CN111110873A - Preparation method of magnetic resonance/nuclear medicine bimodal molecular imaging probe - Google Patents
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Abstract
The invention discloses a preparation method of a magnetic resonance/nuclear medicine bimodal molecular imaging probe, which comprises the steps of firstly preparing magnetic nanoparticles and auxiliary materials into dry powder, directly mixing radioactive nuclide and the dry powder when in use, reacting for a period of time, and marking the radioactive nuclide on the magnetic nanoparticles to obtain the magnetic resonance/nuclear medicine bimodal molecular imaging probe, wherein the prepared dry powder can be stored for a long time and is convenient to transport, is beneficial to scale and industrialization, is beneficial to long-term storage of the magnetic nanoparticles, has important significance for improving the stability and prolonging the quality guarantee period of the magnetic nanoparticles, is beneficial to sterilization by adopting an irradiation mode, and is beneficial to clinical transformation; the method is simple and rapid, can be used without knowledge outside the profession for clinicians and nurses, is beneficial to clinical transformation, and has wide application prospect in actual clinic.
Description
Technical Field
The invention relates to the field of multi-modal molecular imaging probes, in particular to a preparation method of a magnetic resonance/nuclear medicine bimodal molecular imaging probe.
Background
Both magnetic resonance imaging and nuclear medicine imaging are important tools for clinical tumor diagnosis. Magnetic Resonance Imaging (MRI) is safe, non-invasive, high in spatial resolution, not limited by tissue depth, but low in sensitivity. Nuclear medicine imaging (PET/SPECT) has high specificity and sensitivity, but the imaging spatial resolution is low (1-2mm), which makes accurate localization of the lesion difficult. With the increasing demand for early diagnosis of tumors, single magnetic resonance or nuclear medicine imaging techniques have not been able to meet the current needs.
Because the advantages of magnetic resonance imaging and nuclear medicine imaging are just complementary, the development of magnetic resonance/nuclear medicine dual-mode imaging which has high spatial resolution of magnetic resonance imaging and high sensitivity of nuclear medicine imaging is favored by combining the advantages of the magnetic resonance imaging and the nuclear medicine imaging. At present, imaging equipment capable of realizing magnetic resonance/nuclear medicine bimodal imaging is in clinical use, but a commercial magnetic resonance/nuclear medicine bimodal molecular imaging probe matched with the imaging equipment is not yet available. Although researchers have reported a number of methods for preparing mri/nuclear medicine bimodal molecular imaging probes, the complicated preparation process makes it difficult to realize clinical transformation. Therefore, how to simply, conveniently and quickly obtain the magnetic resonance/nuclear medicine bimodal molecular imaging probe can ensure that a clinician can obtain the magnetic resonance/nuclear medicine bimodal molecular imaging probe which can be directly applied without any other professional skills according to the conventional operation, and has great significance for the clinical transformation of the magnetic resonance/nuclear medicine bimodal molecular imaging probe.
Disclosure of Invention
The invention aims to provide a preparation method of a magnetic resonance/nuclear medicine bimodal molecular imaging probe, which aims to solve the problem that the preparation process of the magnetic resonance/nuclear medicine bimodal molecular imaging probe in the prior art is complex.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of a magnetic resonance/nuclear medicine bimodal molecular imaging probe comprises the following steps:
preparing dry powder containing magnetic nanoparticles and auxiliary materials;
adding a radionuclide solution into the dry powder, shaking up to obtain a mixture, wherein the concentration of the magnetic nanoparticles in the mixture is 0.001-200mg/mL, the labeling amount of the radionuclide on the magnetic nanoparticles is 0.1uCi/(mg magnetic nanoparticles) -100mCi/(mg magnetic nanoparticles), and placing the mixture for reaction under the following reaction conditions: the temperature is 0-100 ℃, the reaction time is 30s-6h, and radioactive nuclides are marked on the magnetic nanoparticles to obtain a magnetic resonance/nuclear medicine bimodal molecular imaging probe; the placing process includes resting or shaking.
