Iron oxide nanoparticles and their use in magnetic particle imaging
Octahedral iron oxide nanoparticles were synthesized by high-temperature thermal decomposition, which solved the problem of insufficient sensitivity in existing magnetic particle imaging technology and achieved high-sensitivity and stable magnetic particle imaging effect.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- XIDIAN UNIV
- Filing Date
- 2023-11-15
- Publication Date
- 2026-06-23
AI Technical Summary
In existing magnetic particle imaging technologies, commercial tracers are not sensitive enough, and magnetic particles with low coercivity and high initial magnetic susceptibility are needed to improve imaging sensitivity.
Octahedral iron oxide nanoparticles were synthesized by high-temperature thermal decomposition. By adding surfactants oleic acid and oleylamine and controlling the reaction rate, iron oxide nanoparticles with high magnetic susceptibility and low coercivity were prepared. These nanoparticles were then coated with amphiphilic polymers and biological membranes to form nanomaterials suitable for in vivo imaging.
It improves the sensitivity of magnetic particle imaging, increases the signal intensity to more than 4 times that of commercial contrast agents, achieves better imaging results, and has good stability and long circulation capability in vivo.
Smart Images
Figure CN117776276B_ABST
Abstract
Description
Technical Field
[0001] This application relates to the field of magnetic particle imaging technology, and more specifically, to an iron oxide nanoparticle and its application in magnetic particle imaging. Background Technology
[0002] Magnetic particle imaging (MPI) is an imaging technique proposed by Philips Research in 2005. It uses an oscillating magnetic field to image superparamagnetic iron oxide nanoparticles as tracers. Unlike magnetic resonance imaging (MRI), which measures nuclear magnetic resonance changes in water protons, MPI detects changes in the electronic magnetization of iron, which is 22 million times larger than the nuclear magnetic resonance changes of water protons at 7T. Therefore, MPI has much higher sensitivity than MRI. The existing commercial MPI tracer, Vivo Trax, was originally designed as a commercial contrast agent for MRI, and its magnetic properties are not optimal for MPI. Theoretically, MPI requires iron oxide magnetic particles with high initial magnetic susceptibility and low coercivity. Magnetic particle imaging requires magnetic particles with high initial magnetic susceptibility and low coercivity. This requires adjusting the chemical structure of the magnetic particles to optimize their magnetic properties. In existing magnetic particle tracer research, the shapes of the magnetic particles are mainly spheres and cubes. Spherical magnetic particles are obtained through uniform growth in all directions, while cubic magnetic particles are obtained by adding surfactants to suppress the growth of the {100} crystal facets of magnetite (Fe3O4). The magnetic parameters of these two shapes of magnetic particles are mainly advantageous in terms of initial magnetic susceptibility or coercivity, which leads to insufficient imaging sensitivity for these two shapes of magnetic particles.
[0003] Magnetic particle imaging (MPI), as an emerging medical imaging technology, has seen limited research on tracers for its application, and existing commercial imaging tracers lack sufficient sensitivity. MPI utilizes the nonlinear response of superparamagnetic iron oxide nanoparticles for imaging, requiring magnetic particles with low coercivity and high initial magnetic susceptibility. The coercivity and initial magnetic susceptibility of magnetic particles are influenced by their morphology. Therefore, this invention, based on the requirements of MPI for magnetic particle properties, synthesizes octahedral magnetic particles with excellent magnetic parameters (initial coercivity and initial magnetic susceptibility), thereby improving the sensitivity of magnetic particle imaging from the perspective of magnetic particles themselves. Summary of the Invention
[0004] This disclosure provides iron oxide nanoparticles and their application in magnetic particle imaging. Octahedral iron(III) oxide nanoparticles are synthesized using a high-temperature thermal decomposition method. These nanoparticles exhibit uniform particle size distribution, few defects, monodispersity, high stability, and superparamagnetism. Due to their octahedral shape, they possess high magnetic susceptibility, low coercivity, and superior MPI performance, making them highly suitable for in vivo magnetic particle imaging.
