CN102616735A - Single-formula biocompatible magnetic nanometer crystal size controlling preparation technology - Google Patents
Single-formula biocompatible magnetic nanometer crystal size controlling preparation technology Download PDFInfo
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Abstract
The invention relates to a controllable preparation method for biocompatible magnetic nanometer crystals with different sizes. Under the condition that a metal precursor, a multifunctional group-modified biocompatible macromolecule and micromolecule with alkyl chain jointly exist, gel is formed in high-boiling-point non-polar solvent or high-boiling-point weak-polar solvent, and without changing reaction raw materials and proportioning, and the gel is decomposed at high temperature in a single formula to prepare the biocompatible magnetic nanometer crystals with the different sizes by means of controlling the gelation degree of a reaction system according to the characteristic that the gel can be formed in the reaction system under the condition of preheating. The technical method has the advantages of simplicity and convenience in operation and high repeatability. The size regulating and controlling range of the biocompatible magnetic nanometer crystals prepared by the technical method is 4-25 nanometers, size distribution of the nanometer crystals is narrow, and large-scale and commercialized production can be realized.
Description
Technical field
The present invention relates to the preparation method of biological compatibility magnetic nano crystal size Control.More particularly; Utilize metal ion and the interaction that contains the polymer chemistry thing of multi-functional group; The macromolecule of metal precursor and multi-functional group is formed gel; Utilize this gel as the metal organic precursor body, on the basis that does not change system formulation, prepare the magnetic nano crystal of surface biological compatibility modification with different chemical size.
Background technology
Magnetic nano crystal has boundless using value at biomedical aspect such as Magnetic resonance imaging, medical diagnosis on disease and curative effect detection, magnetic heat cure and aspects such as cell separation and immunoassay.Because quantum size effect and confinement effect, nano material show the physicochemical properties that strong size relies on.In in the past 20 years; Utilize different technologies of preparing effectively to regulate and control to the size of the inorganic nanocrystal of different-shape; Yet develop the controllable synthesis method of novel inorganic nanocrystal, remain the research focus for preparing the inorganic nanocrystal association area based on liquid phase colloid chemistry method.Especially the magnetic inorganic nanocrystal that has wide biomedical applications prospect; Because it has the magnetic property that size relies on; Therefore the ability of its MRI signal enhancing shows strong size-dependent; Simultaneously, show the ability that different effective overcomes biophylaxis system and vascular disorder, and show distribution behavior in the different bodies thus and the imaging characteristics of different parts tissue because the nanocrystal of different size has different size of hydration.Therefore the controllable size preparation method who develops the high-quality biological compatibility magnetic nano crystal has extremely important meaning.
The size Control preparation method of high-quality magnetic nano crystal mainly contains two kinds: a kind of is that the magnetic nano crystal modified of first synthetic surface oleic acid/oleyl amine is as nuclear, and then as the magnetic nano crystal of seed growth large-size.This procedure is loaded down with trivial details, and the character of prepared macro nanometer crystal receives seed The properties big (J.Am.Chem.Soc.2002,124,8204.).Second method is to wait the size (Chem.Mater.2004 of magnetic nano crystal through the chemical property of the chemical property of the prescription that changes reaction system such as reaction temperature, presoma and concentration, surface stabilizer and with the ratio of presoma; 16; 3931.:J.Am.Chem.Soc.2006; 128,1675.; Chem.Commun.2004; 2306.) these two kinds of methods all need change the raw material and the proportioning of chemical reaction system; And up to the present; Shang Weiyou realizes the technology report that the magnetic nano crystal size Control is synthetic under single prescription, the prepared magnetic nano crystal of above-mentioned two kinds of methods can only dissolve or be dispersed in the organic media of nonpolar or low pole simultaneously, is unfavorable for practical application.
Recently, brilliant seminar far away of Institute of Chemistry, Academia Sinica has set up " one pot " prepared in reaction technology (CN03136275.3, CN03136273.7, CN200610114459.X, CN200710187275.0) of water-soluble and biological compatibility magnetic nano crystal.Utilize this technical method directly to prepare water-soluble, biocompatibility (Adv.Mater.2005,17,1001.) through " one pot " reaction but and the surface have the biological compatibility magnetic nano crystal (Adv.Mater.2006,18,2553.) of reactive group.On the basis of patent CN200710187275.0; Utilize metal precursor and the biocompatibility macromolecule effect that contains 2 and 2 above functional groups to form gel, we have invented the single formulation technology of different size high-crystallinity, biological compatibility magnetic nano crystal that decentralization is high.