Preferably, the preparation method of the dry powder comprises the following steps: dissolving magnetic nanoparticles and auxiliary materials in a solvent to obtain a mixed solution, wherein the concentration of the magnetic nanoparticles is 0.001-500mg/mL, the concentration of the auxiliary materials is 0.001-100mg/mL, and drying the mixed solution to obtain dry powder; the drying method comprises freeze-drying and solvent evaporation.
Preferably, the preparation method of the dry powder comprises the following steps: dissolving magnetic nanoparticles in a solvent to obtain a solution, wherein the concentration of the magnetic nanoparticles is 0.001-500mg/mL, drying the solution to obtain magnetic nanoparticle powder, drying an auxiliary material to obtain auxiliary material powder, mixing the magnetic nanoparticle powder and the auxiliary material powder, wherein the mass ratio of the magnetic nanoparticle powder to the auxiliary material powder is 0.1:1-1000:1, and obtaining dry powder, wherein the drying method comprises freeze-drying and solvent evaporation drying.
A preparation method of a magnetic resonance/nuclear medicine bimodal molecular imaging probe comprises the following steps:
dissolving magnetic nanoparticles in a solvent to obtain a solution, wherein the concentration of the magnetic nanoparticles is 0.001-500mg/mL, and drying the solution to obtain magnetic nanoparticle powder, wherein the drying method comprises freeze-drying and solvent volatilization;
adding a radionuclide solution into the magnetic nanoparticle powder to obtain a mixed solution, wherein the concentration of the magnetic nanoparticles in the mixed solution is 0.001-200mg/mL, and the labeling amount of the radionuclide on the magnetic nanoparticles is 0.1uCi/(mg magnetic nanoparticles) -100mCi/(mg magnetic nanoparticles);
adding the mixed solution into auxiliary materials, wherein the mass ratio of the magnetic nano-particle powder to the auxiliary materials is 0.1:1-1000:1, shaking up, and then standing for reaction, wherein the reaction conditions are as follows: the temperature is 0-100 ℃, the reaction time is 30s-6h, and the magnetic resonance/nuclear medicine bimodal molecular imaging probe is prepared; the placing process includes resting or shaking.
A preparation method of a magnetic resonance/nuclear medicine bimodal molecular imaging probe comprises the following steps:
dissolving magnetic nanoparticles in a solvent to obtain a solution, wherein the concentration of the magnetic nanoparticles is 0.001-500mg/mL, and drying the solution to obtain magnetic nanoparticle powder, wherein the drying method comprises freeze-drying and solvent volatilization;
adding the radionuclide solution into the auxiliary materials, uniformly mixing, and reacting to obtain a mixed solution; the reaction time is 10s-10 min;
adding the mixed solution into magnetic nano-particle powder, wherein the mass ratio of the magnetic nano-particle powder to the auxiliary materials is 0.1:1-1000:1, the concentration of the magnetic nano-particles is 0.001-200mg/mL, the labeling amount of the radionuclide on the magnetic nano-particles is 0.1uCi/(mg magnetic nano-particles) -100mCi/(mg magnetic nano-particles), shaking uniformly, and then placing for reaction, wherein the reaction conditions are as follows: the temperature is 0-100 ℃, the reaction time is 30s-6h, and the magnetic resonance/nuclear medicine bimodal molecular imaging probe is prepared; the placing process includes resting or shaking.
As optimization, the preparation method of the magnetic resonance/nuclear medicine bimodal molecular imaging probe further comprises the following steps: the dry powder is irradiated and sterilized, thereby achieving the purpose of disinfection and sterilization.
Preferably, the magnetic nanoparticles are selected from any one of magnetic transition metal, magnetic transition metal oxide, magnetic lanthanide rare earth metal oxide, transition metal doped magnetic oxide, rare earth metal doped magnetic oxide, magnetic lanthanide rare earth metal fluoride or magnetic lanthanide rare earth metal doped fluoride, and the particle size of the magnetic nanoparticles is 1-500 nm.
