CN102451476A - Radionuclide-doped magnetic nano crystal with biocompatibility, and preparation method of radionuclide-doped magnetic nano crystal - Google Patents
Radionuclide-doped magnetic nano crystal with biocompatibility, and preparation method of radionuclide-doped magnetic nano crystal Download PDFInfo
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- CN102451476A CN102451476A CN2010105245100A CN201010524510A CN102451476A CN 102451476 A CN102451476 A CN 102451476A CN 2010105245100 A CN2010105245100 A CN 2010105245100A CN 201010524510 A CN201010524510 A CN 201010524510A CN 102451476 A CN102451476 A CN 102451476A
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Abstract
The invention relates to a radionuclide-doped magnetic nano crystal with biocompatibility, and a preparation method of the radionuclide-doped magnetic nano crystal. The radionuclide-doped magnetic nano crystal can be highly dissolved in a physiological buffer solution and stably dispersed, and has the characteristics of high crystallinity, radioactivity and biocompatibility. The preparation method comprises the steps of: under the condition of a biocompatibility macromolecule or the coexistence of the biocompatibility macromolecule and a molecule with an alkyl chain, decomposing a metal precursor and a radionuclide compound at high temperature in a high-boiling point non-polarity or high-boiling point weak-polarity solvent, and while a magnetic nano crystal is formed, doping the radionuclide and carrying out in-place modification on the biocompatibility macromolecule and the molecule with the alkyl chain on the surface of the nano crystal to obtain the radionuclide-doped magnetic nano crystal with biocompatibility. The radionuclide-doped magnetic nano crystal with biocompatibility, prepared by adopting the method, has the advantages of controllable type and strength, controllable and uniform grain size, high crystallinity, high magnetic responsibility, good biocompatibility and wide application prospect.
Description
Technical field
The present invention relates to materials chemistry, nano science, the field of nuclear medicine, particularly adulterated magnetic nano crystal of radionuclide of biocompatibility and preparation method thereof.
Background technology
Magnetic nano crystal is widely used in biomedical sector, comprising: magnetic resonance radiography (MRI), cell separation are separated with labelling, DNA, the detection of tumor and treatment, target medicine carrier etc.Particularly aspect magnetic resonance radiography, moved towards clinical practice based on the particulate SuperparamagneticIron Oxide of magnetic ferric oxide nano nanoparticles (SPIO) and Ultrasmall Superparamagnetic Iron Oxidenanoparticles (USPIO) type contrast agent.Though nuclear magnetic resonance has higher spatial resolution, and can provide the advantage of anatomical information accurately, but still have the deficiency that sensitivity is poor, sensitivity is low.Compare with nuclear magnetic resonance, have higher sensitivity though the radio nuclide imaging spatial resolution is low.Thereby be main body with the magnetic nano crystal, merge the advantage of two kinds of imaging techniques, development magnetic resonance-nucleic bimodal imaging has caused various countries scientist's very big concern.Realize magnetic resonance-nucleic bimodal imaging; A most important prerequisite is exactly that preparation can be used for the double mode contrast agent of magnetic resonance-nucleic of in-vivo imaging, i.e. preparation can be under physiological condition ability stable existence, good biocompatibility, have radioactive magnetic nano crystal.
At present; Synthetic have radioactive magnetic nano crystal and generally be divided into for two steps; At first synthesize magnetic nano crystal, then it is being carried out radioisotope labeling, mainly contain following labeling method: 1) magnetic nano crystal and radionuclide chemical compound carry out blend (CN01114912.4); 2) coordinating group of magnetic nano-particle through the finishing molecule carries out coordination with radionuclide and combines (CN200410002030.2, J.Nucl.Med., 2008,49,1371); 3) magnetic nano-particle carries out covalency coupling couplet (Angew.Chem.Int.Ed., 2008,47,6259) through finishing molecule and radionuclide chemical compound.Method (1) is owing to just simply mix, and magnetic nano crystal and nucleic combine through weak interaction, comprise Electrostatic Absorption, hydrophobic interaction etc., and radionuclide is very easy to come off from magnetic nano crystal.In method (2) and (3); Magnetic nano crystal utilizes coordinate bond or covalent bond and radionuclide to carry out the coupling couplet through the finishing molecule; Bond strength ratio method (1) is strong; But its preparation route is complicated; The stability of gained coupling matter receives the influence of the binding ability of binding ability, finishing molecule and the radionuclide of finishing molecule and magnetic nano crystal, outside chemical environment many factors such as (as: kind of pH value, other chemical species and concentration), thereby has limited their application.In order to make radionuclide and magnetic nano crystal stable bond, Kim etc. adopt coprecipitation (US7407673B2), in synthesizing magnetic nano crystal, use radionuclide
67Cu
2+Substitute part Fe
2+, prepare radionuclide
67The adulterated magnetic nano crystal of Cu
67Cu
xFe
1-xOFe
2O
3(x=0.1~0.4).Though said method embeds magnetic nano crystal inside with radionuclide; Make radionuclide and magnetic nano crystal stable bond; But because the defective of coprecipitation itself; That nanocrystal product that it prepares is formed is clear and definite inadequately, degree of crystallinity is poor, distribution of sizes is wide, a little less than the magnetic response relatively, these deficiencies will limit their application.
Compare with coprecipitation, the elevated temperature heat decomposition method of rising in recent years can successfully be prepared degree of crystallinity height, narrow size distribution, composition is clear and definite, magnetic response is strong magnetic nano crystal.A large amount of research work are being done aspect the elevated temperature heat decomposition method synthesizing magnetic nano crystal by brilliant seminar far away of Institute of Chemistry, Academia Sinica; Through adopting intensive polar solvent, " one pot " prepared in reaction technology (CN03136275.3, CN200610114459.X) of water-soluble magnetic nanocrystal, " one pot " prepared in reaction technology (CN03136273.7) of biological compatibility magnetic nano crystal have successively been set up as the pyroreaction medium.Utilize " one pot " prepared in reaction technology of biological compatibility magnetic nano crystal directly to obtain water solublity, biocompatibility (Adv.Mater., 2005,17; 1001) but and the surface have the biological compatibility magnetic nano crystal (Adv.Mater. of reactive group; 2006,18,2553).After this, on the basis of CN03136273.7 patent, brilliant far away wait in the clear high-crystallinity of Crinis Carbonisatus, the physiological buffer can high dissolution and " one pot " prepared in reaction technology (CN200710187275.0) of the biological compatibility magnetic nano crystal of stable dispersion.The intensive polar solvent as reaction medium has been abandoned in this invention; The non-ligand solvent of transferring to adopt nonpolar or low pole is as reaction medium; In reaction system, introduce simultaneously can with the biocompatibility macromolecule of magnetic nano crystal surface coordination and the micromolecule of band alkyl chain, but obtained the magnetic nano crystal of in physiological buffer high dissolution and stable dispersion.The magnetic nano crystal that this method prepares has good biocompatibility; Utilize the biocompatibility macromolecule of its finishing and the antibody of radionuclide 127I labelling to carry out the coupling couplet; Prepare magnetic resonance-nucleic bimodulus contrast agent, and successfully realized the interior targeting magnetic resonance of body-nucleic double-mode imaging (Mol.Pharmaceut., 2009 of contrast agent; 6; 1074), join preparation magnetic resonance-nucleic bimodulus contrast agent but adopt magnetic nano crystal finishing molecule and radionuclide to carry out coupling, the bonded stability of magnetic nano crystal and radionuclide still has problems.In order to overcome the deficiency a little less than magnetic nano crystal and the radionuclide bond strength; Inherit the advantage of existing method for preparing simultaneously; On the basis of CN200710187275.0 patent, we invented high-crystallinity, can be in dissolving of physiological buffer camber and stable dispersion, have " one pot " prepared in reaction technology of the adulterated magnetic nano crystal of radionuclide of radioactivity and biocompatibility.
