CN114344489B - Multimode FePt@Fe 3 O 4 Nanometer contrast agent and preparation method and application thereof - Google Patents
Multimode FePt@Fe 3 O 4 Nanometer contrast agent and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a multi-mode FePt@Fe 3 O 4 A nano contrast agent and a preparation method and application thereof. The invention relates to a multi-mode FePt@Fe 3 O 4 The nanometer contrast agent is FePt@Fe with polyethylene glycol modified on the surface 3 O 4 An inorganic nanoparticle; the FePt@Fe 3 O 4 The inorganic nano particles take FePt alloy as a core and Fe 3 O 4 The whole size of the shell is 5-20 nm but not 20nm, and the size of the core area is 1-10 nm. The FePt@Fe provided by the invention 3 O 4 The nano contrast agent can provide positive T1-T2 contrast in an MRI strong magnetic field, and provides an obvious residual magnetic signal in ultra-low field magnetic imaging, so that brand-new T1-T2-ULF multi-mode imaging is realized, and the nano contrast agent can be used in the fields of medical imaging, targeted therapy, visual tracking and the like and has remarkable practical significance and practical value.
Description
Technical Field
The invention relates to a method for preparing FePt@Fe 3 O 4 A method for preparing multi-mode nano contrast agent based on magnetic resonance imaging/ultra-low field magnetic imaging and application thereof 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 due to the limitation of low intrinsic sensitivity it is often necessary to operate with strong magnetic fields above 1T. Due to the interaction of the nano contrast agent and surrounding water protons, the longitudinal (T1) or transverse (T2) relaxation time of nearby water molecules is shortened, the MRI sensitivity can be further improved, and an image with rich information can be obtained. Wherein, T1 weighted imaging can make the relevant focus position present bright change, can better distinguish the tissue, is welcomed by clinician.
The Ultra Low Field (ULF) magnetic imaging can adopt an optical atomic magnetometer as a magnetic field detector with high sensitivity, and can realize imaging of molecules, cells and living animals by means of residual magnetic signals of nano magnetic particles under an ultra low field environment of less than 1mT without using an external strong magnetic field. The combination of multiple imaging modes can yield complementary diagnostic information and provide synergistic advantages over a single mode. Therefore, the development of the T1-T2-ULF multi-mode nano contrast agent with MRI and ultra-low field magnetic imaging has great significance in 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 multi-mode FePt@Fe 3 O 4 Nanometer contrast agent, preparation method and application thereof, wherein the nanometer contrast agent is FePt@Fe 3 O 4 The T1-T2-ULF multi-mode nano contrast agent based on magnetic resonance imaging/ultra-low field magnetic imaging has the advantages that the synthesis method is simple and reproducible, and the biocompatibility is high after surface modification; through optimizing and controlling the concentration and proportion of reactants, the synthesized contrast agent can provide positive T1-T2 contrast under a strong magnetic field, and provide obvious remanence signals under an ultralow field environment, so that T1-T2-ULF multi-mode imaging is realized, and the contrast agent has great potential in biomedical and clinical application.
In a first aspect, the present invention provides a multi-modal FePt@Fe 3 O 4 Nanometer contrast agent which is FePt@Fe with polyethylene glycol modified on surface 3 O 4 An inorganic nanoparticle; the FePt@Fe 3 O 4 The inorganic nano particles take FePt alloy as a core and Fe 3 O 4 The whole size of the shell is 5-20 nm but not 20nm, and the size of the core area is 1-10 nm.
The above-mentioned multi-modal FePt@Fe 3 O 4 In the nano contrast agent, the FePt@Fe 3 O 4 The overall size of the inorganic nano particles can be specifically 8.5-16.5 nm, 8.5nm, 12.5nm or 16.5nm; the size of the core region may be specifically 3.3 to 4.5nm, 3.3nm or 4.5nm.
In a second aspect, the present invention protects the multimode FePt@Fe 3 O 4 The 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 returning the system in an inert atmosphereFlow, obtaining the FePt@Fe 3 O 4 An inorganic nanoparticle;
(2) At the FePt@Fe 3 O 4 Surface modification of inorganic nano particles with polyethylene glycol to obtain PEG/FePt@Fe 3 O 4 Core-shell nanocrystals.