Preferably, the magnetic nanoparticles are selected from iron or its oxide, cobalt, nickel, manganese or its oxide, gadolinium, dysprosium, terbium, holmium, erbium, thulium oxide or fluoride or gadolinium, dysprosium, terbium, holmium, erbium, thulium doped fluoride.
Preferably, the particle size of the magnetic nanoparticles is 1-100 nm.
Preferably, the particle size of the magnetic nanoparticles is 2-20 nm.
Preferably, the magnetic nanoparticles have any one of paramagnetism, superparamagnetism, ferrimagnetism, or ferromagnetism.
Preferably, the magnetic nanoparticles have paramagnetism or superparamagnetism.
Preferably, the radionuclide is capable of emitting gamma rays or positrons, and the radionuclide is selected from99mTc、188Re、111In、64Cu、90Y、123I、124I、125I、131I、177Lu、67Ga、68Ga、18F、59Fe、192Ir、60Co or201Tl.
Preferably, the solvent is one or a mixture of more of water, dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, acetone, isopropanol, ethylene glycol, glycerol, cyclohexane, ethyl acetate, acetonitrile, dioxane, N-dimethylformamide, dimethyl sulfoxide, pyridine and toluene.
Preferably, the auxiliary materials are selected from one or more of stannous chloride, chloramine-T, sodium chloride, glucose and phosphate buffer salt; the adjuvants mainly provide labeling conditions for labeling radionuclide, such as oxidation-reduction conditions, pH value, ionic strength, etc., if some radionuclide labeling is not requiredThese conditions, if not provided, being in the mark99mTc and188when Re is needed, stannous chloride can be added to provide reduction conditions required by the marking; in the mark125I and131in case I, chloramine-T may be added to provide the oxidation conditions required for labeling, and Phosphate Buffered Saline (PBS) may be added to provide the pH conditions required for labeling; in the mark177Lu、111In、68Ga、64In the case of Cu, the marking can be carried out without adding any auxiliary material. In addition, adjuvants may also be used to adjust the osmotic pressure of the labeled product.
As optimization, the surface of the magnetic nanoparticle is provided with ligand modification, and the radionuclide is marked on the ligand through a coordination bond or a covalent bond; the magnetic nano-particles modified by the surface ligand molecules can be obtained by one-step reaction synthesis, or the magnetic nano-particles can be obtained firstly, and then the surface ligand molecules are connected to the magnetic nano-particles by ligand exchange and other modes; the magnetic nanoparticles modified by the surface ligand molecules have water solubility.
The ligand is selected from any one of micromolecule compound, high molecular polymer, block copolymer or their derivatives as optimization; small molecular compounds such as mercaptosuccinic acid, mercaptoacetic acid, etc., and high molecular polymers such as diphosphonic acid polyethylene glycol, dicarboxyl polyethylene glycol, polyacrylic acid, polylysine, polylactic acid, etc.
As optimization, the ligand also contains groups for further functional modification, such as carboxyl, amino, sulfydryl, alkynyl, maleimide group, azide group and the like, so that the obtained magnetic resonance/nuclear medicine bimodal molecular imaging probe can be further coupled with targeting molecules such as antibodies, polypeptides and the like to realize the targeting phenomenon of a focus part.
As optimization, the radioactive nuclide has the effect of radiotherapy, and the obtained magnetic resonance/nuclear medicine bimodal molecular imaging probe can realize the radiotherapy of tumors while imaging.
The magnetic resonance/nuclear medicine bimodal molecular imaging probe can be used for magnetic resonance and nuclear medicine bimodal imaging.
Compared with the prior art, the invention has the beneficial effects that:
according to the preparation method of the magnetic resonance/nuclear medicine bimodal molecular imaging probe, the magnetic nanoparticles and the auxiliary materials are prepared into dry powder, and compared with a solution sample, the dry powder can be stored for a long time and is convenient to transport, large-scale and industrialization are facilitated, long-term storage of the magnetic nanoparticles is facilitated, the preparation method has important significance for improving the stability of the magnetic nanoparticles and prolonging the shelf life, sterilization is facilitated by adopting an irradiation mode, and clinical transformation is facilitated; when in use, the radionuclide and the dry powder are directly mixed and react for a period of time, so that the radionuclide is marked on the magnetic nanoparticles to obtain the magnetic resonance/nuclear medicine bimodal molecular imaging probe.