Summary of the invention
One of the object of the invention provide controllable size, high-crystallinity, can be in dissolving of physiological buffer camber and stable dispersion, have the adulterated magnetic nano crystal of radionuclide of radioactivity and biocompatibility.
The adulterated magnetic nano crystal of the radionuclide that two of the object of the invention provides, wherein the radionuclide of being with mainly radiates other particles such as α, β, gamma-rays and positron or radiates different rays or particle more than 2 kinds and 2 kinds simultaneously.
The adulterated magnetic nano crystal of the radionuclide that three of the object of the invention provides, its surface have polymer-modified layer, and good biocompatibility, magnetic fluid that in physiological buffer solution, forms or colloid solution have the stability of height.
The adulterated magnetic nano crystal of the radionuclide that four of the object of the invention provides, the polymer of its finishing carries carboxyl or amido, and the covalency coupling that can directly be used for adulterated magnetic nano crystal of radionuclide and biomolecule joins.
The adulterated magnetic nano crystal of the radionuclide that five of the object of the invention provides, its size and distribution can be regulated and control through reaction condition.
The adulterated magnetic nano crystal of the radionuclide that six of the object of the invention provides, its radioactivity type and intensity can be regulated and control through reaction condition.
Seven of the object of the invention provide a kind of controllable size, high-crystallinity, can be in dissolving of physiological buffer camber and stable dispersion, have " one pot " reaction method for preparing of the adulterated magnetic nano crystal of radionuclide of radioactivity and biocompatibility.
The present invention reacts through " one pot "; In high boiling nonpolar or high boiling weak polar solvent in pyrolytic organo-metallic compound or the inorganic metal salt compound; Add a certain amount of radionuclide chemical compound; Under biocompatibility macromolecule or small molecule amine, carboxylic acid or the common condition that exists of alcohol at biocompatibility macromolecule and band alkyl chain, through single step reaction prepare high-crystallinity, can be in dissolving of physiological buffer camber and stable dispersion, have the adulterated magnetic nano crystal of radionuclide of radioactivity and biocompatibility.
The adulterated magnetic nano crystal of the radionuclide of biocompatibility of the present invention has paramagnetism, superparamagnetism or ferromagnetism, and particle diameter is 1~60 nanometer, can be in dissolving of physiological buffer camber and stable dispersion.
In the adulterated magnetic nano crystal of described radionuclide; Magnetic part mainly is magnetic transition metal and oxide, magnetic lanthanide rare metallic oxide, transition metal or the adulterated magnetic oxide of rare earth metal; Preferred ferrum and oxide thereof; Cobalt, nickel, manganese or their oxide, and the oxide of gadolinium, terbium, dysprosium, holmium, erbium, thulium.
In the adulterated magnetic nano crystal of described radionuclide; Radionuclide mainly is other particles such as radiation α, β, gamma-rays and positron or radiates different rays more than 2 kinds simultaneously or the metal radionuclide of particle, the radionuclide of preferred ferrum, cobalt, nickel, manganese and magnetic lanthanide rare metal.Radionuclide is 1: 100~1: 100000 with the atomic ratio that forms magnetic nano crystal on-radiation metallic element.
The adulterated magnetic nano crystal of the radionuclide of biocompatibility of the present invention; Its surface has the micromolecule of biocompatibility macromolecule modification or biocompatibility macromolecule and band alkyl chain to modify jointly, and the quality percentage composition that the micromolecule of described biocompatibility macromolecule or biocompatibility macromolecule and band alkyl chain accounts for biological compatibility magnetic nano crystal is 5~85%.
Described biocompatibility macromolecule mainly is the Polyethylene Glycol (PEG) and the derivant (comprising carboxylated Polyethylene Glycol, amination Polyethylene Glycol, telechelic polyglycol with different terminal group etc.) thereof of line style, branching; The Polyethylene Glycol of line style, branching and polyacrylic acid (PAA), polymethylacrylic acid (PMA), PVA (PEI), gather alanine, polylysine, gather leucine, polyglutamic acid, poly-aspartate, polycaprolactone or polylactic acid (one or more in the block copolymer that (PLA) forms; Its molecular weight is 600~20000, and preferred 600~6000.The most important architectural feature of above-mentioned polymer is that biocompatible polymer is Polyethylene Glycol, polyethyleneglycol derivative or the copolymer that has the Polyethylene Glycol segment; Make that the adulterated magnetic nano crystal of radionuclide both can be water-soluble; Can be dissolved in organic solvent again, finally make the adulterated magnetic nano crystal of the radionuclide that obtains have highly-water-soluble and biocompatibility.
The micromolecule of described band alkyl chain is small molecule amine, micromolecule carboxylic acid or the small molecular alcohol that has alkyl chain.Wherein, the selection principle of small molecule amine, micromolecule carboxylic acid or small molecular alcohol is the high temperature that can bear in the pyrolysis process of organo-metallic compound or inorganic metal salt compound, and generally speaking, boiling point is greater than 160 ℃, CH in the alkyl chain
2Unit number be 4~24, preferred 12~18.Especially preferably comprise oleyl amine, lauryl amine, oleic acid, capric acid, 1,2-hexadecane glycol etc. in the present invention with the micromolecule of alkyl chain.
If biocompatiblity molecules of the present invention adopt has the biocompatibility macromolecule of two or more carboxyls and ((or) amine groups; The adulterated magnetic nano crystal of the then prepared radionuclide that obtains surface can carry one or more carboxyl that under temperate condition, can further react or amidos, utilizes this functional group can adulterated magnetic nano crystal of radionuclide of the present invention and biomolecule carried out covalency coupling couplet and be applied to the actual imaging detection range.
Biomolecule of the present invention comprise aminoacid, polypeptide, albumen, biotin, DNA amido derivative or DNA carboxy derivatives and have amido or the carbohydrate of carboxyl etc.
The adulterated magnetic nano crystal of the radionuclide of biocompatibility of the present invention is the ability high dissolution in physiological buffer, and the placement of gained solution does not still have deposition after half a year and separates out.