[0005] In a first aspect, this disclosure provides an iron oxide nanoparticle, wherein the nanoparticle is an octahedral superparamagnetic iron oxide nanoparticle, the nanoparticle is synthesized by high-temperature thermal decomposition method by adding surfactant and controlling the reaction rate, the surfactant including oleic acid and oleylamine, the octahedral superparamagnetic iron oxide nanoparticle is coated with an amphiphilic polymer, the amphiphilic polymer including polymaleic anhydride-1-octadecenoic acid and polystyrene-maleic anhydride copolymer, the amphiphilic polymer being used in biological membranes whose outer layer includes macrophage membranes, erythrocyte membranes, neutrophil membranes and tumor cell membranes.
[0006] Secondly, this disclosure provides a method for preparing iron oxide nanoparticles, wherein the method for preparing the octahedral superparamagnetic iron oxide nanomaterial includes the following steps:
[0007] (1) Superparamagnetic nanoparticles were obtained by reducing iron acetylacetone with an organic solvent through a high-temperature thermal decomposition method; (2) The superparamagnetic nanoparticles and an amphiphilic polymer were dispersed in an organic solvent, the organic solvent was removed by vacuum evaporation to form a thin film, and an aqueous solution of dimethylpyridine was added and sonicated to obtain a monodisperse superparamagnetic nanomaterial in an aqueous system.
[0008] (3) The superparamagnetic iron oxide nanoparticles in aqueous phase and the extracted biological cell membrane are mixed in proportion, and then sonicated in a cell disruptor. The mixture is then circulated and extruded through an extruder to finally obtain superparamagnetic iron oxide nanomaterials with in vivo long-term circulation capability.
[0009] Preferably, the synthesis method includes the following steps:
[0010] S1: At room temperature, add 1-7 mmol of acetylacetone iron, oleic acid, and oleylamine to a 100 mL three-necked flask and stir to obtain a mixture.
[0011] S2: Heat the reaction system to 60-100℃ at a rate of 5-15℃ / min, while maintaining evacuation for 30-60min. Introduce N2 protective gas into the system and heat to 200-240℃ at a rate of 5-15℃ / min to carry out the nucleation process of the particles. The nucleation process takes 20-40min.
[0012] S3: Maintain N2 flow and heat to 300-350℃ at a rate of 5-15℃ / min to carry out particle growth for 60-180 min. Pour the reaction solution into a 50ml centrifuge tube and centrifuge at 6000rpm for 6 min to obtain octahedral superparamagnetic iron oxide nanoparticles;
[0013] S4: The octahedral superparamagnetic iron oxide nanoparticles obtained by washing with n-hexane and anhydrous ethanol are then dispersed in 10 mL of chloroform solution to obtain octahedral superparamagnetic iron oxide nanoparticles dispersed in chloroform.
[0014] Preferably, in step (1), the reaction temperature is 310-340℃ and the reaction time is 90-150min.
[0015] Preferably, in step (1), the centrifugation speed of the product is 6000-8000 rpm, and the centrifugation time is 6-10 min.
[0016] Preferably, in step (1), the amount of the precursor is 1-3 mmol, and the volume ratio of the organic solvent oleic acid to oleylamine is 12.5:(17.5-20) mL.
[0017] Preferably, in step (2), the mass ratio of the magnetic particles to the amphiphilic polymer is 1:(10-50), the mass ratio of the added dimethylpyridine to the amphiphilic polymer is 1:(1-2), and the ultrasonic time is 10-20 min.
[0018] Preferably, in step (3), the volume ratio of the iron oxide nanoparticles in the aqueous phase to the biofilm is 3:(1-2), the power of the cell disruptor is 40-80W, the disruption time is 20-50min, and the mixture is circulated and extruded 8-10 times through the extruder.
[0019] Thirdly, this disclosure provides an application of iron oxide nanoparticles, wherein the superparamagnetic nanomaterial is used as a magnetic particle imaging contrast agent, and the highly sensitive superparamagnetic iron oxide nanoparticles are used as a magnetic particle imaging tracer in in vivo tumor imaging, cell tracking, hemorrhage detection, and vascular imaging.
