CN114344489A - Multi-modal FePt @ Fe3O4Nano contrast agent and preparation method and application thereof - Google Patents
Multi-modal FePt @ Fe3O4Nano contrast agent and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a multimodal FePt @ Fe3O4A nano contrast agent and a preparation method and application thereof. The invention relates to a multimodal FePt @ Fe3O4The nano contrast agent is FePt @ Fe with polyethylene glycol modified on the surface3O4Inorganic nanoparticles; the FePt @ Fe3O4The inorganic nano-particle takes FePt alloy as a core and Fe3O4Is a shell nanocrystal with an overall size of 5-20 nm but not 20nm and a core region size of 1-10 nm. The invention provides FePt @ Fe3O4Nano meterThe contrast agent can provide positive T1-T2 contrast in an MRI strong magnetic field, provides obvious residual magnetic signals in ultra-low field magnetic imaging, realizes brand-new T1-T2-ULF multi-mode imaging, can be used in the fields of medical imaging, targeted therapy, visual tracking and the like, and has obvious practical significance and practical value.
Description
Technical Field
The invention relates to a method for preparing FePt @ Fe3O4Based magnetic resonance imaging-A preparation method and application of a multimode nano contrast agent for ultralow field magnetic imaging belong to the technical field of biological and medical nano materials.
Background
Magnetic Resonance Imaging (MRI) has the advantages of high soft tissue contrast, high spatial resolution, no ionizing radiation, wide clinical applicability and the like, and is a valuable non-invasive imaging means. But generally require operation in strong magnetic fields above 1T due to the inherent low sensitivity limitations. The interaction between the nano contrast agent and the surrounding water protons shortens the longitudinal (T1) or transverse (T2) relaxation time of nearby water molecules, so that the MRI sensitivity can be further improved, and images with rich information can be obtained. Among them, T1 weighted imaging can make the relevant focus position present bright change, can better distinguish the tissue, is welcomed by the clinician.
Ultra-low field (ULF) magnetic imaging can be realized by using an optical atomic magnetometer as a high-sensitivity magnetic field detector and by means of residual magnetic signals of nano magnetic particles under the ultra-low field environment lower than 1mT without using an external strong magnetic field. The combination of multiple imaging modalities can yield complementary diagnostic information and provide synergistic advantages over a single modality. Therefore, the development of a T1-T2-ULF multi-mode nano contrast agent with MRI and ultra-low field magnetic imaging is significant for promoting the development of ultra-low field magnetic imaging technology and biomedical image diagnosis in preclinical and transformation research.
Disclosure of Invention
The invention aims to provide a multimodal FePt @ Fe3O4Nano contrast agent and preparation method and application thereof, wherein the nano contrast agent is FePt @ Fe3O4The T1-T2-ULF multi-mode nano contrast agent based on magnetic resonance imaging/ultra-low field magnetic imaging has simple and reproducible synthetic method and high biocompatibility after surface modification; by optimally controlling the adding concentration and proportion of reactants, the contrast agent obtained by synthesis can provide positive T1-T2 contrast under a strong magnetic field and provide obvious residual magnetism signals under an ultra-low field environment, and T1-T2-ULF multi-mode imaging is realized, so that the contrast agent has biomedical and clinical applicationHas great potential in use.
In a first aspect, the invention protects a multimodal FePt @ Fe3O4The nano contrast agent is FePt @ Fe with the surface modified with polyethylene glycol3O4Inorganic nanoparticles; the FePt @ Fe3O4The inorganic nano-particle takes FePt alloy as a core and Fe3O4Is a shell nanocrystal with an overall size of 5-20 nm but not 20nm and a core region size of 1-10 nm.
Multimodal FePt @ Fe as described above3O4In the nano contrast agent, the FePt @ Fe3O4The overall size of the inorganic nanoparticles can be 8.5-16.5 nm, 8.5nm, 12.5nm or 16.5 nm; the size of the nuclear region can be 3.3-4.5 nm, 3.3nm or 4.5 nm.