Physiological buffer according to the invention is phosphate buffer (PBS), aseptic phosphoric acid physiological buffer (D-PBS), Hank ' s balanced salt solution (HBSS) or Earle ' s balanced salt solution (EBSS).
The method for preparing of the adulterated magnetic nano crystal of radionuclide of biocompatibility involved in the present invention is to adopt " one pot " method, and course of reaction may further comprise the steps:
(1) in reaction vessel with organo-metallic compound or inorganic metal salt compound, promptly magnetic nano crystal presoma (like ferric acetyl acetonade etc.), radionuclide chemical compound (as
57CoCl
2Or
57CoCl
2Aqueous solutions etc.), the micromolecule of biocompatibility macromolecule (is 4000 the two ends Polyethylene Glycol that has carboxyl simultaneously etc. like molecular weight) and band alkyl chain (like oleic acid etc.) is dissolved in the nonpolar or high boiling point weak polar solvent of high boiling point (like phenylate etc.) and forms mixed reaction solution.Wherein, organo-metallic compound or inorganic metal salt compound concentrations are 0.001mol/L~0.2mol/L in the reactant liquor, and preferred concentration is 0.01mol/L~0.1mol/L; The radionuclide compound concentration is 0.01 μ mol/L~2mmol/L, and preferred concentration is 0.1 μ mol/L~1mmol/L; The concentration of biocompatibility macromolecule is 0.001mol/L~1mol/L, preferred 0.05mol/L~0.6mol/L; The concentration of small molecule amine, micromolecule carboxylic acid or the small molecular alcohol of band alkyl chain is 0~0.2mol/L, preferred 0~0.1mol/L;
(2) if the radionuclide chemical compound that adopts in the step (1) is present in the aqueous solution, then the mixed reaction solution with step (1) heats a period of time at vacuum condition, to remove the Free water in the mixed reaction solution, then is cooled to room temperature.Wherein, heating-up temperature is 40~100 ℃, and preferred temperature is 65~85 ℃; Evacuated pressure is 0.5~10kPa, and preferred pressure is 1~4kPa; Be 30~240min heat time heating time, preferred 40~120min;
(3) feed noble gas and get rid of the oxygen in the reaction system, heating steps (1) is the mixed reaction solution of (2) perhaps, and reaction temperature is controlled between 120~350 ℃, preferred 180~280 ℃; Response time is 0.25~24 hour, preferred 0.5~12 hour; When presoma was decomposed to form magnetic nano crystal, the radionuclide chemical compound decomposed simultaneously and radionuclide is got in the middle of the lattice of magnetic nano crystal, obtains the adulterated magnetic nano crystal of radionuclide of biocompatibility;
(4) reactant liquor in the step (3) is cooled to room temperature; Adding volume is organic solvent (ether, ethanol, methanol, acetone, petroleum ether or their the mixture etc.) deposition of 2~50 times of reactant liquor volumes; Deposition is after magnetic separates perhaps centrifugalize; With same organic solvent washing product crystal 3~5 times, magnetic separates or centrifugalize can obtain high-crystallinity, can be in dissolving of physiological buffer camber and stable dispersion, have the adulterated magnetic nano crystal of radionuclide of radioactivity, biocompatibility;
Described organo-metallic compound is the organic coordination compound that contains transition metal or rare earth metal, the organic coordination compound of ferrum, cobalt, nickel, manganese or lanthanide rare metal for example, and its part comprises acetylacetone,2,4-pentanedione, carbonyl, phenyl acetylacetone,2,4-pentanedione, cyclopentadiene.The instantiation of organo-metallic compound includes but not limited to: praseodynium ferrum; Diacetyl acetone ferrum; Iron pentacarbonyl; Praseodynium nickel; Diacetyl acetone nickel; Four carbon back nickel; The praseodynium cobalt; Diacetyl acetone cobalt; Eight carbon backs, two cobalts; Praseodynium manganese; Diacetyl acetone manganese; Cyclopentadiene tricarbonyl manganese; The acetylacetone,2,4-pentanedione gadolinium; Phenyl acetylacetone,2,4-pentanedione gadolinium; Three cyclopentadiene gadoliniums; The acetylacetone,2,4-pentanedione terbium; Three cyclopentadiene terbiums; The acetylacetone,2,4-pentanedione dysprosium; Three cyclopentadiene dysprosiums; The acetylacetone,2,4-pentanedione holmium; Three cyclopentadiene holmiums; The acetylacetone,2,4-pentanedione erbium; Three cyclopentadiene erbiums; The acetylacetone,2,4-pentanedione thulium; Three cyclopentadiene thuliums etc.
Described inorganic metal salt compound is inorganic salt and the hydrated inorganic salt that contains transition metal and rare earth metal, like oleate, stearate, soap, acetate, gluconate, citrate, oxalates, chloride, sulfate, nitrate and the hydrate thereof of ferrum, cobalt, nickel, manganese or lanthanide rare metal.The instantiation of inorganic metal salt compound includes but not limited to: iron oleate; Ferric stearate; Iron acetate; Ferric oxalate; Oleic acid nickel; Nickel stearate; Nickel oxalate; Citric acid nickel; Nickel acetate; Cobalt oleate; Cobaltous octadecanate; Cobaltous acetate; Cobalt oxalate; The capric acid cobalt; The citric acid cobalt; Manganese oleate; Manganese stearate; Manganese acetate; Manganese oxalate; Manganese citrate; Manganese gluconate; The oleic acid gadolinium; The stearic acid gadolinium; Gadolinium acetate; Ethanedioic acid, gadolinium(3+) salt (3:2); The oleic acid terbium; The stearic acid terbium; The acetic acid terbium; The oxalic acid terbium; The oleic acid dysprosium; The stearic acid dysprosium; The acetic acid dysprosium; The oxalic acid dysprosium; The oleic acid holmium; The stearic acid holmium; The acetic acid holmium; Holmium oxalate; The oleic acid erbium; The stearic acid erbium; The acetic acid erbium; Erbium oxalate; The oleic acid thulium; The acetic acid thulium; The stearic acid thulium; Thulium oxalate; Ferric chloride; Ferrous chloride; Four iron chloride hexahydrate; Iron(III) chloride hexahydrate; Ferrous sulfate; Nickel dichloride.; Nickel dichloride hexahydrate; Cobaltous chloride; Cobalt chloride hexahydrate; Manganese chloride; Gadolinium trichloride; Three water Gadolinium trichlorides; Six water Gadolinium trichlorides; Gadolinium trinitrate; Digadolinium trisulfate; Eight water Digadolinium trisulfates; Terbium chloride; Six water terbium chlorides; Terbium nitrate (Tb(NO3)3); The sulphuric acid terbium; Eight water sulphuric acid terbiums; Dysprosium trichloride; Six water Dysprosium trichlorides; Dysprosium trinitrate; Dysprosium sesquisulfate; Eight water Dysprosium sesquisulfates; Holmium trichloride; Six water Holmium trichlorides; Holmium nitrate; The sulphuric acid holmium; Eight water sulphuric acid holmiums; Erbium trichloride; Six water Erbium trichlorides; Erbium trinitrate; Erbium sulfate; Eight water erbium sulfates; Thulium chloride; Six water thulium chlorides; Thulium nitrate; Thulium sulfate or eight water thulium sulfates etc.
