CN102451476B - 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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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 nanocrystal 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 magnetic nano crystal of the radionuclide of biocompatibility doping 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 SuperparamagneticIron Oxide nanoparticles (SPIO) and Ultrasmall Superparamagnetic Iron Oxidenanoparticles (USPIO) the type contrast agent of magnetic ferric oxide nano granule.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 based on 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 can 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 by the finishing molecule and radionuclide carry out coordination and are combined (CN200410002030.2, J.Nucl.Med., 2008,49,1371); 3) magnetic nano-particle carries out covalency by finishing molecule and radionuclide chemical compound and is coupled (Angew.Chem.Int.Ed., 2008,47,6259).Method (1) is owing to just simply mix, and magnetic nano crystal and nucleic combine by 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 be coupled by the finishing molecule, bond strength ratio method (1) is strong, but its preparation route complexity, the stability of gained coupling matter is subjected to the binding ability of binding ability, finishing molecule and the radionuclide of finishing molecule and magnetic nano crystal, all multifactor influences such as (as: kind of pH value, other chemical species and concentration) of outside chemical environment, thereby has limited their application.In order to make radionuclide and magnetic nano crystal stable bond, Kim etc. adopt coprecipitation (US7407673B2), use radionuclide in synthesizing magnetic nano crystal
67Cu
2+Substitute part Fe
2+, prepare radionuclide
67The magnetic nano crystal that Cu mixes
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, nanocrystal product that it prepares form inadequately clear and definite, 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, by adopting intensive polar solvent as the pyroreaction medium, " one pot " prepared in reaction technology (CN03136275.3, CN200610114459.X) of water-soluble magnetic nanocrystal, " one pot " the prepared in reaction technology (CN03136273.7) of biological compatibility magnetic nano crystal have successively been set up.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 Crinis Carbonisatus to understand in high-crystallinity, the physiological buffer can high dissolution and " one pot " the 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, transfer to adopt the non-ligand solvent of nonpolar or low pole 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 be coupled, prepared magnetic resonance-nucleic bimodulus contrast agent, and the interior targeting magnetic resonance of the body of successfully having realized contrast agent-nucleic double-mode imaging (Mol.Pharmaceut., 2009,6,1074), but adopt magnetic nano crystal finishing molecule and radionuclide to be coupled preparation magnetic resonance-nucleic bimodulus contrast agent, the stability that magnetic nano crystal is combined with 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 preparation method simultaneously, on the basis of CN200710187275.0 patent, we invented high-crystallinity, can be in the dissolving of physiological buffer camber and stable dispersion, have " one pot " prepared in reaction technology of the magnetic nano crystal that the radionuclide of radioactivity and biocompatibility mixes.
Summary of the invention
One of purpose of the present invention provide controllable size, high-crystallinity, can be in the dissolving of physiological buffer camber and stable dispersion, have the magnetic nano crystal that the radionuclide of radioactivity and biocompatibility mixes.
The magnetic nano crystal that radionuclide that two of purpose of the present invention provides mixes, 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 magnetic nano crystal that the radionuclide that three of purpose of the present invention provides mixes, its surface have polymer-modified layer, and good biocompatibility, the magnetic fluid that forms in physiological buffer solution or colloid solution have the stability of height.
The magnetic nano crystal that the radionuclide that four of purpose of the present invention provides mixes, the polymer of its finishing carries carboxyl or amido, can be directly used in the magnetic nano crystal of radionuclide doping and the covalency of biomolecule and be coupled.
The magnetic nano crystal that the radionuclide that five of purpose of the present invention provides mixes, its size and distribution can be regulated and control by reaction condition.
The magnetic nano crystal that the radionuclide that six of purpose of the present invention provides mixes, its radioactivity type and intensity can be regulated and control by reaction condition.
Seven of purpose of the present invention provide a kind of controllable size, high-crystallinity, can be in the dissolving of physiological buffer camber and stable dispersion, have " one pot " reaction method for preparing of the magnetic nano crystal that the radionuclide of radioactivity and biocompatibility mixes.