In the preparation method, the molar ratio of the platinum source to the iron source to the stabilizer to the reducing agent to the solvent can be 1 (4-20): 20-100): 2-10): 100-1000, and can be specifically 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 may be 1, 2-hexadecanediol or 1, 10-decanediol;
the solvent may be octadecene, hexadecene, dibenzyl ether or squalane.
In the preparation method, the temperature of stirring and vacuumizing can be 30-80 ℃, and specifically can be 80 ℃; the time can be 15 to 60 minutes, and can be specifically 30 to 60 minutes, 30 minutes or 60 minutes;
the temperature of the reflux can be 250-350 ℃, and specifically can be 300 ℃; the time may be 0.5 to 4 hours, and specifically may be 0.5 hours or 0.75 hours.
The inert atmosphere may be nitrogen or argon.
In the preparation method, after the reflux is finished, the post-treatment can be performed by adopting the following method: adding a poor solvent (such as ethanol) into the reacted system, centrifugally collecting the precipitate, adding the precipitate into a benign solvent (such as cyclohexane), centrifugally collecting the supernatant. The product is finally in the form of a dispersion in a benign solvent (e.g., cyclohexane).
In the preparation method, the FePt@Fe 3 O 4 The feeding mass ratio of the inorganic nano particles to the polyethylene glycolCan be (1-5): 9, specifically, (1.5 to 4.0): 1. (1.6-3.6): 9. 2: 9. 2.4: 9. 3.6:9 or 1.6:9, a step of performing the process;
the polyethylene glycol may be a polyethylene glycol modified with biphosphoric acid, 2, 3-dimercaptosuccinic acid dicarboxyl or dopamine, exemplified by biphosphoric acid modified polyethylene glycol which is specific to the FePt@Fe 3 O 4 Modification of the inorganic nanoparticles is achieved by coordination of p=o on the phosphate group with Fe; polyethylene glycol modified by different groups for modifying FePt@Fe 3 O 4 The reaction temperature, time and solvent of the inorganic nanoparticles are all the same.
The molecular weight of the polyethylene glycol can be 2K-5K.
Further, the polyethylene glycol is a polyethylene glycol modified with biphosphoric acid;
the temperature of the modification may be 30 to 50 ℃, and the time may be 8 to 24 hours, specifically 12 hours.
In the preparation method, the modification can be performed in a benign solvent (such as tetrahydrofuran), and the specific steps can be as follows: dropwise adding the tetrahydrofuran solution of the polyethylene glycol to the FePt@Fe under the stirring condition 3 O 4 The inorganic nano particles are modified in tetrahydrofuran solution. The mass concentration of the tetrahydrofuran solution of the polyethylene glycol can be 10-100 mg/ml; the FePt@Fe 3 O 4 The mass concentration of the tetrahydrofuran solution of the inorganic nano particles can be 3-10 mg/ml.
In the preparation method, the post-treatment can be carried out by adopting the following method after modification: adding a poor solvent (such as cyclohexane) into the modified system, centrifugally collecting precipitate, adding a benign solvent (such as tetrahydrofuran), oscillating and dispersing, and then carrying out vacuum drying; adding water into the product after vacuum drying, centrifugally ultrafiltering in an ultrafiltration tube with the molecular weight cut-off of 10-100K (such as 100K), and collecting filtrate. The product is finally present in the form of a dispersion in water.
In a third aspect, the present invention protects the multimode FePt@Fe 3 O 4 Application of nano contrast agent in T1-T2-ULF multi-mode nano contrast agent used as magnetic resonance imaging/ultra-low field magnetic imaging。
No T1-T2-ULF multi-mode imaging contrast agent is reported in the prior art, and a technical method for regulating T1-T2 MRI dual-mode imaging by a core-shell interface is also not reported. Compared with the traditional Fe with the particle size of 10-100nm 3 O 4 And 1-10nm FePt nanocrystalline T2 contrast agent, the FePt@Fe provided by the invention 3 O 4 The nano contrast agent can provide positive T1-T2 contrast ratio in an MRI strong magnetic field and obvious residual magnetic signals in ultra-low field magnetic imaging through the 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 remarkable practical significance and practical value.