[0020] Preferably, the application method further includes superparamagnetic iron oxide nanoparticles coated with tumor cell membranes for tumor detection, and superparamagnetic iron oxide nanoparticles coated with erythrocyte membranes for blood imaging.
[0021] In summary, this application has the following beneficial effects:
[0022] 1. Since this application uses a high-temperature thermal decomposition method to synthesize 14nm octahedral magnetic particles with oleic acid and oleylamine as surfactants, other methods, such as solvothermal methods, can also synthesize octahedral magnetic particles of similar size by changing the reaction system from a high-temperature and atmospheric-pressure system to a high-temperature and high-pressure system without changing the feed. Using oleic acid alone as a surfactant and adjusting the heating rate may also synthesize octahedral magnetic particles.
[0023] 2. Compared with the cubic iron oxide nanoparticles in the best prior art, the octahedral iron oxide nanoparticles synthesized by this method can overcome the shortcomings of low coercivity of cubic magnetic particles while ensuring high initial magnetic susceptibility, thereby obtaining higher magnetic particle imaging sensitivity. The MPI signal intensity of the best existing cubic magnetic particles is 4 times that of Vivo Trax, while the octahedral magnetic particles prepared in this application achieve a 5.2-fold improvement in the signal intensity of Vivo Trax.
[0024] 3. This application employs a high-temperature thermal decomposition method to synthesize octahedral iron oxide nanoparticles by adding surfactants (oleic acid and oleylamine) and controlling the reaction rate. The nanoparticles synthesized by this method exhibit uniform particle size distribution, few defects, monodispersity, high stability, and superparamagnetism. Due to their octahedral shape, they possess high magnetic susceptibility and low coercivity, making them highly suitable for in vivo magnetic particle imaging.
[0025] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and do not limit the scope of protection of this disclosure. Attached Figure Description
[0026] 1. Figure 1 This is a transmission electron microscope characterization image of the octahedral superparamagnetic iron oxide nanoparticles prepared in Example 1 of this application;
[0027] 2. Figure 2 This is a transmission electron microscope (TEM) characterization image of the octahedral superparamagnetic iron oxide nanomaterial prepared in Example 4 of this application;
[0028] 3. Figure 3 This is an X-ray diffraction characterization image of the octahedral superparamagnetic iron oxide nanoparticles prepared in Example 1 of this application;
[0029] 4. Figure 4 It is the hysteresis loop of the octahedral superparamagnetic iron oxide nanoparticles prepared in Example 1 of this application;
[0030] 5. Figure 5 This is a transmission electron microscope characterization image of the spherical superparamagnetic iron oxide nanoparticles prepared in Example 2 of this application;
[0031] 6. Figure 6 This is a transmission electron microscope characterization image of the spherical octahedral hybrid superparamagnetic iron oxide nanoparticles prepared in Example 3 of this application;
[0032] 7. Figure 7 This is a transmission electron microscope characterization of the magnetic particles coated on the tumor cell membrane in this application;
[0033] 8. Figure 8 This is a magnetic particle imaging image of the octahedral superparamagnetic iron oxide nanoparticles of Application Example 1 of this application.
[0034] 9. Figure 9 This is a bar chart characterizing the MPI performance of magnetic particles of different shapes in this application;
[0035] 10. Figure 10 This application describes the imaging of subcutaneous breast cancer tumors encapsulated by magnetic particles within the tumor cell membrane.
[0036] 11. Figure 11 The imaging results of this application on a subcutaneous breast cancer tumor model are shown in terms of tumor cell membrane coverage versus non-tumor cell membrane coverage.
[0037] 12. Figure 12 The blood half-life of the magnetic particles not coated with the red blood cell membrane and the magnetic particles coated with the red blood cell membrane are as described in this application. Detailed Implementation
[0038] The following detailed description of this application is provided in conjunction with the embodiments. It should be noted that: unless otherwise specified, the conditions in the following embodiments are performed under conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the following embodiments are all from commercially available sources.