The present invention reacts by " 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 the dissolving of physiological buffer camber and stable dispersion, have the magnetic nano crystal that the radionuclide of radioactivity and biocompatibility mixes.
The magnetic nano crystal that the radionuclide of biocompatibility of the present invention mixes has paramagnetism, superparamagnetism or ferromagnetism, and particle diameter is 1～60 nanometer, can be in the dissolving of physiological buffer camber and stable dispersion.
In the magnetic nano crystal that described radionuclide mixes, magnetic part mainly is the magnetic oxide that magnetic transition metal and oxide, magnetic lanthanide rare metal-oxide, transition metal or rare earth metal mix, preferred ferrum and oxide thereof, cobalt, nickel, manganese or their oxide, and the oxide of gadolinium, terbium, dysprosium, holmium, erbium, thulium.
In the magnetic nano crystal that described radionuclide mixes, radionuclide mainly is radiation other particles such as 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 magnetic nano crystal that the radionuclide of biocompatibility of the present invention mixes, 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 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), polyvinylamine (PEI), poly-alanine, polylysine, poly-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, the magnetic nano crystal that makes radionuclide mix both can be water-soluble, can be dissolved in organic solvent again, finally make the magnetic nano crystal of the radionuclide doping 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.The micromolecule of particularly preferred band alkyl chain comprises oleyl amine, lauryl amine, oleic acid, capric acid, 1 in the present invention, 2-hexadecane glycol etc.
If biocompatiblity molecules of the present invention adopt has the biocompatibility macromolecule of two or more carboxyls and ((or) amine groups, then the preparation-obtained radionuclide magnetic nano crystal surface of mixing can carry one or more carboxyl that can further react or amidos under temperate condition, utilizes magnetic nano crystal that this functional group can mix radionuclide of the present invention and biomolecule to carry out covalency and is coupled and is applied to the actual imaging detection range.
Biomolecule of the present invention comprises the carboxy derivatives of the amido derivative of aminoacid, polypeptide, albumen, biotin, DNA or DNA and has amido or the carbohydrate of carboxyl etc.
The magnetic nano crystal that the radionuclide of biocompatibility of the present invention mixes is the energy high dissolution in physiological buffer, and the placement of gained solution does not still have precipitation after half a year and separates out.
Physiological buffer of the present 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 preparation method of the magnetic nano crystal that the radionuclide of biocompatibility involved in the present invention mixes 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, namely magnetic nano crystal presoma (as ferric acetyl acetonade etc.), radionuclide chemical compound (as
57CoCl
2Or
57CoCl
2Aqueous solutions etc.), the micromolecule of biocompatibility macromolecule (be 4000 the two ends Polyethylene Glycol that simultaneously have carboxyl etc. as molecular weight) and band alkyl chain (as oleic acid etc.) is dissolved in the nonpolar or high boiling point weak polar solvent of high boiling point (as 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) the feeding noble gas is got rid of the oxygen in the reaction system, the mixed reaction solution of heating steps (1) or (2), 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 entered in the middle of the lattice of magnetic nano crystal, obtained the magnetic nano crystal of the radionuclide doping 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.) precipitation of 2～50 times of reactant liquor volumes, precipitation is after magnetic separation or centrifugalize, with same organic solvent washing product crystal 3～5 times, magnetic separates or centrifugalize can obtain high-crystallinity, can be in the dissolving of physiological buffer camber and stable dispersion, have the magnetic nano crystal that the radionuclide of radioactivity, biocompatibility mixes;
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, as 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 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 Polyethylene Glycol and the derivant thereof of line style, branching, also comprise in the block copolymer that the Polyethylene Glycol of line style, branching and polyacrylic acid, polymethylacrylic acid, polyvinylamine, poly-alanine, polylysine, poly-leucine, 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 magnetic nano crystal of the radionuclide doping of different size by changing reaction condition.