Drawings
FIG. 1 is an electron micrograph (a) and a particle size distribution (b) of oil-soluble magnetic iron oxide nanoparticles obtained in example 1 of the present invention, and an electron micrograph (c) and a particle size distribution (d) of water-soluble magnetic iron oxide nanoparticles obtained after ligand exchange;
FIG. 2 is a distribution diagram of hydrated particle sizes of water-soluble magnetic iron oxide nanoparticles prepared in example 1 of the present invention before lyophilization and after lyophilization and reconstitution;
FIG. 3 is a graph showing the variation of the hydrated particle size of the lyophilized water-soluble magnetic iron oxide nanoparticle dry powder prepared in example 1 of the present invention after being allowed to stand for different periods of time for reconstitution with standing time;
FIG. 4 is a graph showing a comparison of hydrated particle size distributions before and after labeling of water-soluble magnetic iron oxide nanoparticles prepared in example 2 of the present invention;
FIG. 5 is a graph showing the variation of the labeling rate with the standing time after the lyophilized water-soluble magnetic iron oxide nanoparticle dry powder prepared in example 4 of the present invention was left standing for various periods of time;
FIG. 6 is a SPECT-CT image of the MRI/nuclear medicine bimodal molecular imaging probe obtained in example 10 of the present invention injected into a mouse via tail vein at different time points.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1: (investigating whether the lyophilization operation has an influence on the magnetic nanoparticles)
According to the literature (Advanced Materials,2014,26,2694-2698), oil-soluble magnetic iron oxide nanoparticles with the average particle size of about 3nm are synthesized. FIG. 1a is an electron micrograph of the obtained oil-soluble magnetic iron oxide nanoparticles, and FIG. 1b is a statistical photograph of the particle diameters thereof, the obtained oil-soluble magnetic iron oxide nanoparticles having a uniform particle diameter and an average size of 3.5 nm; referring to the above documents, modifying a polyethylene glycol 2000 molecule with one end being a diphosphate group and the other end being a methoxy group onto the surface of an oil-soluble magnetic iron oxide nanoparticle by means of ligand exchange to obtain a water-soluble magnetic iron oxide nanoparticle, where fig. 1c is an electron microscope photograph of the water-soluble magnetic iron oxide nanoparticle obtained after ligand exchange, and fig. 1d is a statistical photograph of the particle size thereof, it can be seen that the shape and size of the magnetic iron oxide nanoparticle are not significantly changed after ligand exchange.
Taking a series of ampoule bottles, respectively adding 200 mu L of water-soluble magnetic iron oxide nanoparticle aqueous solution with the concentration of 1mg/mL into the series of ampoule bottles, respectively freeze-drying, re-dissolving a freeze-dried sample in water, and then analyzing the hydrated particle size of the sample by using a laser dynamic light scattering instrument, wherein fig. 2 shows the test results of the sample before freeze-drying and after freeze-drying and re-dissolving of the water-soluble magnetic iron oxide nanoparticles, and the test results show that the re-dissolving of the water-soluble magnetic iron oxide nanoparticles after freeze-drying does not influence the hydrated particle size and the particle size distribution of the water-soluble magnetic iron oxide nanoparticles. A series of ampere bottles filled with the freeze-dried water-soluble magnetic iron oxide nanoparticle dry powder are placed at room temperature, redissolved at different time points, and tested for the hydrated particle size, and the result is shown in figure 3, the hydrated particle size of a freeze-dried sample is not obviously changed after redissolved within the monitoring time of 10 months, and the experimental result shows that the freeze-dried dry powder has no influence on the preservation of the water-soluble magnetic iron oxide nanoparticles.