In a second aspect, the invention protects the multimodal FePt @ Fe3O4The preparation method of the nano contrast agent comprises the following steps:
(1) stirring and vacuumizing a system consisting of a platinum source, an iron source, a stabilizer, a reducing agent and a solvent, and then refluxing in an inert atmosphere to obtain the FePt @ Fe3O4Inorganic nanoparticles;
(2) in the FePt @ Fe3O4Modifying the surface of the inorganic nano particles with polyethylene glycol to obtain PEG/FePt @ Fe3O4Core-shell nanocrystals.
In the preparation method, the molar ratio of the platinum source, the iron source, the stabilizer, the reducing agent and the solvent can be 1 (4-20): 20-100): 2-10): 100-1000, and specifically can be 1 (4-20): 20-100): 3-3.6): 125-625, 1:6:20:3.6:140, 1:4:20:3:125, 1:6.7:33:3:208 or 1:20:100:3: 625;
the platinum source may be platinum acetylacetonate;
the iron source can be ferric acetylacetonate, carbonyl iron or ferric oleate;
the stabilizer can be one or more of oleylamine, oleic acid and capric acid, such as oleylamine and oleic acid in a molar ratio of 1: 1;
the reducing agent can be 1, 2-hexadecanediol or 1, 10-decanediol;
the solvent may be octadecene, hexadecene, dibenzyl ether or squalane.
In the preparation method, the temperature for stirring and vacuumizing can be 30-80 ℃, and specifically can be 80 ℃; the time can be 15-60 minutes, specifically 30-60 minutes, 30 minutes or 60 minutes;
the reflux temperature can be 250-350 ℃, and specifically can be 300 ℃; the time period may be 0.5 to 4 hours, specifically 0.5 hour or 0.75 hour.
The inert atmosphere may be nitrogen or argon.
In the above preparation method, after the reflux is finished, the post-treatment can be performed by the following method: adding a poor solvent (such as ethanol) into the reacted system, centrifuging, collecting the precipitate, adding a benign solvent (such as cyclohexane) into the precipitate, centrifuging, and collecting the supernatant. The product is finally present in the form of a dispersion in a benign solvent, such as cyclohexane.
In the preparation method, the FePt @ Fe3O4The feeding mass ratio of the inorganic nanoparticles to the polyethylene glycol can be (1-5): 9, specifically (1.5-4.0): 1. (1.6-3.6): 9. 2: 9. 2.4: 9. 3.6: 9 or 1.6: 9;
the polyethylene glycol can be modified with diphosphoric acid, 2, 3-dimercaptosuccinic acid dicarboxyl or dopamine, for example, the polyethylene glycol modified with diphosphoric acid is modified with FePt @ Fe3O4The modification effect of the inorganic nanoparticles is achieved by forming coordination between P ═ O on a phosphate group and Fe; application of polyethylene glycol modified by different groups in modification of FePt @ Fe3O4The reaction temperature, time and solvent of the inorganic nanoparticles are the same.
The molecular weight of the polyethylene glycol can be 2K-5K.
Further, the polyethylene glycol is modified with diphosphoric acid;
the temperature of the modification can be 30-50 ℃, and the time can be 8-24 hours, specifically 12 hours.
In the above preparation method, the modification may be carried out in a benign solvent (e.g., tetrahydrofuran)) The method comprises the following specific steps: under the condition of stirring, dropwise adding the tetrahydrofuran solution of polyethylene glycol to the FePt @ Fe3O4And modifying in tetrahydrofuran solution of inorganic nanometer particle. The mass concentration of the tetrahydrofuran solution of the polyethylene glycol can be 10-100 mg/ml; the FePt @ Fe3O4The mass concentration of the tetrahydrofuran solution of the inorganic nanoparticles can be 3-10 mg/ml.
In the above preparation method, after the modification, the post-treatment can be performed by the following method: adding a poor solvent (such as cyclohexane) into the modified system, centrifuging, collecting the precipitate, adding a benign solvent (such as tetrahydrofuran), oscillating, dispersing and then carrying out vacuum drying; and adding water into the vacuum-dried product, performing centrifugal ultrafiltration in an ultrafiltration tube with the molecular weight cutoff of 10-100K (such as 100K), and collecting filtrate. The product is finally present in dispersed form in water.