The present invention can make the magnetic nano crystal of the radionuclide doping of different radioactive intensities by changing the ratio of radionuclide chemical compound and magnetic nano crystal precursor.
The present invention prepares the magnetic nano crystal of the radionuclide doping of biocompatibility, its radionuclide is uniformly distributed in magnetic nano crystal inside, both are in conjunction with stable, " one pot " preparation method that adopts has technology characteristics simple, easy and simple to handle, the magnetic nano crystal degree of crystallinity height that the gained radionuclide mixes, narrow particle size distribution, size adjustable, magnetic response are strong, good biocompatibility, can be in the dissolving of physiological buffer camber and stable dispersion, and the surface has functional group, can further carry out biology and be coupled.
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 magnetic nano crystal that Co mixes, magnetic separates and washs three times, obtains the biocompatibility that the surface has carboxyl
57The Fe that Co mixes
3O
4Magnetic nano crystal.After treating its natural drying, the gained nanocrystal is dissolved in the deionized water, utilizes transmission electron microscope (TEM) to what obtain
57The Fe that Co mixes
3O
4Magnetic nano crystal characterizes, and accompanying drawing 1 is biocompatibility
57The Fe that Co mixes
3O
4The transmission electron microscope photo of magnetic nano crystal (A) and histogram of particle size distribution (B) thereof.By electromicroscopic photograph as can be known,
57The Fe that Co mixes
3O
4Magnetic nano crystal is 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 gained
57The Fe that Co mixes
3O
4The X-ray diffraction of magnetic nano crystal (XRD) collection of illustrative plates, gained biocompatibility as seen from the figure
57The Fe that Co mixes
3O
4Fe in the magnetic nano crystal degree of crystallinity height, this spectrogram and accompanying drawing 2 (D)
3O
4Standard spectrogram (PDF#88-0866) meets better, shows the radioactivity of mixing
57The crystal structure of the magnetic nano crystal of Co does not have influence substantially.Accompanying drawing 3 is for being somebody's turn to do
57The Fe that Co mixes
3O
4The hysteresis curve of magnetic nano crystal, the saturation magnetization of crystal 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 Fe that Co mixes
3O
4Magnetic nano crystal is used the inductively coupled plasma mass spectroscopy with after the nitric acid nitrating dissolving, and the result shows,
57The Fe that Co mixes
3O
4In the magnetic nano crystal Fe with
57The atomic ratio of Co is 40099: 1,
57The utilization rate of Co is 39%.The radioactive counter measurement result shows, is somebody's turn to do
57The Fe that Co mixes
3O
4It is 8.0 μ Ci/ (mg that magnetic nano crystal radiates gamma-ray intensity
57The Fe that Co mixes
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 Fe that Co mixes
3O
4The magnetic nano crystal mean diameter is 8.2nm, and radiating gamma-ray intensity is 45.1 μ Ci/ (mg
57The Fe that Co mixes
3O
4Magnetic nano crystal).Gained
57The Fe that Co mixes
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 Fe that Co mixes
3O
4The magnetic nano crystal mean diameter is 8.9nm, and the inductivity coupled plasma mass spectrometry measurement result shows, gained
57The Fe that Co mixes
3O
4In the magnetic nano crystal Fe with
57The atomic ratio of Co is 1605: 1, and the radioactive counter measurement result shows, gained
57The Fe that Co mixes
3O
4It is 202 μ Ci/ (mg that magnetic nano crystal radiates gamma-ray intensity
57The Fe that Co mixes
3O
4Magnetic nano crystal), accompanying drawing 2 (C) is gained
57The Fe that Co mixes
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
57The crystal structure influence of the magnetic nano crystal of Co is little.