Summary of the invention
One of the object of the invention provides the biological compatibility magnetic nano crystal with different size, and its particle diameter distributes and is no more than 15%.
The particle size range of the biological compatibility magnetic nano crystal that two of the object of the invention provides is 4～25 nanometers.
The biological compatibility magnetic nano crystal that three of the object of the invention provides, its size are to utilize the metal ion and the interaction of the biocompatibility macromolecule that contains multi-functional group to form gel, regulate and control through the degree of gelation of the hierarchy of control.
Four of the object of the invention provide a kind of under single prescription the preparation method of the biological compatibility magnetic nano crystal of synthetic different size.
Above-mentioned purpose of the present invention realizes through following technical scheme, that is,
A kind of single prescription biological compatibility magnetic nano crystal size Control preparation method is characterized in that: through a kind of biological compatibility magnetic nano crystal that reacts the formulation different size:
The little molecule of metal precursor, biocompatibility macromolecule and band alkyl chain is dissolved in higher boiling non-polar solven or the higher boiling weak polar solvent forms mother liquor; Feed inert gas and get rid of the oxygen in the reaction system; The constant temperature that under condition of different temperatures, mother liquor is carried out different time is hatched; Form the gel of different viscosities, obtain the biological compatibility magnetic nano crystal of different size then through the elevated temperature heat decomposition reaction
Wherein,
Described biocompatibility macromolecule is 2 macromolecules that above functional group is modified,
Described incubation temperature scope is 15 degrees centigrade～200 degrees centigrade,
Described incubation time scope is 0～5 day,
The range of viscosities of described gel is in 0.01～200 handkerchief second.
The present invention reacts through " one pot "; Pyrolytic metallo-organic compound or metal inorganic chemicals in high boiling nonpolar or high boiling weak polar solvent; Under the condition of the biocompatibility macromolecule that contains 2 above functional groups and small molecule amine that has alkyl chain or the common existence of little molecule acid; Precursor solution is hatched different time under different temperatures, prepare the high-crystallinity and the biological compatibility magnetic nano crystal of different size.
The high-crystallinity of different size of the present invention and biological compatibility magnetic nano crystal, particle size range are 4～25 nanometers, in the magnetic nano crystal finishing 2 above functional group biocompatibility macromolecules are arranged; Or the magnetic nano crystal finishing have 2 above functional group biocompatibility macromolecules with the band alkyl chain little molecule.
Described 2 above functional group biocompatibility macromolecules are meant that sulfydryl, carboxyl, amino and phosphate group etc. are the polyethyleneglycol derivative of end group, and the biomolecule that contains a plurality of sulfydryls, carboxyl, amino and phosphate group.
Described magnetic nano crystal mainly is magnetic transition metal oxide, lanthanide rare metal oxide, transition metal oxide and transient metal doped type magnetic oxide; The oxide and the ferrite of preferred iron, cobalt, nickel, manganese, and the oxide of rare earth gadolinium, dysprosium, holmium, erbium, thulium.
The size Control synthetic technology is to adopt " one pot " method under biological compatibility magnetic nano crystal of the present invention and the single prescription, and course of reaction may further comprise the steps:
(1) in reaction vessel, Organometallic Chemistry thing or inorganic metal compound (like ferric acetyl acetonade etc.), biocompatibility macromolecule (is that 2000 end groups are the polyethylene glycol of carboxyl etc. like molecular weight) and alkyl small molecule amine are dissolved in the nonpolar or higher boiling weak polar solvent of higher boiling (like diphenyl ether; Benzyl ether etc.) in; And logical inert gas is discharged the oxygen in the reaction system, the formation reaction mother liquor.
(2) reaction mother liquor is hatched in the different temperature scope respectively, obtain the mother liquor of certain gel degree, and the mother liquor of the different gel degree that will obtain heating, prepare the magnetic nano crystal of biocompatibility; Incubation temperature is that 15 degree are to 200 degree; Incubation time is 0～5 day; Reaction temperature is higher than 160 degree; Reaction time is 30 minutes to 4 hours.