In a third aspect, the invention protects the multimodal FePt @ Fe3O4The application of the nano-contrast agent in T1-T2-ULF multi-modal nano-contrast agent as magnetic resonance imaging/ultra-low field magnetic imaging.
T1-T2-ULF multimode imaging contrast agents and a technical method for core-shell interface regulation T1-T2 MRI bimodal imaging are not reported in the prior art. Compared with the traditional 10-100nm Fe3O4And 1-10nm FePt nanocrystalline T2 contrast agent, FePt @ Fe provided by the invention3O4The nano contrast agent can provide positive T1-T2 contrast in an MRI strong magnetic field and provide obvious residual magnetic signals in ultra-low field magnetic imaging through regulation and control of a core-shell interface structure, realizes brand-new T1-T2-ULF multi-mode imaging, can be used in the fields of medical imaging, targeted therapy, visual tracking and the like, and has obvious practical significance and practical value.
Drawings
FIG. 1 shows FePt @ Fe prepared in example 13O4TEM characterization of the nanophase contrast agent.
FIG. 2 shows FePt @ Fe prepared in example 23O4TEM characterization of the nanophase contrast agent.
FIG. 3 is a preparation of example 3FePt @ Fe of3O4TEM characterization of the nanophase contrast agent.
FIG. 4 is FePt @ Fe prepared in example 43O4TEM characterization of the nanophase contrast agent.
FIG. 5 is FePt @ Fe prepared for comparative example3O4TEM characterization of the nanophase contrast agent.
FIG. 6 shows FePt @ Fe prepared in examples 1-43O4X-ray diffraction patterns of nano-contrast agents.
FIG. 7 is FePt @ Fe prepared in example 13O4Electron diffraction patterns of nano-contrast agents.
FIG. 8 shows FePt @ Fe prepared in examples 1-43O4Hydrodynamic radius of the nano-contrast agent.
FIG. 9 shows FePt @ Fe prepared in examples 1-43O4Hysteresis loop of nano contrast agent at 300K.
FIG. 10 shows FePt @ Fe prepared in examples 1-43O4MRI T1 weighted imaging of nano-contrast agents.
FIG. 11 is FePt @ Fe prepared in examples 1-43O4MRI T2 weighted imaging of nano-contrast agents.
FIG. 12 is FePt @ Fe prepared for comparative example3O4MRI T1T 2 weighted imaging of nano-contrast agents.
FIG. 13 is FePt @ Fe prepared in example 13O4Cytotoxicity of nano-contrast agents.
FIG. 14 is FePt @ Fe prepared in example 13O4The mouse tumors of the nanopaint T1 were imaged with T2.
FIG. 15 is FePt @ Fe prepared in example 13O4Ultra-low field scan profiles of nano-contrast agents.
FIG. 16 is FePt @ Fe prepared in example 13O4Ultra-low field in vivo magnetic imaging of tumor cells labeled with nano contrast agents.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments, which are given for the purpose of illustration only and are not intended to limit the scope of the invention. The examples provided below serve as a guide for further modifications by a person skilled in the art and do not constitute a limitation of the invention in any way.
The experimental procedures in the following examples, unless otherwise indicated, are conventional and are carried out according to the techniques or conditions described in the literature in the field or according to the instructions of the products. Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The PEG in the following examples is diphosphonate modified PEG (DP-PEG 2000-Mal, molecular weight 2K-5K), composed of MAL-PEG2000-NH2Synthesized to obtain MAL-PEG2000-NH2Purchased from Saian Ruixi and having a product designation R-1404-X. The DP-PEG 2000-Mal synthesis method comprises the following steps: 2.0g H3PO3，20ml H2O, 1.0ml concentrated hydrochloric acid is fully dissolved, and Mal-PEG-NH is added2(4.0g), the oil bath was warmed to 90 ℃. Slowly adding 3.0ml formaldehyde (37% solution) dropwise with a constant pressure funnel, heating to 110 deg.C, reacting at constant temperature for 90min, closing the reaction, and cooling to room temperature. The reaction solution was transferred to a 150ml single-neck flask, and the solvent was removed by rotary evaporation at 70 ℃. Adding 50-70 ml of ethanol to form a viscous mixture, adding 15ml of ethanol to dissolve the viscous mixture, and filtering the viscous mixture into a conical flask through a sand core funnel. Precipitating with 500ml of ethyl acetate, standing at-20 ℃ for 30min, performing suction filtration to obtain a precipitate, and adding 15-20 ml of ethanol for dissolving. Repeating the precipitation for 2 times, transferring the final precipitation into a small beaker, vacuum drying at normal temperature for 24h, and finally sealing and storing at-20 ℃.