Embodiment 4-is stability in PBS
With what obtain among the embodiment 1
57The Fe that Co mixes
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 precipitation 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 0.53g ferric acetyl acetonade, the two carboxyl PEG2000 of 6g, 2.0mL oleyl amine and 25mL phenylate, after treating that all raw materials all dissolve, logical nitrogen deoxygenation 30min, back flow reaction 30min is cooled to room temperature with reaction system, goes out the magnetic nano crystal that radioactivity is mixed with ether sedimentation, magnetic separates and washs three times, obtains the biocompatibility that the surface has carboxyl
57The Fe that Co mixes
3O
4Magnetic nano crystal, the mean diameter of gained granule are 8.2nm, and the radioactive counter measurement result shows, is somebody's turn to do
57The Fe that Co mixes
3O
4It is 7.8 μ Ci/ (mg that magnetic nano crystal radiates gamma-ray intensity
57The Fe that Co mixes
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 Fe that Co mixes
3O
4The magnetic nano crystal mean diameter is 12.5nm, and radiating gamma-ray intensity is 8.8 μ Ci/ (mg
57The Fe that Co mixes
3O
4Magnetic nano crystal).Accompanying drawing 5 is the gained biocompatibility
57The Fe that Co mixes
3O
4The transmission 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 Fe that Co mixes
3O
4The magnetic nano crystal mean diameter is 16.1nm, and radiating gamma-ray intensity is 8.1 μ Ci/ (mg
57The Fe that Co mixes
3O
4Magnetic nano crystal).Accompanying drawing 6 is the gained biocompatibility
57The Fe that Co mixes
3O
4The transmission electron microscope photo of magnetic nano crystal (A) and histogram of particle size distribution (B) thereof.
Embodiment 8-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 Fe that Co mixes
3O
4The magnetic nano crystal mean diameter is 16.1nm, and radiating gamma-ray intensity is 9.3 μ Ci/ (mg
57The Fe that Co mixes
3O
4Magnetic nano crystal).
Embodiment 9-raw material iron pentacarbonyl is only used 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, after treating that all raw materials all dissolve, 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 magnetic nano crystal particle diameter that Ni mixes is 7～14nm, should
56The magnetic nano crystal that Ni mixes 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 gained
55The transmission electron microscope photo of the MnO nanocrystal that Fe mixes obtains
55The MnO nanocrystal mean diameter that Fe mixes is 6.1nm, and the inductivity coupled plasma mass spectrometry measurement result shows, gained
57In the MnO nanocrystal that Fe mixes 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, with 0.71g ferric acetyl acetonade, 0.26g diacetyl acetone nickel, 16g Polyethylene Glycol and polyacrylic acid block copolymer (PEG-b-PAA) (synthetic agent: adopt the ATRP method, be macromole evocating agent with PEG2000, 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 ferronickel oxidate nano crystal that Co mixes, its mean diameter is 6.7nm, the inductivity coupled plasma mass spectrometry measurement result shows, 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 ferronickel oxidate nano plane of crystal that Co mixes 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 Fe that Cu mixes
3O
4The magnetic nano crystal mean diameter is 7.0nm, and the inductivity coupled plasma mass spectrometry measurement result shows, gained
54The Fe that Cu mixes
3O
4In the magnetic nano crystal Fe with
64The atomic ratio of Cu is 4218: 1.With the biocompatibility for preparing
64The Fe that Cu mixes
3O
4Magnetic nano crystal is soluble in water, by will not having the material of magnetic to separate with magnetic crystal in the system under 1 hour the situation of externally-applied magnetic field, through radioactivity determination, this composite magnetic crystal still has radioactivity, illustrates 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 steps
65The Fe that Zn mixes
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 Fe that Dy mixes
3O
4The magnetic nano crystal particle diameter is 7～14nm, and the inductivity coupled plasma mass spectrometry measurement result shows, gained
159The Fe that Dy mixes
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 Dy that Co mixes
2O
3Nanocrystal, the average-size of gained granule 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 make 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 Er that Dy mixes
2O
3Nanocrystal, remaining last handling process is identical with the correlation step among the embodiment 1, and the average-size of gained granule is 4.3 nanometers, and the inductivity coupled plasma mass spectrometry measurement result shows, gained
159The Er that Dy mixes
2O
3In the nanocrystal Er with
159The atomic ratio of Dy is 2018: 1, and Fig. 9 is
159The Er that Dy mixes
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 make 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 Gd that Fe mixes
2O
3Nanocrystal, remaining last handling process is identical with the correlation step among the embodiment 1, and the average-size of gained granule 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 Co that Fe mixes
3O
4Nanocrystal is of a size of 8～17 nanometers, and the inductivity coupled plasma mass spectrometry measurement result shows, gained
55The Co that Fe mixes
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 make 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 Ho that Dy mixes
2O
3Nanocrystal, remaining last handling process is identical with the correlation step among the embodiment 1, and the average-size of gained granule is 6.8 nanometers.
