101008643B (en) * | 2006-01-23 | 2013-03-27 | 中国人民解放军军事医学科学院生物医学分析中心 | Metal chelated nanometer magnetic beads and preparation method and application therefor |
| WO2010130206A1 (en) | 2009-05-12 | 2010-11-18 | 无锡纳奥新材料科技有限公司 | Composite nanogranules from polymer/inorganic nanoparticles, preparation method thereof and use of the same |
| US9139430B2 (en) | 2009-05-12 | 2015-09-22 | Wuxi Now Materials Corp. | Composite nanogranules from polymer/inorganic nanoparticles, preparation method thereof and use of the same |
| WO2016078576A1 (en) * | 2014-11-19 | 2016-05-26 | 正大天晴药业集团股份有限公司 | Method for preparing modified superparamagnetic ferric oxide |
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| CN1277751C (en) | 2006-10-04 |
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Granted publication date: 20061004 Termination date: 20130603 |