Example 1 Synthesis of FePt @ Fe3O4Multimodal nano-contrast agent (c4.5s12.5)
A50 ml three-necked flask was charged with 0.5mmol of platinum acetylacetonate, 3mmol of iron acetylacetonate, 5mmol of oleic acid, 5mmol of oleylamine, 1.8mmol of 1, 2-hexadecanediol and 10ml (35mmol) of hexadecene, and vacuum was applied under stirring at 80 ℃ for 60 minutes, followed by reflux at 300 ℃ for 30 minutes under nitrogen. Cooling to room temperature after the reaction is finished, adding ethanol 6000r/min for centrifugal separation for 10 minutes, precipitating, adding cyclohexane for centrifugal separation, taking supernate, repeating the centrifugal separation operation for 2 times, dispersing the product into cyclohexane, and placing the product in a refrigerator at 4 ℃ for later use. In the above 2ml oil phase40ml of acetone 6000r/min is added into a sample (the mass concentration is about 18mg/ml) for centrifugal separation for 10 minutes, a precipitate (about 36mg) is taken out, 4ml of tetrahydrofuran is added, stirring is carried out at a low temperature of 40 ℃, and 3ml of 30mg/ml PEG tetrahydrofuran solution is slowly dropped. After the reaction for 12 hours, adding 45ml of cyclohexane for 5000r/min, centrifugally separating for 5 minutes, taking the precipitate, adding 4ml of tetrahydrofuran, shaking and dispersing, and repeatedly centrifugally shaking for 3 times. Vacuum drying, adding water, transferring to ultrafiltration tube with molecular weight cutoff of 100k, centrifuging at 5000r/min for ultrafiltration for 10min, transferring the liquid in the filter core to a sample bottle, and storing in 4 deg.C refrigerator, i.e. FePt @ Fe3O4A multimodal nano-contrast agent.
The resulting FePt @ Fe3O4The TEM image of the multi-modal nano contrast agent is shown in FIG. 1, and the multi-modal nano contrast agent has a distinct core-shell structure, and the side length of the shell and the diameter of the inner core are respectively 12.5nm and 4.5nm, so the mark is c4.5s12.5. The X-ray diffraction pattern is shown in FIG. 6, and FePt standard card (04-0326, blue) and Fe appear3O4Mixed diffraction peaks of standard card (19-0629, black). The electron diffraction pattern of c4.5s12.5 is shown in FIG. 7, and the rings correspond to the (110) crystal plane and Fe of FePt respectively3O4The (220), (311), (440) crystal plane of (c). The hydrodynamic radius of c4.5s12.5 is shown in fig. 8, showing good aqueous solution stability. The hysteresis loop of c4.5s12.5 is shown in fig. 9, the MRI T1 and T2 weighted imaging is shown in fig. 10 and 11, and the longitudinal relaxation rate r1 and the transverse relaxation rate r2 are shown in table 1. In contrast to the contrast agents prepared in the other examples below, the cytotoxicity of c4.5s12.5 cells after 24h incubation with 4T1 mouse breast cancer cells was tested as shown in FIG. 13 for cytotoxicity evaluation due to the best saturation magnetization and T1-T2 contrast. 5-week-old BALB/c female mice (body weight 20-25g) were selected for mouse subcutaneous tumor imaging, and each mouse was injected with 5 x 10 injections of the right posterior hip6A 4T1Cells, tumor diameter reached 4-5mm after about one week of culture, at which time mice were injected with contrast agent c4.5s12.5 tail vein (injection amount 4mg/kg) followed by MRI imaging using a 1.5T small animal magnetic imager. The resulting MRI T1 and T2 images as in fig. 14, T1 and T2 of the tumor region showed the most significant signal changes at 1h post injection simultaneously. The ultra-low field scanning curve of c4.5s12.5 is shown in FIG. 15, and the obvious pT magnitude ultra-low field remanence signal is shown. C4.5s12.5-labeled 4T1 cells were injected subcutaneously into mice and subjected to ultra-low field imaging using an ultra-low field atomic magnetometer. And performing inversion simulation on the data of the scanning magnetic field curve to obtain the space location of the tumor cell population in the living mouse. The ultra-low field in vivo magnetic imaging is shown in figure 16, and accurate positioning is shown at 231mm, which indicates that ultra-low field cell tracing application research can be carried out.