Drawings
FIG. 1 is a sample of FePt@Fe prepared in example 1 3 O 4 TEM characterization of nanocontrast agents.
FIG. 2 is FePt@Fe prepared in example 2 3 O 4 TEM characterization of nanocontrast agents.
FIG. 3 is FePt@Fe prepared in example 3 3 O 4 TEM characterization of nanocontrast agents.
FIG. 4 is FePt@Fe prepared in example 4 3 O 4 TEM characterization of nanocontrast agents.
FIG. 5 is a graph of FePt@Fe prepared in comparative example 3 O 4 TEM characterization of nanocontrast agents.
FIG. 6 is FePt@Fe prepared in examples 1-4 3 O 4 X-ray diffraction pattern of nano-contrast agent.
FIG. 7 is a sample of FePt@Fe prepared in example 1 3 O 4 Electron diffraction pattern of nano-contrast agent.
FIG. 8 is FePt@Fe prepared in examples 1-4 3 O 4 Hydrodynamic radius of the nano-contrast agent.
FIG. 9 is FePt@Fe prepared in examples 1-4 3 O 4 Hysteresis loop of nano contrast agent at 300K.
FIG. 10 is FePt@Fe prepared in examples 1-4 3 O 4 MRI T1 weighted imaging of nano-contrast agents.
FIG. 11 is FePt@Fe prepared in examples 1-4 3 O 4 MRI T2 weighted imaging of nano-contrast agents.
FIG. 12 is a graph of FePt@Fe prepared in comparative example 3 O 4 MRI T1T 2 weighted imaging of nano-contrast agents.
FIG. 13 is FePt@Fe prepared in example 1 3 O 4 Cytotoxicity of nano-contrast agents.
FIG. 14 is FePt@Fe prepared in example 1 3 O 4 Mouse tumors T1 and T2 were imaged with nano-contrast agent.
FIG. 15 is FePt@Fe prepared in example 1 3 O 4 Ultra low field scan profile of a nano-contrast agent.
FIG. 16 is FePt@Fe prepared in example 1 3 O 4 The nanometer contrast agent marks the ultralow field living body magnetic imaging of the tumor cells.
Detailed Description
The following detailed description of the invention is provided in connection with the accompanying drawings that are presented to illustrate the invention and not to limit the scope thereof. The examples provided below are intended as guidelines for further modifications by one of ordinary skill in the art and are not to be construed as limiting the invention in any way.
The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are carried out according to techniques or conditions described in the literature in the field or according to the product specifications. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The PEG in the following examples was biphosphoric acid modified PEG (DP-PEG 2000-Mal, molecular weight 2K-5K), MAL-PEG2000-NH 2 Obtained by synthesis of MAL-PEG2000-NH 2 Purchased from siraixi under the product number R-1404-X. DP-PEG 2000-Mal synthesis method: will be 2.0g H 3 PO 3 ，20ml H 2 After O,1.0ml of concentrated hydrochloric acid is fully dissolved, mal-PEG-NH is added 2 (4.0 g) the oil bath was warmed to 90 ℃. 3.0ml of formaldehyde (37% solution) is slowly added dropwise by using a constant pressure funnel, the temperature is raised to 110 ℃, the reaction is closed after the constant temperature reaction is carried out for 90min, and the temperature is reduced to room temperature. The reaction solution was transferred to 150ml of a single portIn the flask, the solvent was removed by rotary evaporation at 70 ℃. After adding 50-70 ml of ethanol to form a viscous state, adding 15ml of ethanol for dissolution, and filtering the mixture into a conical flask by a sand core funnel. Precipitating with 500ml of glacial ethyl ether, standing at-20 ℃ for 30min, filtering to obtain precipitate, and adding 15-20 ml of ethanol for dissolution. Repeating the precipitation for 2 times, transferring the last precipitation into a small beaker, vacuum drying at normal temperature for 24 hours, and sealing and preserving at-20 ℃.