(3) reactant liquor in the step (2) is cooled to room temperature; The adding volume is the magnetic nano crystal that the organic solvent (ethanol, carrene, chloroform, ether, benzinum, cyclohexane, n-hexane or their mixture etc.) of 5 times of reactant liquors is settled out biocompatibility; And with behind the identical organic solvent washing three times, magnet separates or centrifugation obtains biological compatibility magnetic nano crystal.
(4) biological compatibility magnetic nano crystal that step (3) is obtained is dissolved in the deionized water, dialyses and carries out purifying in 2 days, obtains directly carrying out the aqueous solution of the magnetic nano crystal of biologic applications.
Described metallo-organic compound is the organic complex that contains transition metal or rare earth metal, like praseodynium iron, diacetyl acetone iron, iron pentacarbonyl, phenyl ferric acetyl acetonade, iron oleate, ferric stearate, diacetyl acetone manganese, phenyl manganese acetylacetonate, manganese oleate, manganese stearate, diacetyl acetone nickel, nickel carbonyl, oleic acid nickel, nickel stearate, diacetyl acetone cobalt, cobalt octacarbonyl, cobalt oleate, cobaltous octadecanate, praseodynium gadolinium, oleic acid gadolinium, stearic acid gadolinium, praseodynium dysprosium, oleic acid dysprosium, stearic acid dysprosium, praseodynium holmium, praseodynium erbium, oleic acid erbium, stearic acid erbium, praseodynium thulium, praseodynium thulium, oleic acid thulium, stearic acid thulium.
Described metal inorganic compound is inorganic matter and the hydrated inorganic salt that contains transition metal and rare earth metal; The acetate, citrate, oxalates, chlorate, nitrate, sulfate and the hydrate thereof that comprise above-mentioned metal,, four iron chloride hexahydrate ferrous, Iron(III) chloride hexahydrate, ferric nitrate, ferric sulfate, cobalt acetate, citric acid cobalt, cobalt oxalate, cobaltic chloride, manganese acetate, manganese oxalate, protochloride manganese, manganese nitrate, manganese sulfate, gadolinium acetate, gadolinium chloride, three hydration gadolinium chlorides, six hydration gadolinium chlorides, gadolinium nitrate, acetic acid dysprosium, dysprosium chloride, three hydration dysprosium chlorides, six hydration dysprosium chlorides, dysprosium nitrate, acetic acid holmium, holmium chloride, three hydration holmium chlorides, six hydration holmium chlorides, holmium nitrate, acetic acid erbium, erbium chloride, three hydration erbium chlorides, six hydration erbium chlorides, erbium nitrate, acetic acid thulium, thulium chloride, three hydration thulium chlorides, six hydration thulium chlorides, thulium nitrate like: ferric acetate, ironic citrate, ferric oxalate, ferric trichloride, dichloride.
The molecular weight of described biocompatibility macromolecule is 600～20000, and preferred 600～6000; The polyethylene glycol of main line style, branching, also comprise line style, branching polyethylene glycol and polyacrylic acid, polymethylacrylic acid, polyacrylic acid, polylysine, gather a kind of in the block copolymer of leucine, polyglutamic acid, poly-aspartate or PLA formation.The most important architectural feature of above-mentioned biocompatibility macromolecule is to contain functional group carboxyl, amido, sulfydryl, phosphate more than 2 at high molecular segment or two ends.
The present invention prepares the technical method that the different size biological compatibility magnetic nano crystal adopted and has technology characteristics simple, easy and simple to handle; Promptly through " one pot " reaction; Do not change the raw material and the ratio of reaction system, under single prescription, realize the controlled preparation of different size biological compatibility magnetic nano crystal.The size of resulting magnetic nano crystal can be regulated and control to 25 nanometers from 4 nanometers, high, the narrow particle size distribution of this biological compatibility magnetic nano crystal degree of crystallinity simultaneously, and surface-functionalized biocompatibility macromolecule is modified the requirement that guarantees its biologic applications.This technical method is easy and simple to handle, repeatability is high, can be used for large-scale commercialization.