Example 2 Synthesis of FePt @ Fe3O4Multimodal nano-contrast agent (c3.3s8.5)
A50 ml three-necked flask was charged with 0.5mmol of platinum acetylacetonate, 2mmol of iron acetylacetonate, 5mmol of oleic acid, 5mmol of oleylamine, 1.5mmol of 1, 2-hexadecanediol and 20ml (62.5mmol) of octadecene, and vacuum-pumping was carried out with stirring at 80 ℃ for 30 minutes, followed by reflux at 300 ℃ for 30 minutes under nitrogen. Cooling to room temperature after the reaction is finished, adding ethanol 6000r/min for centrifugal separation for 10 minutes, precipitating, adding cyclohexane for centrifugal separation, taking supernate, repeating the centrifugal separation operation for 2 times, dispersing the product into cyclohexane, and placing the product in a refrigerator at 4 ℃ for later use. 40ml of acetone 6000r/min is added into the 2ml of oil phase sample (the mass concentration is about 12mg/ml) for centrifugal separation for 10 minutes, precipitate is taken out, 4ml of tetrahydrofuran is added, stirring is carried out at the low temperature of 40 ℃, and 3ml of 30mg/ml PEG tetrahydrofuran solution is slowly dropped. After the reaction for 12 hours, adding 45ml of cyclohexane for 5000r/min, centrifugally separating for 5 minutes, taking the precipitate, adding 4ml of tetrahydrofuran, shaking and dispersing, and repeatedly centrifugally shaking for 3 times. Vacuum drying, adding water, transferring to ultrafiltration tube with molecular weight cutoff of 100k, centrifuging at 5000r/min for ultrafiltration for 10min, transferring the liquid in the filter core to a sample bottle, and storing in 4 deg.C refrigerator, i.e. FePt @ Fe3O4A multimodal nano-contrast agent.
The resulting FePt @ Fe3O4The TEM image of the multi-modal nano-contrast agent is shown in FIG. 2, and has a distinct core-shell structure, with the shell side length and the core diameter of 8.5nm and 3.3nm, respectively, and therefore, the mark is c3.3s8.5. The X-ray diffraction pattern is shown in FIG. 6, and FePt standard card (04-0326, blue) and Fe appear3O4Mixed diffraction peaks of standard card (19-0629, black). The hydrodynamic radius of c3.3s8.5 is shown in fig. 8, showing good aqueous solution stability. The hysteresis loop of c3.3s8.5 is shown in FIG. 9, MRI T1 andt2 weighted imaging is shown in fig. 10 and 11, with longitudinal r1 and transverse r2 relaxation rates as in table 1. For the contrast agents of examples 3 and 4 below, c3.3s8.5 had a larger r1 value and better T1-weighted imaging due to its smaller overall size.