Example 2: (magnetic nanoparticles are mixed with adjuvant solution and lyophilized together)
Preparing water-soluble magnetic iron oxide nanoparticles according to the method of example 1, preparing the water-soluble magnetic iron oxide nanoparticles into a magnetic iron oxide nanoparticle aqueous solution with the iron concentration of 1mg/mL, and taking 10 muL of SnCl2Putting the solution (1mg/mL dissolved in 0.1M HCl) into an ampoule bottle, adding 200 μ L of magnetic iron oxide nanoparticle aqueous solution with concentration of 1mg/mL into the ampoule bottle, mixing to obtain mixed solution, freeze-drying the mixed solution to obtain dry powder, adding 300 μ L of radioactive Na into the dry powder99mTcO4The solution (medium is physiological saline) has the radioactivity of 2mCi, the solution is shaken up and then placed for reaction for 5min, the test labeling rate is 92%, FIG. 4 shows the hydration particle size test result of the water-soluble magnetic iron oxide nanoparticles before and after labeling, and the test result shows that the hydration size of the water-soluble magnetic iron oxide nanoparticles cannot be changed in the labeling process.
Example 3: (the magnetic nanoparticles and the excipients were lyophilized separately and then mixed)
Preparing water-soluble magnetic iron oxide nanoparticles according to the method of example 1, preparing the water-soluble magnetic iron oxide nanoparticles into a magnetic iron oxide nanoparticle aqueous solution with the iron concentration of 1mg/mL, and taking 10 muL of SnCl2Placing the solution (1mg/mL, dissolved in 0.1M HCl) in an ampoule bottle, freeze-drying 200 μ L of magnetic iron oxide nanoparticle aqueous solution with concentration of 1mg/mL, adding the freeze-dried magnetic iron oxide nanoparticles into an ampoule bottle containing freeze-dried SnCl2, mixing to obtain mixed dry powder, adding 300 μ L of radioactive Na into the mixed dry powder99mTcO4The solution (medium is normal saline) with the radioactivity of 2mCi is shaken up and then placed for reaction for 30min, and the test labeling rate is 96%.
Example 4: (investigating whether the labeling rate of the magnetic nanoparticles is affected by standing for a period of time after the lyophilization process)
Preparing water-soluble magnetic iron oxide nanoparticles according to the method of example 1, preparing the water-soluble magnetic iron oxide nanoparticles into an aqueous solution of magnetic iron oxide nanoparticles with an iron concentration of 1mg/mL, taking a series of ampoules, and adding 10 μ L of SnCl into the ampoules2Solution (1mg/mL in 0.1M HCl) and lyophilized; then a series of 200 microliter magnetic iron oxide nano-particle water solution with the concentration of 1mg/mL is taken for freeze drying, and a series of freeze-dried magnetic iron oxide nano-particles are added into the SnCl filled with freeze-dried powder2Mixing in a series of Ampere bottles to obtain mixed dry powder, sealing the mixed dry powder with nitrogen gas, storing at room temperature, taking one Ampere bottle at intervals, adding 300 μ L radioactive Na99mTcO4The solution (medium is normal saline) with the radioactivity of 2mCi is shaken up and then placed for reaction for 30min, and the labeling rate is tested; fig. 5 shows the change of different labeling rates with the standing time after lyophilization, and it can be seen from the graph that the labeling rates of the magnetic iron oxide nanoparticles are all above 95%, and the standing time has no obvious influence on the labeling rates.
Example 5: (Mark125I)
According to the literature (Advanced Materials,2014,26,2694-2698), oil-soluble magnetic iron oxide nanoparticles with the average particle size of 3nm are synthesized, polyethylene glycol 2000 with one end being a diphosphate group and the other end being a phenolic hydroxyl group is modified on the surface of the oil-soluble magnetic iron oxide nanoparticles in a ligand exchange mode to obtain water-soluble magnetic iron oxide nanoparticles, and then the water-soluble magnetic iron oxide nanoparticles are prepared into a magnetic nanoparticle aqueous solution with the iron concentration of 1 mg/mL. Placing 50 μ L of TB buffer solution (pH 7.2) with concentration of 100mM in an ampoule, adding 10 μ L of 10mg/mL chloramine-T solution (prepared with 500mM PB buffer solution, pH 7.3), mixing well, and freeze-drying; then 200 mul of magnetic iron oxide nano-particle aqueous solution with the concentration of 1mg/mL is taken for freeze drying, and the freeze-dried magnetic iron oxide nano-particles are added into the solution filled with the freeze-dried chloramine-TMixing well to obtain dry powder, adding 200 μ L Na125And (3) uniformly mixing the solution I (with the radioactivity of 1mCi), and reacting at room temperature for 5min, wherein the test labeling rate is 75%.