Description of drawings
The inversion photo of Fig. 1 embodiment of the invention 1 gained gel.
The viscosity of Fig. 2 embodiment of the invention 1 gained gel is with the variation diagram of incubation temperature and incubation time.
The transmission electron microscope photo of Fig. 3 embodiment of the invention 2 gained samples and column distribution map thereof.
The x-ray diffractogram of powder (a) of Fig. 4 embodiment of the invention 2 gained samples and gained sample hysteresis curve figure (b) under externally-applied magnetic field.
The dynamic light scattering distribution map of Fig. 5 embodiment of the invention 2 gained samples in water.
The transmission electron microscope photo of Fig. 6 embodiment of the invention 3 gained samples and column distribution map thereof.
The transmission electron microscope photo of Fig. 7 embodiment of the invention 4 gained samples and column distribution map thereof.
The transmission electron microscope photo of Fig. 8 embodiment of the invention 5 gained samples and column distribution map thereof.
The transmission electron microscope photo of Fig. 9 embodiment of the invention 6 gained samples and column distribution map thereof.
The transmission electron microscope photo of Figure 10 embodiment of the invention 7 gained samples and column distribution map thereof.
The transmission electron microscope photo and the electron diffraction diagram of Figure 11 embodiment of the invention 8 gained samples.
The transmission electron microscope photo of Figure 12 embodiment of the invention 9 gained samples and column distribution map thereof.
The specific embodiment
Embodiment 1:
Take by weighing the praseodynium iron (Fe (acac) of 2.12g
3); 7.9mL oleyl amine and two carboxy polyethylene glycol 2000 (HOOC-PEG-COOH) of 24.0g be dissolved in the 100mL diphenyl ether; With the logical nitrogen deoxygenation 2h of reaction mixture; Then reactant liquor is spent to hatch to spend in 0 hour, 40 to hatch to spend in 12 hours, 40 to hatch to spend in 3 days, 40 to hatch to spend in 5 days, 80 to hatch to spend in 4 hours, 140 40 and hatched 4 hours, obtain the mother liquor of different gel degree.Fig. 1 has shown that praseodynium iron and two carboxy polyethylene glycol and oleyl amine form the inversion photo of gel in diphenyl ether.Fig. 2 has shown the gel variation tendency that viscosity prolongs with incubation time under different incubation temperature.
Embodiment 2:
Take by weighing the praseodynium iron (Fe (acac) of 2.12g
3); 7.9mL oleyl amine and two carboxy polyethylene glycol 2000 (HOOC-PEG-COOH) of 24.0g be dissolved in the 100mL diphenyl ether; With the logical nitrogen deoxygenation 2h of reaction mixture, directly reaction mother liquor is heated to 253 degree in 15min then, under the mechanical agitation condition of 400rpm, react.Behind the reaction 30min, reactant liquor is cooled to room temperature, adds the reaction solution of the mixed solvent deposition gained of ethanol and ether; After magnetic separation and purification 3 times; Magnetic nano crystal is dissolved in the deionized water, and dialysed 2 days, the aqueous solution of the magnetic nano crystal that promptly obtains directly to use.Fig. 3 is transmission electron microscope (TEM) photo of gained magnetic nano crystal, can know that by figure the average diameter of nano particle is 11.3nm, and size distribution is 13%.Fig. 4 a is powder x-ray diffraction (XRD) figure of gained magnetic nanoparticle, shows that prepared sample is the Fe of spinelle face-centered cubic crystal structure
3O
4Nanocrystal.In addition, adopt phenanthroline colour developing measuring Fe content results to show Fe
3+: Fe
2+Ratio be 2: 1, confirmed that further prepared sample is Fe
3O
4Nanocrystal.The magnetic property of magnetic nano crystal adopts vibrating specimen magnetometer (VSM) to measure; Magnetic nano crystal hysteresis curve at room temperature is shown in Fig. 4 b; The result shows that prepared sample has superparamagnetism; Saturation magnetization is 20.5emu/g, in conjunction with the mensuration result of thermogravimetric analysis to the plane of crystal content of organics, pure Fe
3O
4The saturation magnetization of nanocrystal is 50.2emu/g.Utilize dynamic light scattering that sample fluid mechanics size is carried out hydrodynamics test (Fig. 5), the result shows Fe shown in Figure 1
3O
4Nanocrystal has kept good dispersiveness in water, do not assemble and the deposition generation.