Embodiment 20-radionuclide and magnetic nano crystal stable bond
With the biocompatibility for preparing among the embodiment 1
57The Fe that Co mixes
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, changed one time water every 2 hours, changed one time water later on every 12 hours.In the monitoring bag filter
57The Fe that Co mixes
3O
4The radioactive intensity of magnetic nano crystal, result show that its radioactive intensity is constant substantially 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 Fe that Co mixes
3O
4The radioactive intensity of magnetic nano crystal is constant substantially in time.
The magnetic nano crystal that embodiment 22-radionuclide mixes 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 is after 15 minutes under the room temperature, PBS (pH=8.0) solution that adds the anti-stomach cancer target antibody 3H11 of 0.5mL 2mg/mL, room temperature reaction 4 hours.Prepare and be coupled 3H11 antibody
57The Fe that Co mixes
3O
4Magnetic resonance-nucleic bimodulus probe molecule with tumor-targeting, go into corresponding gastric cancer tumor nude mouse in by tail vein injection above molecular probe and carry out nuclear magnetic resonance and radiological measuring, the radioactive counter result shows that gamma-ray intensity is 8.3 μ Ci, and the magnetic resonance radiography result as 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, presents tangible T2 radiography effect.This experiment shows that the nanocrystal that is coupled the nucleic doping of stomach cancer target 3H11 antibody has been realized targeting magnetic resonance radiography function, has radioactivity simultaneously because of this probe simultaneously, can also realize radio nuclide imaging in the body.
Claims (11)
1. the magnetic nano crystal that mixes 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, wherein said biocompatibility macromolecule has one or more carboxyls or amido, molecular weight is 600～6000, be selected from line style, the Polyethylene Glycol of branching, described Polyethylene Glycol is optional by carboxylated, amination or have the distant pawl of heterodoxy base, line style, the Polyethylene Glycol of branching and polyacrylic acid, polyvinylamine, polymethylacrylic acid, poly-alanine, polylysine, poly-leucine, polyglutamic acid, poly-aspartate, in the block copolymer that polycaprolactone or polylactic acid form one or more, and the micromolecule of described band alkyl chain is the small molecule amine of band alkyl chain, micromolecule carboxylic acid and small molecular alcohol, wherein alkyl chain CH
2Unit number is 4～24,
The magnetic nano crystal that the radionuclide of described biocompatibility mixes is to prepare by following one pot reaction:
Will be as the organo-metallic compound of magnetic nano crystal precursor or soap, acetate, gluconate, citrate, oxalates, chloride, sulfate, nitrate and the hydrate thereof of ferrum, cobalt, nickel, manganese or lanthanide rare metal, radionuclide chemical compound or its solution, the micromolecule of biocompatibility macromolecule and band alkyl chain is dissolved in high boiling point non-polar solven or the high boiling point weak polar solvent, feed the oxygen in the noble gas eliminating 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 precipitation, separate or centrifugalize obtains having the magnetic nano crystal that the radionuclide of biocompatibility mixes by 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, the concentration of biocompatibility macromolecule is 0.001mol/L～1mol/L, the micromolecular concentration of band alkyl chain is 0mol/L～0.2mol/L, reaction temperature control is at 120～350 ℃, response time is 0.25～24 hour, described organo-metallic compound is ferrum, cobalt, nickel, the organic coordination compound of manganese or lanthanide rare metal, its part is acetylacetone,2,4-pentanedione, carbonyl, the phenyl acetylacetone,2,4-pentanedione, cyclopentadiene.