Example 6: (labeling of rare earth nanoparticles, labeling188Re)
Oil-soluble magnetic NaGdF4: Yb, Tm and Ca nanoparticles with the average particle size of about 30nm are synthesized according to a document (Nanosacle,2018,10,21772-21781.), and then according to the document, polyethylene glycol 2000 molecules with one end being a diphosphate group and the other end being a methoxyl group are modified on the surfaces of the magnetic NaGdF4: Yb, Tm and Ca nanoparticles in a ligand exchange mode, and the nanoparticles after ligand exchange are prepared into a magnetic NaGdF4: Yb, Tm and Ca nanoparticle aqueous solution with the Gd concentration of 1 mg/mL. 20 μ L of SnCl was taken2The solution (1mg/mL in 0.1M HCl) was placed in an ampoule and lyophilized; then 300 microliter of magnetic NaGdF4: Yb, Tm and Ca nano-particle water solution with the concentration of 1mg/mL is taken for freeze drying, and the freeze-dried magnetic NaGdF4: Yb, Tm and Ca nano-particles are added into the solution filled with the freeze-dried SnCl2Mixing well to obtain dry powder, adding 200 μ L radioactive Na into the dry powder99mReO4The solution (medium is normal saline) with the radioactivity of 1mCi is shaken up and then placed for reaction for 30min, and the test labeling rate is 83%.
Example 7: (Mark177Lu)
Water-soluble magnetic iron oxide nanoparticles were prepared according to the method of example 1, and the ligand-exchanged magnetic iron oxide nanoparticles were prepared into an aqueous solution of magnetic iron oxide nanoparticles having an iron concentration of 1 mg/mL. Putting 50 mu L of 0.2M acetic acid-sodium acetate buffer solution (pH is 4.8) into an ampoule bottle, freeze-drying 200 mu L of magnetic iron oxide nanoparticle aqueous solution with the concentration of 1mg/mL, adding the freeze-dried magnetic iron oxide nanoparticles into an ampoule bottle filled with freeze-dried acetic acid-sodium acetate, mixing uniformly to obtain dry powder, and adding 300 mu L of radioactive sodium acetate into the dry powder177LuCl3The solution (medium 0.04MHCl) with a radioactivity of 1mCi was shaken up and left to react for 30min, and the test labeling rate was 98%.
Example 8: (Mark111In)
Magnetic iron oxide nanoparticles with the average particle size of about 11nm and the surface modified by dicarboxy PEG are synthesized according to the literature (J.Am.chem.Soc.,2011,133,19512-19523), and the obtained magnetic iron oxide nanoparticles are dissolved in ethanol to prepare a magnetic iron oxide nanoparticle ethanol solution with the iron concentration of 2 mg/mL; placing 50 μ L of 0.2M acetic acid-sodium acetate buffer solution (pH 4.0) in an ampoule bottle, and lyophilizing; then taking 300 mu L of magnetic iron oxide nano-particle ethanol solution with the concentration of 1mg/mL for volatilization and drying, adding the dried magnetic iron oxide nano-particles into an ampere bottle filled with freeze-dried acetic acid-sodium acetate, uniformly mixing to obtain dry powder, and adding 300 mu L of radioactivity into the dry powder111InCl3The solution (medium 0.05M HCl) with a radioactivity of 1mCi was shaken up and left to react for 30min, with a test labeling rate of 97%.