Example 3 Synthesis of FePt @ Fe3O4Multimodal nano-contrast agent (c3.3s12.5)
A50 ml three-necked flask was charged with 0.3mmol of platinum acetylacetonate, 2mmol of iron acetylacetonate, 5mmol of oleic acid, 5mmol of oleylamine, 0.9mmol of 1, 2-hexadecanediol and 20ml (62.5mmol) of octadecene, and vacuum-pumping was carried out at 80 ℃ for 30 minutes with stirring, followed by reflux at 300 ℃ for 45 minutes under nitrogen. Cooling to room temperature after the reaction is finished, adding ethanol 6000r/min for centrifugal separation for 10 minutes, precipitating, adding cyclohexane for centrifugal separation, taking supernate, repeating the centrifugal separation operation for 2 times, dispersing the product into cyclohexane, and placing the product in a refrigerator at 4 ℃ for later use. 40ml of acetone 6000r/min is added into the 2ml of oil phase sample (the mass concentration is about 10mg/ml) for centrifugal separation for 10 minutes, precipitate is taken out, 4ml of tetrahydrofuran is added, stirring is carried out at the low temperature of 40 ℃, and 3ml of 30mg/ml PEG tetrahydrofuran solution is slowly dropped. After the reaction for 12 hours, adding 45ml of cyclohexane for 5000r/min, centrifugally separating for 5 minutes, taking the precipitate, adding 4ml of tetrahydrofuran, shaking and dispersing, and repeatedly centrifugally shaking for 3 times. Vacuum drying, adding water, transferring to ultrafiltration tube with molecular weight cutoff of 100k, centrifuging at 5000r/min for ultrafiltration for 10min, transferring the liquid in the filter core to a sample bottle, and storing in 4 deg.C refrigerator, i.e. FePt @ Fe3O4A multimodal nano-contrast agent.
The resulting FePt @ Fe3O4The TEM image of the multi-modal nano-contrast agent is shown in FIG. 3, and has a distinct core-shell structure, with the side length of the shell and the diameter of the core being 12.5nm and 3.3nm, respectively, so that the mark is c3.3s12.5. The X-ray diffraction pattern is shown in FIG. 6, and FePt standard card (04-0326, blue) and Fe appear3O4Mixed diffraction peaks of standard card (19-0629, black). The hydrodynamic radius of c3.3s12.5 is shown in figure 8, showing good aqueous solution stability. The hysteresis loop of c3.3s12.5 is shown in fig. 9, the MRI T1 and T2 weighted imaging is shown in fig. 10 and 11, and the longitudinal relaxation rate r1 and the transverse relaxation rate r2 are shown in table 1. Contrast Agents of comparative examples 2 and 4, c3.3s12.5 has balanced r1 and r2 values due to their moderate overall size. By optimizing the reactant feeding concentration and proportion, the size of the inner core is increased under the condition of controlling the overall size of the nanocrystalline to be unchanged, the interface effect of the core-shell structure is adjusted, and a better T1-T2 dual-mode imaging effect is obtained.
Example 4 Synthesis of FePt @ Fe3O4Multimodal nano-contrast agent (c3.3s16.5)
A50 ml three-necked flask was charged with 0.1mmol of platinum acetylacetonate, 2mmol of iron acetylacetonate, 5mmol of oleic acid, 5mmol of oleylamine, 0.3mmol of 1, 2-hexadecanediol and 20ml (62.5mmol) of octadecene, and vacuum-pumping was carried out at 80 ℃ for 60 minutes with stirring, followed by reflux at 300 ℃ for 30 minutes under nitrogen. Cooling to room temperature after the reaction is finished, adding ethanol 6000r/min for centrifugal separation for 10 minutes, precipitating, adding cyclohexane for centrifugal separation, taking supernate, repeating the centrifugal separation operation for 2 times, dispersing the product into cyclohexane, and placing the product in a refrigerator at 4 ℃ for later use. 40ml of acetone 6000r/min is added into the 2ml of oil phase sample (the mass concentration is about 8mg/ml) for centrifugal separation for 10 minutes, precipitate is taken out, 4ml of tetrahydrofuran is added, stirring is carried out at the low temperature of 40 ℃, and 3ml of 30mg/ml PEG tetrahydrofuran solution is slowly dropped. After the reaction for 12 hours, adding 45ml of cyclohexane for 5000r/min, centrifugally separating for 5 minutes, taking the precipitate, adding 4ml of tetrahydrofuran, shaking and dispersing, and repeatedly centrifugally shaking for 3 times. Vacuum drying, adding water, transferring to ultrafiltration tube with molecular weight cutoff of 100k, centrifuging at 5000r/min for ultrafiltration for 10min, transferring the liquid in the filter core to a sample bottle, and storing in 4 deg.C refrigerator, i.e. FePt @ Fe3O4A multimodal nano-contrast agent.