[0039] Example
[0040] Example 1
[0041] Synthesis of Octahedral Iron Oxide
[0042] At room temperature, 353 mg of ferric acetylacetone, 12.5 mL of oleic acid, and 17.5 mL of oleylamine were added to a 100 mL three-necked flask and stirred to obtain a mixture. The reaction system was heated to 80 °C at a rate of 10 °C / min, with evacuation maintained for 30 min. N2 protective gas was introduced into the system, and the temperature was increased to 220 °C at a rate of 10 °C / min for particle nucleation, which lasted for 30 min. N2 was then introduced, and the temperature was increased to 330 °C at a rate of 10 °C / min for particle growth, which lasted for 90 min. The resulting solution was poured into 50 mL centrifuge tubes and centrifuged at 6000 rpm for 6 min to obtain octahedral superparamagnetic iron oxide nanoparticles. The obtained octahedral superparamagnetic iron oxide nanoparticles were washed with n-hexane and anhydrous ethanol, and then dispersed in 10 mL of chloroform solution to obtain octahedral superparamagnetic iron oxide nanoparticles dispersed in chloroform.
[0043] The TEM characterization image of the octahedral iron oxide nanoparticles prepared in this embodiment is as follows: Figure 1 As shown, the size of the obtained octahedral iron oxide nanoparticles is 14-17 nm.
[0044] X-ray diffraction of the octahedral iron oxide nanoparticles prepared in this embodiment is as follows: Figure 2 As shown. This proves that the obtained nanoparticles have an inverse spinel crystal structure of iron(III) oxide. The magnetization curve is shown in... Figure 3 As shown, the obtained nanoparticles are superparamagnetic, with high saturation magnetization and low coercivity.
[0045] Example 2
[0046] Synthesis of spherical magnetic particles
[0047] At room temperature, 353 mg of ferric acetylacetone, 12.5 mL of oleic acid, and 17.5 mL of oleylamine were added to a 100 mL three-necked flask and stirred to obtain a mixture. The reaction system was heated to 130 °C at a rate of 10 °C / min, with evacuation maintained for 30 min. N2 protective gas was introduced into the system, and the temperature was increased to 220 °C at a rate of 10 °C / min for particle nucleation, which lasted for 30 min. N2 was then introduced, and the temperature was increased to 350 °C at a rate of 10 °C / min for particle growth, which lasted for 90 min. The resulting solution was poured into a 50 mL centrifuge tube and centrifuged at 6000 rpm for 6 min to obtain spherical superparamagnetic iron oxide nanoparticles.
[0048] The TEM characterization image of the spherical iron oxide nanoparticles prepared in this embodiment is as follows: Figure 4 As shown, the size of the obtained spherical iron oxide nanoparticles is 10-15 nm.
[0049] Example 3
[0050] Synthesis of mixed spherical and octahedral magnetic particles
[0051] At room temperature, 353 mg of ferric acetylacetone, 12.5 mL of oleic acid, and 17.5 mL of oleylamine were added to a 100 mL three-necked flask and stirred to obtain a mixture. The reaction system was heated to 130 °C at a rate of 10 °C / min, with evacuation maintained for 30 min. N2 protective gas was introduced into the system, and the temperature was increased to 220 °C at a rate of 10 °C / min for particle nucleation, which lasted for 30 min. N2 was then introduced, and the temperature was increased to 310 °C at a rate of 10 °C / min for particle growth, which lasted for 120 min. The resulting solution was poured into 50 mL centrifuge tubes and centrifuged at 6000 rpm for 6 min to obtain spherical and octahedral mixed superparamagnetic iron oxide nanoparticles.
[0052] The TEM characterization image of the iron oxide nanoparticles prepared in this embodiment is as follows: Figure 5 As shown, the size of the obtained spherical iron oxide nanoparticles is 10-15 nm.
[0053] Example 4
[0054] Synthesis of Octahedral Superparamagnetic Nanomaterials
[0055] 10-50 mg of iron oxide nanoparticles synthesized in Examples 1, 2, and 3 were dispersed with 0.5-2 g of polymaleic anhydride-1-octadecene in 20 mL of chloroform. The organic solvent was removed by vacuum evaporation. 10 mL of an aqueous solution of 1 g of dimethylpyridine was added, and the solution was sonicated until clear. Monodisperse octahedral iron oxide nanoparticles in the aqueous phase were obtained. The morphology of the aqueous octahedral iron oxide nanoparticles was characterized by transmission electron microscopy, and the results are as follows. Figure 6 As shown, the magnetic particles are uniformly dispersed in the aqueous phase, with a core size of approximately 14-17 nm.