Embodiment 3:
According to the step of embodiment 1, reaction mixture is hatched and obtained reaction mother liquor in 12 hours at 40 degree, this reaction mother liquor is prepared biological compatibility magnetic nano crystal according to the method for embodiment 2.Fig. 6 is the gained magnetic Fe
3O
4The transmission electron microscope of nanocrystal (TEM) photo can know that by figure the average diameter of magnetic nano crystal is 12.1nm, and size distribution is 14%.
Embodiment 4:
According to the step of embodiment 1, reaction mixture is hatched and obtained reaction mother liquor in 3 days at 40 degree, this reaction mother liquor is prepared biological compatibility magnetic nano crystal according to the method for embodiment 2.Fig. 7 is the gained magnetic Fe
3O
4The transmission electron microscope of nanocrystal (TEM) photo can know that by figure the average diameter of magnetic nano crystal is 14.1nm, and size distribution is 11%.
Embodiment 5:
According to the step of embodiment 1, reaction mixture is hatched and obtained reaction mother liquor in 5 days at 40 degree, this reaction mother liquor is prepared biological compatibility magnetic nano crystal according to the method for embodiment 2.Fig. 8 is the gained magnetic Fe
3O
4The transmission electron microscope of nanocrystal (TEM) photo can know that by figure the average diameter of magnetic nano crystal is 14.3nm, and size distribution is 11%.
Embodiment 6:
According to the step of embodiment 1, reaction mixture is hatched 4h and obtained reaction mother liquor at 80 degree, this reaction mother liquor is prepared biological compatibility magnetic nano crystal according to the method for embodiment 2.Fig. 9 is the gained magnetic Fe
3O
4The transmission electron microscope of nanocrystal (TEM) photo can know that by figure the average diameter of magnetic nano crystal is 15.6nm, and size distribution is 12%.
Embodiment 7:
According to the step of embodiment 1, reaction mixture is hatched 4h and obtained reaction mother liquor at 140 degree, this reaction mother liquor is prepared biological compatibility magnetic nano crystal according to the method for embodiment 2.Figure 10 is the gained magnetic Fe
3O
4The transmission electron microscope of nanocrystal (TEM) photo can know that by figure the average diameter of magnetic nano crystal is 18.9nm, and size distribution is 11%.
Embodiment 8:
Take by weighing the manganese acetylacetonate (Mn (acac) of 1.52g
2), two carboxy polyethylene glycol 2000 (HOOC-PEG-COOH) of the oleyl amine of 7.9mL and 24.0g are dissolved in the 100mL diphenyl ether, with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.Step according to embodiment 2 directly is heated to 253 degree with reaction mother liquor in 15min then, under the mechanical agitation condition of 400rpm, reacts.Behind the reaction 2h; Reactant liquor is cooled to room temperature, adds the reaction solution of the mixed solvent deposition gained of ethanol and ether, after centrifugalizing purifying 3 times, magnetic nano crystal is dissolved in the deionized water; And dialysed the aqueous solution of the magnetic nano crystal that promptly obtains directly to use 2 days.Figure 11 is transmission electron microscope (TEM) photo of gained magnetic nano crystal, can know that by figure the average diameter of nano particle is 40.4nm, and corresponding electronic diffraction result shows that prepared magnetic nano crystal is Mn
3O
4Nanocrystal.
Embodiment 9:
Take by weighing the manganese acetylacetonate (Mn (acac) of 0.087g
2) and the praseodynium iron (Fe (acac) of 0.212g
3), two carboxy polyethylene glycol 2000 (HOOC-PEG-COOH) of the oleyl amine of 0.3mL and 3.6g are dissolved in the 15mL diphenyl ether, with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.Step according to embodiment 2 directly is heated to 253 degree with reaction mother liquor in 15min then, under the mechanical agitation condition of 400rpm, reacts.All the other operations are all with embodiment 2.Figure 12 is transmission electron microscope (TEM) photo of the magnetic nano crystal of gained; Can know that by figure the average diameter of nano particle is 4.8nm; Recording Mn in the prepared magnetic nano crystal: Fe through inductively coupled plasma emission spectrum (ICP) is 1: 2, shows that prepared magnetic nano crystal is MnFe
2O
4Nanocrystal.