Example 1 Synthesis of FePt@Fe 3 O 4 Multi-modal nano contrast agent (c4.5s12.5)
Into a 50ml three-necked flask, 0.5mmol of platinum acetylacetonate, 3mmol of iron acetylacetonate, 5mmol of oleic acid, 5mmol of oleylamine, 1.8mmol of 1, 2-hexadecanediol and 10ml (35 mmol) of hexadecene were charged, and stirring and vacuum-pumping were carried out at 80℃for 60 minutes, followed by high-temperature reflux at 300℃under nitrogen for 30 minutes. Cooling to room temperature after the reaction is finished, adding ethanol 6000r/min for centrifugal separation for 10 minutes, adding cyclohexane for centrifugal separation, taking supernatant, repeating the centrifugal separation operation for 2 times, dispersing the product into cyclohexane, and placing the cyclohexane in a refrigerator at 4 ℃ for standby. To the above-mentioned 2ml oil phase sample (mass concentration about 18 mg/ml), 40ml of acetone 6000r/min was added, and the precipitate (about 36 mg) was obtained by centrifugation for 10 minutes, followed by adding 4ml of tetrahydrofuran and stirring at 40℃under low temperature, and slowly dropping 3ml of a 30mg/ml PEG tetrahydrofuran solution. After the reaction for 12 hours, 45ml cyclohexane 5000r/min is added for centrifugal separation for 5 minutes, sediment is taken, 4ml tetrahydrofuran is added for shaking dispersion, and centrifugal shaking is repeated for 3 times. Vacuum drying, adding water, transferring to a ultrafiltration tube with molecular weight cut-off of 100k, centrifuging at 5000r/min, ultrafiltering for 10min, transferring the liquid in the filter element to sample bottle, and storing in 4deg.C refrigerator to obtain FePt@Fe 3 O 4 A multi-modal nano-contrast agent.
The obtained FePt@Fe 3 O 4 The TEM image of the multi-modal nano-contrast agent is shown in FIG. 1, and has a remarkable core-shell structure, wherein the shell side length and the core diameter are respectively 12.5nm and 4.5nm, so that the mark is c4.5s12.5. The X-ray diffraction diagram is shown in figure 6, and FePt standard card (04-0326, blue) and Fe appear 3 O 4 Mixed diffraction peaks of standard cards (19-0629, black). The electron diffraction pattern of c4.5s12.5 is shown in FIG. 7, and the circles correspond to the (110) crystal face of FePt and Fe, respectively 3 O 4 (220),(311) And (440) crystal plane. The hydrodynamic radius of c4.5s12.5 is shown in FIG. 8, showing good aqueous stability. The hysteresis loop of c4.5s12.5 is shown in FIG. 9, MRI T1 and T2 weighted imaging is shown in FIGS. 10 and 11, and the longitudinal relaxation rate r1 and the transverse relaxation rate r2 are shown in Table 1. Compared with the contrast medium prepared in other examples below, the contrast medium prepared in other examples below has optimal saturation magnetization and T1-T2 contrast, and is subjected to cytotoxicity assessment as shown in FIG. 13, and cell activity after 24h of co-culture with 4T1 mouse breast cancer cells is tested. BALB/c females (weight 20-25 g) 5 weeks old were selected for subcutaneous tumor imaging in mice, each injected 5X 10 into the right rear buttocks 6 4T 1 Cells, after about one week of culture, reached a tumor diameter of 4-5mm, at which time mice were injected with contrast c4.5s12.5 tail vein (4 mg/kg injection) and subsequently subjected to MRI imaging using a 1.5T small animal magnetic imager. The resulting MRI T1 and T2 images are shown in fig. 14, with T1 and T2 images of the tumor region showing the most pronounced signal changes at 1h post injection. The ultralow field scan curve of c4.5s12.5 is shown in FIG. 15, and shows a significant pT magnitude ultralow field remanence signal. C4.5s12.5 labeled 4T1 cells were subcutaneously injected into mice and ultra-low field imaging was performed using an ultra-low field atomic magnetometer. And carrying out inversion simulation on the data of the scanning magnetic field curve to obtain the spatial positioning of the tumor cell population in the living mice. The ultra-low field in-vivo magnetic imaging is shown in fig. 16, and the accurate positioning is shown at 231mm, which shows that the ultra-low field cell tracking application research can be carried out.