Described radionuclide is can radiate a kind of ray or particle (for example other particles such as α, β, gamma-rays and positron) or radiate different rays more than 2 kinds simultaneously or the transition metal and the lanthanide rare metal nucleic of particle, as
51Cr,
54Mn,
55Fe,
59Fe,
57Co,
58Co,
60Co,
56Ni,
64Cu,
65Zn,
90Y,
99Mo,
99MlTc,
103Pd,
110MlAg,
109Cd,
186Re,
192Ir,
194Ir,
198Au,
147Pm,
153Gd,
159Dy,
169Yb etc., preferred
54Mn,
55Fe,
57Co,
60Co,
56Ni,
64Cu,
147Pm,
153Gd,
159Dy,
169Yb.
The inorganic salt that described radionuclide chemical compound is above-mentioned radionuclide, hydrated inorganic salt, organo-metallic compound and their aqueous solution, the chloride of preferred above-mentioned radionuclide, nitrate.
Described biocompatibility macromolecule is Polyethylene Glycol, polyethyleneglycol derivative or the copolymer that has the Polyethylene Glycol segment, and molecular weight is 600~20000, preferred 600~6000; Mainly be selected from the Polyethylene Glycol and the derivant thereof of line style, branching; Also comprise line style, branching Polyethylene Glycol and polyacrylic acid, polymethylacrylic acid, PVA, gather alanine, polylysine, gather leucine, in the block copolymer that polyglutamic acid, poly-aspartate or polylactic acid form one or more; The biocompatibility macromolecule that has an above carboxyl or amine groups on the preferred polymer segment, preferred especially two carboxy polyethylene glycol, α-carboxyl-omega-amino-Polyethylene Glycol.
The micromolecule of described band alkyl chain is small molecule amine, micromolecule carboxylic acid and the small molecular alcohol compounds that has alkyl chain, wherein alkyl chain CH
2Unit number is 4~24, preferred 12~18, as: oleyl amine, oleic acid, lauryl amine, 1,2-hexadecane glycol etc.
Nonpolar or the high boiling point weak polar solvent of described high boiling point is characterized in that the boiling point of solvent is higher than 160 ℃, preferred phenylate, dibenzyl ether, 1-octadecylene, oleyl amine, trioctylamine, tri-n-butylamine or above-claimed cpd derivant and analog.
The present invention can comprise that the concentration of metallic precursor, the concentration of biocompatibility macromolecule, the micromolecular concentration of being with alkyl chain, response time, temperature-rise period etc. prepare the adulterated magnetic nano crystal of radionuclide of different size through changing reaction condition.
The present invention can make the adulterated magnetic nano crystal of radionuclide of different radioactive intensities through changing the ratio of radionuclide chemical compound and magnetic nano crystal precursor.
The present invention prepares the adulterated magnetic nano crystal of radionuclide of biocompatibility; Its radionuclide is uniformly distributed in magnetic nano crystal inside; Both combine to stablize; " one pot " method for preparing that adopts has technology characteristics simple, easy and simple to handle; The adulterated magnetic nano crystal degree of crystallinity height of gained radionuclide, narrow particle size distribution, size adjustable, magnetic response are strong, good biocompatibility, can be in dissolving of physiological buffer camber and stable dispersion, and the surface has functional group, can further carry out biological coupling and join.
Description of drawings
Fig. 1. the transmission electron microscope photo (A) of the embodiment of the invention 1 gained sample and column particle size distribution figure (B) thereof.
Fig. 2. the X-ray diffraction spectrogram (A-C) of embodiment of the invention 1-3 gained sample and PDF#88-0866 standard spectrogram (D).
Fig. 3. the hysteresis curve of the embodiment of the invention 1 gained sample.
Fig. 4. the photo of the embodiment of the invention 4 gained magnetic fluids in magnetic field.
Fig. 5. the transmission electron microscope photo (A) of the embodiment of the invention 6 gained samples and column particle size distribution figure (B) thereof.
Fig. 6. the transmission electron microscope photo (A) of the embodiment of the invention 7 gained samples and column particle size distribution figure (B) thereof.
Fig. 7. the transmission electron microscope photo of the embodiment of the invention 10 gained samples.
Fig. 8. the transmission electron microscope photo of the embodiment of the invention 11 gained samples.
Fig. 9. the transmission electron microscope photo of the embodiment of the invention 16 gained samples.
Figure 10. the magnetic resonance radiography figure of the embodiment of the invention 1 gained sample.
Reference numeral
1. Magnet
The specific embodiment
In the four-hole boiling flask of 50mL, 0.53g ferric acetyl acetonade, the two carboxyl PEG2000 of 6g, 2.0mL oleyl amine are dissolved in the 25mL phenylate, add 1 * 10
-3Mol/L's
57CoCl
2Aqueous solution 96 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min then are cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 30min is cooled to room temperature with reaction system, goes out with ether sedimentation
57The adulterated magnetic nano crystal of Co, magnetic separates and washs three times, obtains the biocompatibility that the surface has carboxyl
57The adulterated Fe of Co
3O
4Magnetic nano crystal.After treating its natural drying, the gained nanocrystal is dissolved in the deionized water, utilizes transmission electron microscope (TEM) what obtain
57The adulterated Fe of Co
3O
4Magnetic nano crystal characterizes, and accompanying drawing 1 is a biocompatibility
57The adulterated Fe of Co
3O
4Transmission electron microscope photo of magnetic nano crystal (A) and histogram of particle size distribution (B) thereof.Can know by electromicroscopic photograph,
57The adulterated Fe of Co
3O
4Magnetic nano crystal is an almost spherical, and mean diameter is 8.4 nanometers, and the particle diameter relative standard deviation is 13%, and monodispersity is good.Accompanying drawing 2 (A) is a gained
57The adulterated Fe of Co
3O
4The X-ray diffraction of magnetic nano crystal (XRD) collection of illustrative plates can be known the gained biocompatibility by figure
57The adulterated Fe of Co
3O
4Magnetic nano crystal degree of crystallinity is high, Fe in this spectrogram and the accompanying drawing 2 (D)
3O
4Standard spectrogram (PDF#88-0866) meets better, shows the radioactivity of mixing
57Co does not have influence basically to the crystal structure of magnetic nano crystal.Accompanying drawing 3 is for being somebody's turn to do
57The adulterated Fe of Co
3O
4The hysteresis curve of magnetic nano crystal, crystalline saturation magnetization is 26.8emu/g, has superparamagnetism.The thermal weight loss experiment shows that the quality percentage composition of the biocompatibility macromolecule that gained biological compatibility magnetic nano crystal particle surface is modified is about 60%.Will
57The adulterated Fe of Co
3O
4Magnetic nano crystal is used the inductively coupled plasma mass spectroscopy with after the nitric acid nitrating dissolving, and the result shows,
57The adulterated Fe of Co
3O
4In the magnetic nano crystal Fe with
57The atomic ratio of Co is 40099: 1,
57The utilization rate of Co is 39%.Radioactive counter is measured the result and is shown, should
57The adulterated Fe of Co
3O
4It is 8.0 μ Ci/ (mg that magnetic nano crystal radiates gamma-ray intensity
57The adulterated Fe of Co
3O
4Magnetic nano crystal).