The resulting FePt @ Fe3O4The TEM image of the multi-modal nano-contrast agent is shown in FIG. 4, and has a distinct core-shell structure, with 16.5nm and 3.3nm for the shell side length and the core diameter, respectively, and is therefore labeled c3.3s16.5. The X-ray diffraction pattern is shown in FIG. 6, and FePt standard card (04-0326, blue) and Fe appear3O4Mixed diffraction peaks of standard card (19-0629, black). The hydrodynamic radius of c3.3s16.5 is shown in fig. 8, showing good aqueous solution stability. The hysteresis loop of c3.3s16.5 is shown in fig. 9, the MRI T1 and T2 weighted imaging is shown in fig. 10 and 11, and the longitudinal relaxation rate r1 and the transverse relaxation rate r2 are shown in table 1. To pairCompared with the contrast agents of examples 2 and 3, c3.3s16.5 has a larger r2 value and better T2 weighted imaging effect due to the larger overall size.
FePt @ Fe prepared in Table 1, examples 1-43O4Longitudinal relaxation rate r of nano contrast agent1And transverse relaxation rate r2
Comparative example, FePt @ Fe having poor multimodal imaging Effect3O4Nano contrast agent (c4.5s20)
A50 ml three-necked flask was charged with 0.3mmol of platinum acetylacetonate, 2mmol of iron acetylacetonate, 15mmol of oleic acid, 15mmol of oleylamine, 1.8mmol of 1, 2-hexadecanediol and 10ml (35mmol) of hexadecene, and vacuum was applied under stirring at 80 ℃ for 30 minutes, followed by reflux at 300 ℃ for 45 minutes under nitrogen. Cooling to room temperature after the reaction is finished, adding ethanol 6000r/min for centrifugal separation for 10 minutes, precipitating, adding cyclohexane for centrifugal separation, taking supernate, repeating the centrifugal separation operation for 2 times, dispersing the product into cyclohexane, and placing the product in a refrigerator at 4 ℃ for later use. 40ml of acetone 6000r/min is added into the 2ml of oil phase sample (the mass concentration is about 18mg/ml) for centrifugal separation for 10 minutes, precipitate is taken out, 4ml of tetrahydrofuran is added, stirring is carried out at the low temperature of 40 ℃, and 3ml of 30mg/ml PEG tetrahydrofuran solution is slowly dropped. After the reaction for 12 hours, adding 45ml of cyclohexane for 5000r/min, centrifugally separating for 5 minutes, taking the precipitate, adding 4ml of tetrahydrofuran, shaking and dispersing, and repeatedly centrifugally shaking for 3 times. Vacuum drying, adding water, transferring to ultrafiltration tube with molecular weight cutoff of 100k, centrifuging at 5000r/min for ultrafiltration for 10min, transferring the liquid in the filter core to a sample bottle, and storing in 4 deg.C refrigerator, i.e. FePt @ Fe3O4A multimodal nano-contrast agent.
The resulting FePt @ Fe3O4The TEM image of the multi-modal nano-contrast agent is shown in FIG. 5, and the multi-modal nano-contrast agent has a distinct core-shell structure, and the side length of the shell and the diameter of the inner core are respectively 20nm and 4.5nm, so the multi-modal nano-contrast agent is marked as c4.5s20. The MRI T1 and T2 weighted images are shown in FIG. 12, and the contrast agent of comparative example 1, c4.5s20, is oversized as a whole, although it has a strong effectThe T2 weighted imaging effect, but the T1 weighted imaging effect is significantly poor.
Claims (7)
1. Multi-modal FePt @ Fe3O4The nano contrast agent is FePt @ Fe with the surface modified with polyethylene glycol3O4Inorganic nanoparticles; the FePt @ Fe3O4The inorganic nano-particle takes FePt alloy as a core and Fe3O4Is a shell nanocrystal with an overall size of 5-20 nm but not 20nm and a core region size of 1-10 nm.