Embodiment 10:
Take by weighing the acetylacetone cobalt (Co (acac) of 0.1927g
2), the diamine base Macrogol 2000 (H of the oleic acid of 1.7mL and 24.0g
2N-PEG-NH
2) be dissolved in the 25mL diphenyl ether, with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.Step according to embodiment 2 directly is heated to 253 degree with reaction mother liquor in 15min then, under the mechanical agitation condition of 400rpm, reacts.Behind the reaction 4h; Reactant liquor is cooled to room temperature, adds the reaction solution of the mixed solvent deposition gained of ethanol and ether, after centrifugalizing purifying 3 times, magnetic nano crystal is dissolved in the deionized water; And dialysed the aqueous solution of the magnetic nano crystal that promptly obtains directly to use 2 days.The average diameter of gained CoO magnetic nano crystal is 5nm.
Embodiment 11:
Take by weighing the praseodynium iron (Fe (acac) of 2.12g
3), the oleyl amine of 7.9mL and the polyethylene glycol of 24.0g (PEG) are dissolved in the 100mL diphenyl ether with the block copolymer (PLAA-PEG-PLAA) that gathers alanine (PLAA), with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.Step according to embodiment 2 directly is heated to 253 degree with reaction mother liquor in 15min then, under the mechanical agitation condition of 400rpm, reacts.All the other operations are all with embodiment 2.Prepared biological compatibility magnetic nano crystal is of a size of 12nm.
Embodiment 12:
Take by weighing the ferric trichloride (FeCl of 2.12g
3), two carboxy polyethylene glycol 2000 (HOOC-PEG-COOH) of the oleyl amine of 7.9mL and 24.0g are dissolved in the 100mL diphenyl ether, with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.Step according to embodiment 2 directly is heated to 253 degree with reaction mother liquor in 15min then, under the mechanical agitation condition of 400rpm, reacts.All the other operations are all with embodiment 2.Gained biological compatibility magnetic ferric oxide nano crystal is of a size of 8～15nm.
Embodiment 13:
Take by weighing the praseodynium gadolinium (Gd (acac) of 2.72g
3), two carboxy polyethylene glycol 2000 (HOOC-PEG-COOH) of the oleyl amine of 7.9mL and 24.0g are dissolved in the 100mL diphenyl ether, with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.All the other operations are all with embodiment 2,3,6.The size of prepared gadolinium oxide magnetic nano crystal is at 8～25nm.
Embodiment 14
Take by weighing the praseodynium dysprosium (Dy (acac) of 2.76g
3), two carboxy polyethylene glycol 2000 (HOOC-PEG-COOH) of the oleyl amine of 7.9mL and 24.0g are dissolved in the 100mL diphenyl ether, with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.All the other operations are all with embodiment 2,3,6.The size of prepared dysprosia magnetic nano crystal is at 5～20nm.
Embodiment 15:
Take by weighing the tri-chlorination holmium (HoCl of 1.628g
3), two carboxy polyethylene glycol 2000 (HOOC-PEG-COOH) of the oleyl amine of 7.9mL and 24.0g are dissolved in the 100mL diphenyl ether, with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.All the other operations are all with embodiment 2,3,6.The size of prepared holimium oxide magnetic nano crystal is at 7～22nm.
Embodiment 16:
Take by weighing the praseodynium gadolinium (Gd (acac) of 2.72g
3), two sulfydryl Macrogol 2000s (HS-PEG-SH) of the oleyl amine of 7.9mL and 24.0g are dissolved in the 100mL diphenyl ether, with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.All the other operations are all with embodiment 2,3,6.The size of prepared gadolinium oxide magnetic nano crystal is at 8～25nm.
Embodiment 17:
Take by weighing the praseodynium iron (Fe (acac) of 2.12g
3), two carboxy polyethylene glycol 2000 (HOOC-PEG-COOH) of the oleyl amine of 7.9mL and 24.0g are dissolved in the 100mL trioctylamine, with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.All the other operations are all with embodiment 2,3,6.The size of prepared iron oxide magnetic nano crystal is at 4～25nm.