Example 9: (Sterilization by irradiation, control with example 3)
Preparing water-soluble magnetic iron oxide nanoparticles according to the method of example 1, and preparing the ligand-exchanged magnetic iron oxide nanoparticles into a magnetic iron oxide nanoparticle aqueous solution with an iron concentration of 1 mg/mL; taking 10 mu L of SnCl2The solution (1mg/mL in 0.1M HCl) was placed in an ampoule and lyophilized; then 200 microliter of magnetic iron oxide nano-particle aqueous solution with the concentration of 1mg/mL is taken for freeze drying, and the freeze-dried magnetic iron oxide nano-particles are added into the SnCl filled with freeze-dried powder2Mixing the above materials, charging nitrogen, sealing, sterilizing with 60Co irradiation source at 25kGy irradiation dose, and adding 300 μ L radioactive Na99mTcO4The solution (medium is physiological saline) with the radioactivity of 2mCi is shaken up and then placed for reaction for 30min, and the test labeling rate is 97%; there was no significant change in the labeling rate (96%) compared to example 3, indicating that irradiation sterilization of the lyophilized powder did not affect the radionuclide labeling of the magnetic nanoparticles.
Example 10:
water-soluble magnetic iron oxide nanoparticles prepared according to the method of example 1, ligand-exchanged magnetic iron oxide nanoparticlesPreparing magnetic iron oxide nano-particle aqueous solution with iron concentration of 1 mg/mL. Taking 10 mu L of SnCl2The solution (1mg/mL in 0.1M HCl) was placed in an ampoule and lyophilized; then 200 microliter of magnetic iron oxide nano-particle aqueous solution with the concentration of 1mg/mL is taken for freeze drying, and the freeze-dried magnetic iron oxide nano-particles are added into the SnCl filled with freeze-dried powder2Mixing well to obtain mixed dry powder, and adding 300 μ L radioactive Na into the mixed dry powder99mTcO4And (3) shaking the solution (the medium is physiological saline) with the radioactivity of 2mCi, standing for reaction for 30min to finish labeling, and obtaining the magnetic resonance/nuclear medicine bimodal molecular imaging probe. The obtained probe solution is directly injected into a mouse body through a tail vein, dynamic tracking imaging is carried out on the distribution of the probe in the mouse body by SPECT-CT, and figure 6 is a SPECT-CT picture acquired at different time points.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Claims (10)
1. A method for preparing a magnetic resonance/nuclear medicine bimodal molecular imaging probe is characterized by comprising the following steps:
preparing dry powder containing magnetic nanoparticles and auxiliary materials;
and adding a radioactive nuclide solution into the dry powder to mark the radioactive nuclide on the magnetic nanoparticles to obtain the magnetic resonance/nuclear medicine bimodal molecular imaging probe.
2. The method for preparing a magnetic resonance/nuclear medicine bimodal molecular imaging probe according to claim 1, wherein the method for preparing the dry powder comprises the following steps: dissolving the magnetic nano-particles and the auxiliary materials in a solvent, and drying to obtain dry powder.
3. The method for preparing a magnetic resonance/nuclear medicine bimodal molecular imaging probe according to claim 1, wherein the method for preparing the dry powder comprises the following steps: dissolving the magnetic nano-particles in a solvent, drying to obtain magnetic nano-particle powder, drying the auxiliary material to obtain auxiliary material powder, and mixing the magnetic nano-particle powder and the auxiliary material powder to obtain dry powder.
4. The method for preparing a magnetic resonance/nuclear medicine bimodal molecular imaging probe according to claim 2 or 3, wherein: the solvent is one or a mixture of more of water, dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, acetone, isopropanol, glycol, glycerol, cyclohexane, ethyl acetate, acetonitrile, dioxane, N-dimethylformamide, dimethyl sulfoxide, pyridine and toluene.
5. The method of claim 1, wherein the method comprises: the magnetic nanoparticles are selected from any one of magnetic transition metal, magnetic transition metal oxide, magnetic lanthanide rare earth metal oxide, transition metal doped magnetic oxide, rare earth metal doped magnetic oxide, magnetic lanthanide rare earth metal fluoride or magnetic lanthanide rare earth metal doped fluoride, and the particle size of the magnetic nanoparticles is 1-500 nm.