Embodiment 2-mixes not commensurability Co (1)
In the four-hole boiling flask of 50mL, 0.53g ferric acetyl acetonade, the two carboxyl PEG2000 of 6g, 2.0mL oleyl amine are dissolved in the 25mL phenylate, add 1 * 10
-3Mol/L's
57CoCl
2Aqueous solution 500 μ L, mix homogeneously, under the system pressure of 4kPa, 90 ℃ of heating 80min then are cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 30min is cooled to room temperature with reaction system, and last handling process is identical with embodiment 1, obtains
57The adulterated Fe of Co
3O
4The magnetic nano crystal mean diameter is 8.2nm, and radiating gamma-ray intensity is 45.1 μ Ci/ (mg
57The adulterated Fe of Co
3O
4Magnetic nano crystal).Gained
57The adulterated Fe of Co
3O
4The X-ray diffracting spectrum of magnetic nano crystal is shown in accompanying drawing 2 (B).
Embodiment 3-mixes not commensurability Co (2)
In the four-hole boiling flask of 50mL, 0.53g ferric acetyl acetonade, the two carboxyl PEG2000 of 6g, 2.0mL oleyl amine are dissolved in the 25mL phenylate, add 1 * 10
-2Mol/L's
57CoCl
2Aqueous solution 200 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min then are cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 30min is cooled to room temperature with reaction system, and last handling process is identical with embodiment 1, obtains
57The adulterated Fe of Co
3O
4The magnetic nano crystal mean diameter is 8.9nm, and inductivity coupled plasma mass spectrometry is measured the result and shown gained
57The adulterated Fe of Co
3O
4In the magnetic nano crystal Fe with
57The atomic ratio of Co is 1605: 1, and radioactive counter is measured the result and shown gained
57The adulterated Fe of Co
3O
4It is 202 μ Ci/ (mg that magnetic nano crystal radiates gamma-ray intensity
57The adulterated Fe of Co
3O
4Magnetic nano crystal), accompanying drawing 2 (C) is a gained
57The adulterated Fe of Co
3O
4X-ray diffracting spectrum in the X-ray diffracting spectrum of magnetic nano crystal, itself and embodiment 1 and 2 is closely similar, shows the radioactivity of mixing
57Co is little to the crystal structure influence of magnetic nano crystal.
Embodiment 4-is stability in PBS
With what obtain among the embodiment 1
57The adulterated Fe of Co
3O
4Magnetic nano crystal is dissolved in 0.01M PBS, and (phosphate buffer pH=7.4), is made into the magnetic fluid of 3g/L, and the nothing deposition was separated out after this magnetic fluid was placed half a year.Accompanying drawing 4 is placed for this magnetic fluid and is placed on the other photo of taking of Magnet half a year.
Embodiment 5-
57CoCl
2Change solid into
In the four-hole boiling flask of 50mL, add 1 * 10
-3Mol/L's
57CoCl
2Aqueous solution 96 μ L, vacuum drying obtains
57CoCl
2Solid, then add the two carboxyl PEG2000 of 0.53g ferric acetyl acetonade, 6g, 2.0mL oleyl amine and 25mL phenylate, treat that all raw materials are all after the dissolving; Logical nitrogen deoxygenation 30min; Back flow reaction 30min is cooled to room temperature with reaction system, goes out the adulterated magnetic nano crystal of radioactivity with ether sedimentation; Magnetic separates and washs three times, obtains the biocompatibility that the surface has carboxyl
57The adulterated Fe of Co
3O
4Magnetic nano crystal, the particulate mean diameter of gained is 8.2nm, radioactive counter is measured the result and is shown, should
57The adulterated Fe of Co
3O
4It is 7.8 μ Ci/ (mg that magnetic nano crystal radiates gamma-ray intensity
57The adulterated Fe of Co
3O
4Magnetic nano crystal).
Embodiment 6-changes charging sequence
In the four-hole boiling flask of 50mL, 0.53g ferric acetyl acetonade, the two carboxyl PEG2000 of 6g are dissolved in the 25mL phenylate, add 1 * 10
-3Mol/L's
57CoCl
2Aqueous solution 96 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min; Then be cooled to room temperature, add the 2.0mL oleyl amine, mix homogeneously, logical nitrogen deoxygenation 30min; Back flow reaction 30min is cooled to room temperature with reaction system, and last handling process is identical with embodiment 1, obtains
57The adulterated Fe of Co
3O
4The magnetic nano crystal mean diameter is 12.5nm, and radiating gamma-ray intensity is 8.8 μ Ci/ (mg
57The adulterated Fe of Co
3O
4Magnetic nano crystal).Accompanying drawing 5 is the gained biocompatibility
57The adulterated Fe of Co
3O
4Transmission electron microscope photo of magnetic nano crystal (A) and histogram of particle size distribution (B) thereof.
Embodiment 7-changes concentration
In the four-hole boiling flask of 50mL, 0.53g ferric acetyl acetonade, the two carboxyl PEG2000 of 6g, 2.0mL oleyl amine are dissolved in the 15mL phenylate, add 1 * 10
-3Mol/L's
57CoCl
2Aqueous solution 96 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min then are cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 120min is cooled to room temperature with reaction system, and last handling process is identical with embodiment 1, obtains
57The adulterated Fe of Co
3O
4The magnetic nano crystal mean diameter is 16.1nm, and radiating gamma-ray intensity is 8.1 μ Ci/ (mg
57The adulterated Fe of Co
3O
4Magnetic nano crystal).Accompanying drawing 6 is the gained biocompatibility
57The adulterated Fe of Co
3O
4Transmission electron microscope photo of magnetic nano crystal (A) and histogram of particle size distribution (B) thereof.
Embodiment 8-is with oleic acid and PEG6000
In the four-hole boiling flask of 100mL, 1.06g ferric acetyl acetonade, the two carboxyl PEG6000 of 18g, 2.6mL oleic acid are dissolved in the 50mL phenylate, add 1 * 10
-3Mol/L's
57CoCl
2Aqueous solution 200 μ L, mix homogeneously, under the system pressure of 2.0kPa, 80 ℃ of heating 60min then are cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 30min is cooled to room temperature with reaction system, and last handling process is identical with embodiment 1, obtains
57The adulterated Fe of Co
3O
4The magnetic nano crystal mean diameter is 16.1nm, and radiating gamma-ray intensity is 9.3 μ Ci/ (mg
57The adulterated Fe of Co
3O
4Magnetic nano crystal).