[0056] Example 5
[0057] Preparation of biomembrane-coated octahedral superparamagnetic iron oxide nanoparticles
[0058] The extracted biomembranes (tumor cell membranes, erythrocyte membranes) were resuspended and dispersed in PBS. 1-2 mg of the aqueous superparamagnetic iron oxide nanoparticles synthesized in Example 4 were mixed with the extracted biomembranes at a volume ratio of 3:1. The mixture was then sonicated at 60W for 30 min using a cell disruptor. The mixture was then circulated through an extruder 8-10 times to obtain superparamagnetic iron oxide nanomaterials with in vivo long-term cycling capability. Transmission electron microscopy showed that the cell membranes were successfully coated onto the nanoparticle surface. The results are as follows: Figure 7 As shown.
[0059] Application examples
[0060] Application Example 1
[0061] Superparamagnetic iron oxide nanoparticles for magnetic particle imaging
[0062] The concentration of the iron(III) oxide nanoparticles converted to water in Example 4 was diluted to 1 mg / mL according to the iron content, and 1 mg / mL of the commercial magnetic particle imaging tracer Vivo Trax was prepared. 100 μL of each was placed in centrifuge tubes. Scanning was then performed using a magnetic particle imaging system, and the results are as follows: Figure 7 As shown. Figure 8 The results show the magnetic particle imaging intensity of different magnetic particles mentioned in this invention. The magnetic particle imaging signal intensity of the octahedral magnetic particles is 5.2 times that of the commercial contrast agent Vivo Trax, indicating that this superparamagnetic nanomaterial can serve as an excellent magnetic particle imaging contrast agent. These highly sensitive superparamagnetic iron oxide nanoparticles show promising application prospects as magnetic particle imaging tracers in fields such as in vivo tumor imaging, cell tracking, hemorrhage detection, and vascular imaging.
[0063] Application Example 2
[0064] Superparamagnetic iron oxide nanoparticles coated with tumor cell membranes are used for tumor detection.
[0065] A subcutaneous mouse model of breast cancer was constructed. The water-converting magnetic particles from Example 4 and the octahedral magnetic particles coated with tumor cell membranes from Example 5 were injected into mice via the tail vein. Scans were then performed using a magnetic particle imaging system (MagneticInsight, Inc., USA) at 0h, 12h, 24h, 36h, and 48h. The results are shown in the figure. After 12h, the magnetic nanomaterials synthesized in Example 5 exhibited better tumor imaging capabilities. Quantitative analysis showed that the signal at the tumor site of the magnetic nanomaterials synthesized in Example 5 was nearly 5 times stronger than that in Example 4. Figure 10 As shown, the superparamagnetic iron oxide nanomaterials coated with tumor cell membranes have excellent tumor diagnostic capabilities in vivo.
[0066] Application Example 3
[0067] Red blood cell membrane-coated superparamagnetic iron oxide nanoparticles for blood imaging
[0068] In Example 4, octahedral magnetic particles coated with erythrocyte membranes were injected into mice via the tail vein. The concentration of magnetic particles in the blood was measured at 0h, 2h, 4h, 8h, and 16h. For example... Figure 11 As shown, the blood half-life of the magnetic particles synthesized in Example 5 was increased by 8 times compared with that of the magnetic particles in Example 4, indicating that the superparamagnetic iron oxide nanomaterials coated with red blood cell membranes have excellent long-term in vivo circulation capability.
[0069] The above description is merely an exemplary embodiment of this disclosure, but the scope of protection of this disclosure is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in this disclosure should be included within the scope of protection of this disclosure. Therefore, the scope of protection of this disclosure should be determined by the scope of the claims.