2. the magnetic nano crystal that mixes of the radionuclide of biocompatibility according to claim 1, it is characterized in that: the magnetic nano crystal that described radionuclide mixes has magnetic and radioactivity simultaneously.
3. the magnetic nano crystal that mixes 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 radioactivity transition metal and the radioactivity lanthanide rare metallic element of particle.
4. the magnetic nano crystal that mixes of the radionuclide of biocompatibility according to claim 1, it 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 magnetic nano crystal that mixes 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 metal-oxide, the particle diameter of magnetic nano crystal is 1～60 nanometer, has paramagnetism, superparamagnetism or ferromagnetism.
6. the magnetic nano crystal that mixes of the radionuclide of biocompatibility according to claim 1, it is characterized in that: described soap is oleate or stearate.
7. the magnetic nano crystal that mixes 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, have on its polymer chain more than one can be directly and biomolecule carry out carboxyl or the amido that covalency is coupled.
8. the magnetic nano crystal that mixes of the radionuclide of biocompatibility according to claim 1 is characterized in that: the quality percentage composition of magnetic nano crystal that the micromolecule of described biocompatibility macromolecule or biocompatibility macromolecule and band alkyl chain accounts for the radionuclide doping of biocompatibility is 5～85%.
9. method for the preparation of the magnetic nano crystal that mixes according to the radionuclide of each described biocompatibility of claim 1～8 is characterized in that course of reaction is following one pot reaction:
Will be as the organo-metallic compound of magnetic nano crystal precursor or soap, acetate, gluconate, citrate, oxalates, chloride, sulfate, nitrate and the hydrate thereof of ferrum, cobalt, nickel, manganese or lanthanide rare metal, radionuclide chemical compound or its solution, the micromolecule of biocompatibility macromolecule and band alkyl chain is dissolved in high boiling point non-polar solven or the high boiling point weak polar solvent, feed the oxygen in the noble gas eliminating 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 precipitation, separate or centrifugalize obtains having the magnetic nano crystal that the radionuclide of biocompatibility mixes by magnetic,
Wherein said biocompatibility macromolecule has one or more carboxyls or amido, molecular weight is 600～6000, be selected from line style, the Polyethylene Glycol of branching, described Polyethylene Glycol is optional by carboxylated, amination or have the distant pawl of heterodoxy base, line style, the Polyethylene Glycol of branching and polyacrylic acid, polyvinylamine, polymethylacrylic acid, poly-alanine, polylysine, poly-leucine, polyglutamic acid, poly-aspartate, in the block copolymer that polycaprolactone or polylactic acid form one or more, the micromolecule of described band alkyl chain is the small molecule amine of band alkyl chain, micromolecule carboxylic acid and small molecular alcohol, wherein alkyl chain CH
2Unit number is 4～24, and
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, the concentration of biocompatibility macromolecule is 0.001mol/L～1mol/L, the micromolecular concentration of band alkyl chain is 0mol/L～0.2mol/L, reaction temperature control is at 120～350 ℃, response time is 0.25～24 hour, described organo-metallic compound is ferrum, cobalt, nickel, the organic coordination compound of manganese or lanthanide rare metal, its part is acetylacetone,2,4-pentanedione, carbonyl, the phenyl acetylacetone,2,4-pentanedione, cyclopentadiene.
10. method according to claim 9, it is characterized in that: described soap is oleate or stearate.
11. method according to claim 9 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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