Embodiment 9-raw material is used iron pentacarbonyl, only uses α-carboxyl-omega-amino-PEG without oleyl amine
In the four-hole boiling flask of 50mL, add 1 * 10
-2Mol/L's
56NiCl
2Aqueous solution 100 μ L, vacuum drying obtains
56NiCl
2Solid, then add 0.29g iron pentacarbonyl, 6g α-carboxyl-omega-amino-PEG2000 and 25mL phenylate, treat that all raw materials are all after the dissolving; Logical nitrogen deoxygenation 30min; Reacting by heating system to 200 ℃, stopped reaction after 8 hours is cooled to room temperature with reaction system; All the other operations are all with embodiment 1, and the gained finishing has amino biocompatibility
56The adulterated magnetic nano crystal particle diameter of Ni is 7~14nm, should
56The adulterated magnetic nano crystal of Ni has ferromagnetism.
Embodiment 10-raw material changes manganese acetate into and mixes
55Fe
In the four-hole boiling flask of 50mL; (synthetic agent: the synthetic method route is to utilize terminal hydroxy group PEG2000 to cause the lactide polyreaction with 0.37g four water acetic acid manganese, 10g carboxy polyethylene glycol and polylactic-acid block copolymer (PEG-b-PLA); Obtain block polymer; Obtain the block polymer that the PLA end has carboxyl with the maleic anhydride reaction again, molecular weight is between 3000-5000) be dissolved in the 25mL oleyl amine, add 5 * 10
-3Mol/L's
55FeCl
3Aqueous solution 100 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min; Then be cooled to room temperature, logical nitrogen deoxygenation 30min, reacting by heating system to 200 ℃ reaction 15min; Reaction system is cooled to room temperature, and last handling process is identical with embodiment 1, and accompanying drawing 7 is a gained
55The transmission electron microscope photo of the adulterated MnO nanocrystal of Fe obtains
55The adulterated MnO nanocrystal of Fe mean diameter is 6.1nm, and inductivity coupled plasma mass spectrometry is measured the result and shown gained
57In the adulterated MnO nanocrystal of Fe Mn with
55The atomic ratio of Fe is 8000: 1.
Embodiment 11-raw material changes nickel acetylacetonate into and ferric acetyl acetonade is mixed
57Co synthesizes Ni ferrite
In the four-hole boiling flask of 100mL, (synthetic agent: adopting the ATRP method, is macromole evocating agent with PEG2000 with 0.71g ferric acetyl acetonade, 0.26g diacetyl acetone nickel, 16g Polyethylene Glycol and polyacrylic acid block copolymer (PEG-b-PAA); Adopt living polymerisation process to obtain above-mentioned block polymer, mean molecule quantity is 5500, and document sees reference: Langmuir; 2005; 21 (9), 4205), the 2.0mL oleyl amine is dissolved in the 50mL phenylate adding 1 * 10
-3Mol/L's
57CoCl
2Aqueous solution 96 μ L, mix homogeneously is under the system pressure of 2.5kPa; 80 ℃ of heating 60min then are cooled to room temperature, logical nitrogen deoxygenation 30min; Reacting by heating system to 200 ℃ reaction 6 hours is cooled to room temperature with reaction system, and last handling process is identical with embodiment 1.Accompanying drawing 8 is the gained biocompatibility
57The transmission electron microscope photo of the adulterated ferronickel oxidate nano of Co crystal, its mean diameter is 6.7nm, inductivity coupled plasma mass spectrometry is measured the result and is shown, in the gained nanocrystal in Fe, Ni,
57The atomic ratio of Co is 25060: 8010: 1.The thermal weight loss experiment shows the gained biocompatibility
57The quality percentage composition of the biocompatibility macromolecule that the adulterated ferronickel oxidate nano of Co plane of crystal is modified is about 70%.
Embodiment 12-mixes
64Cu
In the four-hole boiling flask of 50mL, 1.35g iron oleate, the two carboxyl PEG4000 of 12g, 1.75g lauryl amine are dissolved in the 25mL dibenzyl ether, add 1 * 10
-2Mol/L's
64CuCl
2Aqueous solution 200 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min; Then be cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 1 hour; Reaction system is cooled to room temperature, last handling process is identical with embodiment 1, and obtaining the surface has carboxyl modified
64The adulterated Fe of Cu
3O
4The magnetic nano crystal mean diameter is 7.0nm, and inductivity coupled plasma mass spectrometry is measured the result and shown gained
54The adulterated Fe of Cu
3O
4In the magnetic nano crystal Fe with
64The atomic ratio of Cu is 4218: 1.With the biocompatibility for preparing
64The adulterated Fe of Cu
3O
4Magnetic nano crystal is soluble in water; Through under 1 hour the situation of externally-applied magnetic field the material that does not have magnetic in the system being separated with magnetic crystal; Through radioactivity determination, this composite magnetic crystal still has radioactivity, explains that radionuclide is that stable bond is in magnetic nano crystal.
Embodiment 13-mixes
65Zn
According to the formulated reaction solution of embodiment 1, molal quantitys such as usefulness
65ZnCl
2Replace
57CoCl
2, can obtain size 5~13nm's through identical reactions step
65The adulterated Fe of Zn
3O
4Magnetic nano crystal.
Embodiment 14-mixes rare earth
159Dy
In the four-hole boiling flask of 50mL, 0.5g ferric stearate, 6g are had branching PEG2000, the 0.2g 1 of carboxyl, 2-cetyl glycol is dissolved in the 25mL octadecylene, adds 1 * 10
-3Mol/L's
159DyCl
3Aqueous solution 200 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min; Then be cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 2 hours; Reaction system is cooled to room temperature, all the other operations are identical with embodiment 1, and obtaining the surface has carboxyl modified
159The adulterated Fe of Dy
3O
4The magnetic nano crystal particle diameter is 7~14nm, and inductivity coupled plasma mass spectrometry is measured the result and shown gained
159The adulterated Fe of Dy
3O
4In the magnetic nano crystal Fe with
159The atomic ratio of Dy is 22673: 1.
Embodiment 15-raw material changes acetylacetone,2,4-pentanedione Dy into and mixes
57Co
In the four-hole boiling flask of 50mL, 0.89g acetylacetone,2,4-pentanedione dysprosium, the two carboxyl PEG2000 of 3.6g and 1.8g decyl amine are dissolved in the 25mL phenylate, add 1 * 10
-3Mol/L's
57CoCl
2Aqueous solution 96 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min; Then be cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 8 hours; Reaction system is cooled to room temperature, last handling process is identical with embodiment 1, obtains the surface and has carboxyl modified
57The adulterated Dy of Co
2O
3Nanocrystal, the particulate average-size of gained is about 3nm.