Claims
1. A method for preparing nanoparticles, characterized in that, The nanoparticles are octahedral superparamagnetic iron oxide nanoparticles, synthesized via a high-temperature thermal decomposition method by adding surfactants and controlling the reaction rate. The surfactants include oleic acid and oleylamine. The octahedral superparamagnetic iron oxide nanoparticles are coated with an amphiphilic polymer, including polymaleic anhydride. 1 Octadecenoic acid and polystyrene-maleic anhydride copolymer, the amphiphilic polymer being used in biological membranes for the outer coating of macrophage membranes, erythrocyte membranes, neutrophil membranes, and tumor cell membranes; The preparation method of the octahedral superparamagnetic iron oxide nanoparticles includes the following steps: (1) Octahedral superparamagnetic iron oxide nanoparticles were obtained by reducing iron acetylacetone with surfactants through high-temperature thermal decomposition. The amount of iron acetylacetone used is 1-7 mmol, the reaction temperature is 310-340℃, and the reaction time is 90-150 min. (2) The octahedral superparamagnetic iron oxide nanoparticles and the amphiphilic polymer are dispersed in a surfactant, the surfactant is removed by vacuum evaporation to form a film, and an aqueous solution of dimethylpyridine is added and sonicated to obtain monodisperse octahedral superparamagnetic iron oxide nanoparticles in an aqueous system. The mass ratio of the octahedral superparamagnetic iron oxide nanoparticles to the amphiphilic polymer is 1:(10-50), the mass ratio of the added dimethylpyridine to the amphiphilic polymer is 1:(1-2), and the volume ratio of the surfactant oleic acid to oleylamine is 12.5:(6-25)mL. (3) After mixing the monodisperse octahedral superparamagnetic iron oxide nanoparticles in an aqueous system with the extracted biological cell membrane at a volume ratio of 3:(1-2), the mixture was sonicated in a cell disruptor and then circulated through an extruder to finally obtain octahedral superparamagnetic iron oxide nanoparticles with in vivo long-term circulation capability.
2. The method for preparing nanoparticles according to claim 1, characterized in that, In step (2), the ultrasound time is 10-20 min.
3. The method for preparing nanoparticles according to claim 1, characterized in that, In step (3), the power of the cell disruptor is 40-80W, the disruption time is 20-50min, and the mixture is circulated and extruded 8-10 times through the extruder.
4. The method for preparing nanoparticles according to claim 1, characterized in that, Includes the following steps: S1: At room temperature, add 1-7 mmol of acetylacetone iron, oleic acid, and oleylamine to a 100 mL three-necked flask and stir to obtain a mixture. S2: Heat the reaction system to 60-100℃ at a rate of 5-15℃ / min, while maintaining evacuation for 30-60min. Introduce N2 protective gas into the system and heat to 200-240℃ at a rate of 5-15℃ / min to carry out the nucleation process of the particles. The nucleation process takes 20-40min. S3: Keep N2 flowing in and heat to 300-350℃ at a rate of 5-15℃ / min to carry out the particle growth process. The growth process takes 60-180min. Pour the solution after reaction into a 50ml centrifuge tube and centrifuge at 6000rpm for 6min to obtain octahedral superparamagnetic iron oxide nanoparticles. S4: The octahedral superparamagnetic iron oxide nanoparticles obtained by washing with n-hexane and anhydrous ethanol are then dispersed in 10 mL of chloroform solution to obtain octahedral superparamagnetic iron oxide nanoparticles dispersed in chloroform.
5. The application of the nanoparticles prepared according to any one of claims 1-4, characterized in that, The octahedral superparamagnetic iron oxide nanoparticles are used as magnetic particle imaging contrast agents, or as magnetic particle imaging tracers in in vivo tumor imaging, cell tracking, hemorrhage detection, and vascular imaging.
6. The application of the nanoparticles according to claim 5, characterized in that, The application method also includes the use of octahedral superparamagnetic iron oxide nanoparticles coated with tumor cell membranes for tumor detection.
7. The application of the nanoparticles according to claim 5, characterized in that, The application method also includes the use of octahedral superparamagnetic iron oxide nanoparticles coated with red blood cell membranes for blood imaging.