2. PEG/FePt @ Fe as claimed in claim 13O4The preparation method of the core-shell nanocrystal comprises the following steps:
(1) stirring and vacuumizing a system consisting of a platinum source, an iron source, a stabilizer, a reducing agent and a solvent, and then refluxing in an inert atmosphere to obtain the FePt @ Fe3O4Inorganic nanoparticles;
(2) in the FePt @ Fe3O4Modifying the surface of the inorganic nano particle with polyethylene glycol to obtain the PEG/FePt @ Fe3O4Core-shell nanocrystals.
3. The method of claim 2, wherein: the molar ratio of the platinum source to the iron source to the stabilizer to the reducing agent to the solvent is 1 (4-20): 20-100): 2-10): 100-1000;
the platinum source is platinum acetylacetonate;
the iron source is ferric acetylacetonate, carbonyl iron or iron oleate;
the stabilizer is one or more of oleylamine, oleic acid and capric acid;
the reducing agent is 1, 2-hexadecanediol or 1, 10-decanediol;
the solvent is octadecene, hexadecene, dibenzyl ether or squalane.
4. The production method according to claim 2 or 3, characterized in that: the stirring and vacuumizing temperature is 30-80 ℃, and the time is 15-60 minutes;
the reflux temperature is 250-350 ℃, and the reflux time is 0.5-4 hours.
5. The production method according to any one of claims 2 to 4, characterized in that: the FePt @ Fe3O4The mass ratio of the inorganic nanoparticles to the polyethylene glycol is (1.5-4.0): 1;
the polyethylene glycol is modified with diphosphoric acid, 2, 3-dimercaptosuccinic acid dicarboxyl or dopamine;
the molecular weight of the polyethylene glycol is 2K-5K.
6. The production method according to any one of claims 2 to 5, characterized in that: the polyethylene glycol is modified with diphosphonic acid;
the temperature of the modification is 30-50 ℃, and the time is 8-24 hours.
7. The multimodal FePt @ Fe of claim 13O4The application of the nano-contrast agent in T1-T2-ULF multi-modal nano-contrast agent as magnetic resonance imaging/ultra-low field magnetic imaging.
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| CN115255360A (en) * | 2022-07-20 | 2022-11-01 | 中国科学院化学研究所 | High-performance FePt @ Fe shell-core structure magnetic nanocrystal and preparation method thereof |
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| CN102526769A (en) * | 2010-09-28 | 2012-07-04 | 谢达斌 | Double-developer for CT and MRI simultaneously and preparation method thereof |
| CN106501553A (en) * | 2016-12-08 | 2017-03-15 | 中国科学院化学研究所 | A kind of ultralow field nanometer magnetic probe and preparation method and application |
| CN108705078A (en) * | 2018-06-19 | 2018-10-26 | 中国科学院化学研究所 | A kind of double magnetic core-shell structures of metal alloy-metal oxide are nanocrystalline and the preparation method and application thereof |
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| CN102526769A (en) * | 2010-09-28 | 2012-07-04 | 谢达斌 | Double-developer for CT and MRI simultaneously and preparation method thereof |
| CN106501553A (en) * | 2016-12-08 | 2017-03-15 | 中国科学院化学研究所 | A kind of ultralow field nanometer magnetic probe and preparation method and application |
| CN108705078A (en) * | 2018-06-19 | 2018-10-26 | 中国科学院化学研究所 | A kind of double magnetic core-shell structures of metal alloy-metal oxide are nanocrystalline and the preparation method and application thereof |
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| CN115255360A (en) * | 2022-07-20 | 2022-11-01 | 中国科学院化学研究所 | High-performance FePt @ Fe shell-core structure magnetic nanocrystal and preparation method thereof |
| CN115255360B (en) * | 2022-07-20 | 2024-01-16 | 中国科学院化学研究所 | High-performance FePt@Fe shell-core structure magnetic nanocrystalline and preparation method thereof |
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