Embodiment 16-raw material changes the acetylacetone,2,4-pentanedione erbium into and mixes
159Dy
The two carboxyl PEG2000 of 0.9g acetylacetone,2,4-pentanedione erbium, 3.6g and 2.0mL oleyl amine be dissolved in the 25mL1-octadecylene process reactant liquor, then reactant liquor is transferred in the 50mL four-hole bottle, add 1 * 10
-2Mol/L's
159DyCl
3Aqueous solution 200 μ L, mix homogeneously is under the system pressure of 2.5kPa; 80 ℃ of heating 60min then are cooled to room temperature, logical nitrogen deoxygenation 30min; Back flow reaction 6 hours is cooled to room temperature with reaction system, adds excessive ether sedimentation and obtains the surface and have carboxyl modified
159The adulterated Er of Dy
2O
3Nanocrystal, remaining last handling process is identical with the correlation step among the embodiment 1, and the particulate average-size of gained is 4.3 nanometers, and inductivity coupled plasma mass spectrometry is measured the result and is shown gained
159The adulterated Er of Dy
2O
3In the nanocrystal Er with
159The atomic ratio of Dy is 2018: 1, and Fig. 9 does
159The adulterated Er of Dy
2O
3The electromicroscopic photograph of nano-particle.
Embodiment 17-raw material changes Gadolinium trichloride into and mixes
55Fe
The two carboxyl PEG2000 of 0.40g Gadolinium trichloride, 6g and 2.0mL oleyl amine be dissolved in the 30mL phenylate process reactant liquor, then reactant liquor is transferred in the 50mL four-hole bottle, add 5 * 10
-3Mol/L's
55FeCl
3Aqueous solution 100 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min then are cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 6 hours, cooling reaction system is to room temperature, adds excessive ether sedimentation and obtains the surface and have carboxyl
55The adulterated Gd of Fe
2O
3Nanocrystal, remaining last handling process is identical with the correlation step among the embodiment 1, and the particulate average-size of gained is 7.5 nanometers.
Embodiment 18-raw material changes cobalt oleate into and mixes
55Fe
In the four-hole boiling flask of 50mL, 0.5g cobalt oleate, 6g mono carboxylic PEG6000 and 0.5g oleic acid are dissolved in the 15mL phenylate, add 5 * 10
-3Mol/L's
55FeCl
3Aqueous solution 100 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min then are cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 1 hour is cooled to room temperature with reaction system.Remaining last handling process is identical with the correlation step among the embodiment 1, the gained biocompatibility
55The adulterated Co of Fe
3O
4Nanocrystal is of a size of 8~17 nanometers, and inductivity coupled plasma mass spectrometry is measured the result and shown gained
55The adulterated Co of Fe
3O
4In the nanocrystal Co with
55The atomic ratio of Fe is 9736: 1.
Embodiment 19-raw material changes six hydration Holmium trichlorides into and mixes
159Dy
The two carboxyl PEG2000 of 0.6g six hydration Holmium trichlorides, 6g and 2mL oleyl amine be dissolved in the 25mL phenylate process reactant liquor, then reactant liquor is transferred in the 50mL four-hole bottle, add 1 * 10
-2Mol/L's
159DyCl
3Aqueous solution 100 μ L, mix homogeneously, under the system pressure of 2.5kPa, 80 ℃ of heating 60min then are cooled to room temperature, logical nitrogen deoxygenation 30min, back flow reaction 6 hours, cooling reaction system is to room temperature, adds excessive ether sedimentation and obtains the surface and have carboxyl
159The adulterated Ho of Dy
2O
3Nanocrystal, remaining last handling process is identical with the correlation step among the embodiment 1, and the particulate average-size of gained is 6.8 nanometers.
Embodiment 20-radionuclide and magnetic nano crystal stable bond
With the biocompatibility for preparing among the embodiment 1
57The adulterated Fe of Co
3O
4Magnetic nano crystal is soluble in water; Be made into the magnetic fluid of 5g/L, it is 8000~12000 bag filter that this magnetic fluid of 10mL is put into molecular cut off, then bag filter is placed 500mL 0.01M PBS (phosphate buffer; PH=7.4) dialysis is 3 days in; Preceding 12 hours, every primary water that changed at a distance from 2 hours, every later on primary water that changed at a distance from 12 hours.In the monitoring bag filter
57The adulterated Fe of Co
3O
4The radioactive intensity of magnetic nano crystal, result show that its radioactive intensity is constant basically in time, and radionuclide is described
57Co and Fe
3O
4The magnetic nano crystal stable bond.
Embodiment 21-radionuclide and magnetic nano crystal stable bond
According to the operating procedure among the embodiment 17, changing 0.01M PBS into pH is 5,6,7,8,9 aqueous solution (regulating with hydrochloric acid and sodium hydroxide), dialyses three days, and the result shows in the bag filter
57The adulterated Fe of Co
3O
4The radioactive intensity of magnetic nano crystal is constant basically in time.
The adulterated magnetic nano crystal of embodiment 22-radionuclide is in the application in bio-imaging field
The dry powder sample that obtains behind the vacuum drying among the embodiment 1 is dissolved in the solution that is made into 5g/L among the 0.01M PBS (pH=6.5); Get this solution 0.5mL; Add 2 μ mol EDCHCl (1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride) and 5 μ mol Sulfo-NHS (N-hydroxy thiosuccinimide); Reaction added PBS (pH=8.0) solution of the anti-stomach cancer target antibody 3H11 of 0.5mL 2mg/mL, room temperature reaction 4 hours after 15 minutes under the room temperature.Prepare coupling and join 3H11 antibody
57The adulterated Fe of Co
3O
4Magnetic resonance-nucleic bimodulus probe molecule with tumor-targeting; Above molecular probe is gone in the corresponding gastric cancer tumor nude mouse through tail vein injection and carried out nuclear magnetic resonance and radiological measuring, and the radioactive counter result shows that gamma-ray intensity is 8.3 μ Ci, and the magnetic resonance radiography result is shown in figure 10; Behind the injection dual-mode molecular probe; Along with the nano-probe prolongation of circulation time in vivo, tumor locus is deepening gradually, demonstrates tangible T2 radiography effect.This experiment shows that coupling is associated with the adulterated nanocrystal of nucleic of stomach cancer target 3H11 antibody and has realized targeting magnetic resonance radiography function, has radioactivity simultaneously because of this probe simultaneously, can also realize radio nuclide imaging in the body.
Claims (13)
1. the adulterated magnetic nano crystal of the radionuclide of a biocompatibility; It is characterized in that: described radionuclide stable bond is in magnetic nano crystal, and the magnetic nano crystal finishing has biocompatibility macromolecule or is modified with biocompatibility macromolecule and the micromolecule of being with alkyl chain.
2. the adulterated magnetic nano crystal of the radionuclide of biocompatibility according to claim 1, it is characterized in that: the adulterated magnetic nano crystal of said radionuclide has magnetic and radioactivity simultaneously.
3. the adulterated magnetic nano crystal of the radionuclide of biocompatibility according to claim 1 is characterized in that: described radionuclide is can radiate a kind of ray or particle or radiate different rays more than 2 kinds simultaneously or the radioactivity transition metal and the radioactivity lanthanide rare metallic element of particle.