Embodiment 18:
Take by weighing the praseodynium iron (Fe (acac) of 2.12g
3), two carboxy polyethylene glycol 4000 (HOOC-PEG-COOH) of the oleyl amine of 7.9mL and 48.0g are dissolved in the 100mL diphenyl ether, with the logical nitrogen deoxygenation 2h of reaction mixture, obtain reaction mother liquor.All the other operations are all with embodiment 2,3,6.The size of prepared iron oxide magnetic nano crystal is at 5～20nm.
From above-mentioned each embodiment and remaining experiment, we can draw to draw a conclusion: the macromolecule of (1) metal precursor and multi-functional group forms gel, can be used as the precursor of reaction; (2) control its gelation intensity through regulating incubation temperature and incubation time, higher temperature can make reaction mother liquor shorten incubation time; (3) gel of different gelation intensity is done presoma, can prepare the biological compatibility magnetic nano crystal of different size; (4) through control precursor gel degree methods, under the condition that does not change reaction raw materials and proportioning, can realize the regulation and control of biological compatibility magnetic nano crystal size under the single prescription.
Claims (10)
1. single prescription biological compatibility magnetic nano crystal size Control preparation method is characterized in that: through a kind of biological compatibility magnetic nano crystal that reacts the formulation different size:
The little molecule of metal precursor, biocompatibility macromolecule and band alkyl chain is dissolved in higher boiling non-polar solven or the higher boiling weak polar solvent forms mother liquor; Feed inert gas and get rid of the oxygen in the reaction system; The constant temperature that under condition of different temperatures, mother liquor is carried out different time is hatched; Form the gel of different viscosities, obtain the biological compatibility magnetic nano crystal of different size then through the elevated temperature heat decomposition reaction
Wherein,
Described biocompatibility macromolecule is 2 macromolecules that above functional group is modified,
Described incubation temperature scope is 15 degrees centigrade～200 degrees centigrade,
Described incubation time scope is 0～5 day,
The range of viscosities of described gel is in 0.01～200 handkerchief second.
2. preparation method according to claim 1 is characterized in that: described biological compatibility magnetic nano crystal has paramagnetism, superparamagnetism or ferromagnetism.
3. preparation method according to claim 1 is characterized in that: the size modification scope of described biological compatibility magnetic nano crystal is 4～25 nanometers.
4. preparation method according to claim 1; It is characterized in that: described biocompatibility macromolecule is selected from polyethylene glycol or contains the block copolymer of polyethylene glycol segment; Above-mentioned polymer molecular weight is 600～20000, and end group is modified with carboxyl, sulfydryl, amido or the phosphate group more than 2.
5. preparation method according to claim 1; It is characterized in that: described biocompatibility macromolecule is the polyethylene glycol of line style, branching, the polyethylene glycol of line style, branching and polyacrylic acid, polymethylacrylic acid, polyvinylamine, gather alanine, polylysine, gather leucine, a kind of in the block copolymer that polyglutamic acid, poly-aspartate, polycaprolactone or PLA form.
6. preparation method according to claim 1 is characterized in that: described metal precursor is organic coordination compound or the inorganic compound that contains transition metal or rare earth metal.
7. preparation method according to claim 6 is characterized in that: at least a in described transition metal or rare earth element chosen from Fe, cobalt, nickel, manganese and the lanthanide rare metallic element.
8. preparation method according to claim 6 is characterized in that: the organic compound of described transition metal or rare earth metal comprises acetyl acetone complex, oleic acid complex, stearic acid complex, phenyl acetyl acetone complex, carbonyl-complexes; The inorganic compound of described transition metal or rare earth metal comprises chlorate, oxalates, acetate, sulfate, nitrate.
9. preparation method according to claim 1 is characterized in that: the boiling point of described higher boiling non-polar solven or higher boiling weak polar solvent is higher than 160 ℃.
10. preparation method according to claim 1, this method is further comprising the steps of:
Add organic solvent deposit and wash biological compatibility magnetic nano crystal, separate obtaining biological compatibility magnetic nano crystal through centrifugation or magnetic; The gained biological compatibility magnetic nano crystal is dissolved in the deionized water, carries out purifying, obtain biological compatibility magnetic nano crystal solution through dialysis.
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