6. A magnetic resonance/nuclear medicine bimodal according to claim 1The preparation method of the molecular imaging probe is characterized by comprising the following steps: said radionuclide being capable of emitting gamma rays or emitting positrons, said radionuclide being selected from99mTc、188Re、111In、64Cu、90Y、123I、124I、125I、131I、177Lu、67Ga、68Ga、18F、59Fe、192Ir、60Co or201Tl.
7. The method of claim 1, wherein the method comprises: the auxiliary materials are selected from one or more of stannous chloride, chloramine-T, sodium chloride, glucose and phosphate buffer salt.
8. The method of claim 1, wherein the method comprises: the surface of the magnetic nano-particle is provided with ligand modification, and the radionuclide is marked on the ligand through a coordination bond or a covalent bond.
9. The method of claim 8, wherein the method comprises: the ligand is selected from any one of small molecular compounds, high molecular polymers, block copolymers or derivatives thereof.
10. The method of claim 8, wherein the method comprises: the ligand contains one or more of carboxyl, amino, sulfydryl, alkynyl, maleimide group and azide group.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116077687A (en) * | 2022-11-08 | 2023-05-09 | 苏州大学 | Nanometer nuclear medicine, preparation method and application thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102295685A (en) * | 2011-07-03 | 2011-12-28 | 江苏省原子医学研究所 | 18F-labeled PRGD2 compound, kit thereof, preparation method of kit thereof, and application thereof |
| CN102451476A (en) * | 2010-10-29 | 2012-05-16 | 中国科学院化学研究所 | Radionuclide-doped magnetic nano crystal with biocompatibility, and preparation method of radionuclide-doped magnetic nano crystal |
| CN104645363A (en) * | 2014-12-24 | 2015-05-27 | 东华大学 | Preparation method of folate-targeted 99mTc marked manganese-based chelate MR/SPECT dual-mode probe |
| 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 |
| WO2019241503A1 (en) * | 2018-06-13 | 2019-12-19 | Enterin, Inc. | Methods and compositions for treating and/or preventing the progression and/or onset of age-related neurodegeneration |
-
2020
- 2020-02-24 CN CN202010112481.0A patent/CN111110873A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102451476A (en) * | 2010-10-29 | 2012-05-16 | 中国科学院化学研究所 | Radionuclide-doped magnetic nano crystal with biocompatibility, and preparation method of radionuclide-doped magnetic nano crystal |
| CN102295685A (en) * | 2011-07-03 | 2011-12-28 | 江苏省原子医学研究所 | 18F-labeled PRGD2 compound, kit thereof, preparation method of kit thereof, and application thereof |
| CN104645363A (en) * | 2014-12-24 | 2015-05-27 | 东华大学 | Preparation method of folate-targeted 99mTc marked manganese-based chelate MR/SPECT dual-mode probe |
| 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 |
| WO2019241503A1 (en) * | 2018-06-13 | 2019-12-19 | Enterin, Inc. | Methods and compositions for treating and/or preventing the progression and/or onset of age-related neurodegeneration |
Non-Patent Citations (3)
| Title |
|---|
| AFSANEH LAHOOTI,ET AL.: "PEGylated superparamagnetic iron oxide nanoparticles labeled with 68Ga as a PET/MRI contrast agent: a biodistribution study", 《J RADIOANAL NUCL CHEM》 * |
| JIYUN SHI, ET AL.: "PET Imaging of Neovascularization with 68Ga-3PRGD2 for Assessing Tumor Early Response to Endostar Antiangiogenic Therapy", 《MOL. PHARMACEUTICS》 * |
| 王晓等: "SPECT/MRI双模态显像剂SPION-DMSA-99Tcm的制备及其性质研究", 《原子能科学技术》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116077687A (en) * | 2022-11-08 | 2023-05-09 | 苏州大学 | Nanometer nuclear medicine, preparation method and application thereof |
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