4. the adulterated magnetic nano crystal of the radionuclide of biocompatibility according to claim 1 is characterized in that: radionuclide is 1: 100~1: 100000 with the atomic ratio that forms magnetic nano crystal on-radiation metallic element.
5. the adulterated magnetic nano crystal of the radionuclide of biocompatibility according to claim 1; It is characterized in that: described magnetic nano crystal is selected from magnetic transition metal and oxide thereof, magnetic lanthanide rare metallic oxide; The particle diameter of magnetic nano crystal is 1~60 nanometer, has paramagnetism, superparamagnetism or ferromagnetism.
6. the adulterated magnetic nano crystal of the radionuclide of biocompatibility according to claim 1; It is characterized in that: described biocompatibility macromolecule has one or more carboxyls or amido; Molecular weight is 600~6000; Be selected from the Polyethylene Glycol of line style, branching; Said Polyethylene Glycol is optional by carboxylated, amination or have the distant pawl of heterodoxy base, the Polyethylene Glycol of line style, branching and polyacrylic acid, PVA, polymethylacrylic acid, gather alanine, polylysine, gather leucine, in the block copolymer of polyglutamic acid, poly-aspartate, polycaprolactone or polylactic acid formation one or more.
7. the adulterated magnetic nano crystal of the radionuclide of biocompatibility according to claim 1; It is characterized in that: described biocompatibility macromolecule after modifying on the magnetic nano crystal surface, can have on its polymer chain one or more can be directly and biomolecule carry out carboxyl or the amido that the covalency coupling joins.
8. the adulterated magnetic nano crystal of the radionuclide of biocompatibility according to claim 1 is characterized in that: the quality percentage composition that the micromolecule of described biocompatibility macromolecule or biocompatibility macromolecule and band alkyl chain accounts for the adulterated magnetic nano crystal of radionuclide of biocompatibility is 5~85%.
9. the adulterated magnetic nano crystal of the radionuclide of biocompatibility according to claim 1 is characterized in that: the micromolecule of described band alkyl chain is small molecule amine, micromolecule carboxylic acid and the small molecular alcohol of band alkyl chain, wherein alkyl chain CH
2Unit number is 4~24.
10. one kind is used to prepare the method according to the adulterated magnetic nano crystal of radionuclide of each described biocompatibility of claim 1~9, it is characterized in that course of reaction is following one pot reaction:
To be dissolved in high boiling point non-polar solven or the high boiling point weak polar solvent as the organo-metallic compound of magnetic nano crystal precursor or the micromolecule of inorganic metal salt compound, radionuclide chemical compound or its solution, biocompatibility macromolecule and band alkyl chain; Feed noble gas and get rid of the oxygen in the reaction system; The reacting by heating system is mixed radionuclide when forming magnetic nano crystal; After the reactant liquor cooling, add organic solvent and make the magnetic nano crystal deposition, separate the adulterated magnetic nano crystal of radionuclide that perhaps centrifugalize obtains having biocompatibility through magnetic,
Wherein, In reactant liquor; The concentration of magnetic nano crystal precursor is 0.001mol/L~0.2mol/L; The radionuclide compound concentration is 0.01 μ mol/L~2mmol/L, and the concentration of biocompatibility macromolecule is 0.001mol/L~1mol/L, and the micromolecular concentration of band alkyl chain is 0mol/L~0.2mol/L.Reaction temperature is controlled at 120~350 ℃, and the response time is 0.25~24 hour.
11. method according to claim 10 is characterized in that: described organo-metallic compound is the organic coordination compound of ferrum, cobalt, nickel, manganese or lanthanide rare metal, and its part comprises acetylacetone,2,4-pentanedione, carbonyl, phenyl acetylacetone,2,4-pentanedione, cyclopentadiene.
12. method according to claim 10 is characterized in that: described inorganic metal salt compound is oleate, stearate, soap, acetate, gluconate, citrate, oxalates, chloride, sulfate, nitrate and the hydrate thereof of ferrum, cobalt, nickel, manganese or lanthanide rare metal.
13. method according to claim 10 is characterized in that: described radionuclide chemical compound is can radiate a kind of ray or particle or radiate different rays or the transition metal of particle and inorganic salt, hydrated inorganic salt, the organo-metallic compound of lanthanide rare metal more than 2 kinds simultaneously.
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105097170A (en) * | 2014-05-14 | 2015-11-25 | 中国科学院宁波材料技术与工程研究所 | Magnetic nanoparticles, preparation method and application therefor |
CN106975086A (en) * | 2017-02-22 | 2017-07-25 | 北京万德高科技发展有限公司 | A kind of magnetic resonance/nuclear medicine bimodal molecular image probe and preparation method thereof |
CN111110873A (en) * | 2020-02-24 | 2020-05-08 | 苏州欣影生物医药技术有限公司 | Preparation method of magnetic resonance/nuclear medicine bimodal molecular imaging probe |
CN114522238A (en) * | 2022-02-25 | 2022-05-24 | 西安交通大学 | Lanthanide-based oxyfluoride nanocrystal-based miRNA vector and application thereof |
WO2023070743A1 (en) * | 2021-10-25 | 2023-05-04 | 中国科学院福建物质结构研究所 | Radioactive medical isotope labeled rare-earth doped nanomaterial, pet imaging diagnosis and treatment agent, preparation method therefor and application thereof |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101241788A (en) * | 2007-01-15 | 2008-08-13 | 中国科学院化学研究所 | Biological compatibility magnetic nano crystal for high dissolving and stable distribution in physiologicalbuffer liquid and its making method |
-
2010
- 2010-10-29 CN CN 201010524510 patent/CN102451476B/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101241788A (en) * | 2007-01-15 | 2008-08-13 | 中国科学院化学研究所 | Biological compatibility magnetic nano crystal for high dissolving and stable distribution in physiologicalbuffer liquid and its making method |
Non-Patent Citations (1)
Title |
---|
SHUJIE LIU, ET AL.: "A Novel Type of Dual-Modality Molecular Probe for MR and Nuclear Imaging of Tumor: Preparation, Characterization and in Vivo Application", 《MOLECULAR PHARMACEUTICS》, vol. 6, no. 4, 15 June 2009 (2009-06-15), pages 1074 - 1082 * |
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CN105097170A (en) * | 2014-05-14 | 2015-11-25 | 中国科学院宁波材料技术与工程研究所 | Magnetic nanoparticles, preparation method and application therefor |
CN106975086A (en) * | 2017-02-22 | 2017-07-25 | 北京万德高科技发展有限公司 | A kind of magnetic resonance/nuclear medicine bimodal molecular image probe and preparation method thereof |
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WO2023070743A1 (en) * | 2021-10-25 | 2023-05-04 | 中国科学院福建物质结构研究所 | Radioactive medical isotope labeled rare-earth doped nanomaterial, pet imaging diagnosis and treatment agent, preparation method therefor and application thereof |
CN114522238A (en) * | 2022-02-25 | 2022-05-24 | 西安交通大学 | Lanthanide-based oxyfluoride nanocrystal-based miRNA vector and application thereof |
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