Example 2 Synthesis of FePt@Fe 3 O 4 Multi-modal nano contrast agent (c3.3s8.5)
Into a 50ml three-necked flask, 0.5mmol of platinum acetylacetonate, 2mmol of iron acetylacetonate, 5mmol of oleic acid, 5mmol of oleylamine, 1.5mmol of 1, 2-hexadecanediol and 20ml (62.5 mmol) of octadecene were charged, and vacuum-pumping was carried out under stirring at 80℃for 30 minutes, followed by high-temperature reflux at 300℃under nitrogen for 30 minutes. Cooling to room temperature after the reaction is finished, adding ethanol 6000r/min for centrifugal separation for 10 minutes, adding cyclohexane for centrifugal separation, taking supernatant, repeating the centrifugal separation operation for 2 times, dispersing the product into cyclohexane, and placing the cyclohexane in a refrigerator at 4 ℃ for standby. Adding 40ml acetone 6000r/min into the 2ml oil phase sample (mass concentration about 12 mg/ml), centrifuging for 10minThe precipitate was further added with 4ml of tetrahydrofuran and stirred at 40℃and 3ml of a 30mg/ml PEG tetrahydrofuran solution was slowly added dropwise. After the reaction for 12 hours, 45ml cyclohexane 5000r/min is added for centrifugal separation for 5 minutes, sediment is taken, 4ml tetrahydrofuran is added for shaking dispersion, and centrifugal shaking is repeated for 3 times. Vacuum drying, adding water, transferring to a ultrafiltration tube with molecular weight cut-off of 100k, centrifuging at 5000r/min, ultrafiltering for 10min, transferring the liquid in the filter element to sample bottle, and storing in 4deg.C refrigerator to obtain FePt@Fe 3 O 4 A multi-modal nano-contrast agent.
The obtained FePt@Fe 3 O 4 The TEM image of the multi-modal nanocontrast agent is shown in fig. 2, with a distinct core-shell structure, with shell side lengths and core diameters of 8.5nm and 3.3nm, respectively, and therefore labeled herein as c3.3s8.5. The X-ray diffraction diagram is shown in figure 6, and FePt standard card (04-0326, blue) and Fe appear 3 O 4 Mixed diffraction peaks of standard cards (19-0629, black). The hydrodynamic radius of c3.3s8.5 is shown in FIG. 8, showing good aqueous stability. The hysteresis loop of c3.3s8.5 is shown in FIG. 9, MRI T1 and T2 weighted imaging is shown in FIGS. 10 and 11, and the longitudinal relaxation rate r1 and the transverse relaxation rate r2 are shown in Table 1. Compared with the contrast agents of examples 3 and 4 below, c3.3s8.5 has a larger r1 value due to its smaller overall size, and the T1 weighted imaging effect is better.
Example 3 Synthesis of FePt@Fe 3 O 4 Multi-modal nano contrast agent (c3.3s12.5)
Into a 50ml three-necked flask, 0.3mmol of platinum acetylacetonate, 2mmol of iron acetylacetonate, 5mmol of oleic acid, 5mmol of oleylamine, 0.9mmol of 1, 2-hexadecanediol and 20ml (62.5 mmol) of octadecene were charged, and vacuum-pumping was carried out under stirring at 80℃for 30 minutes, followed by high-temperature reflux at 300℃under nitrogen for 45 minutes. Cooling to room temperature after the reaction is finished, adding ethanol 6000r/min for centrifugal separation for 10 minutes, adding cyclohexane for centrifugal separation, taking supernatant, repeating the centrifugal separation operation for 2 times, dispersing the product into cyclohexane, and placing the cyclohexane in a refrigerator at 4 ℃ for standby. To the above-mentioned 2ml oil phase sample (mass concentration about 10 mg/ml), 40ml of acetone 6000r/min was added, and the precipitate was obtained by centrifugation for 10 minutes, and then 4ml of tetrahydrofuran was added, followed by stirring at a low temperature of 40℃and slowly dropwise addition of 3ml of a 30mg/ml PEG tetrahydrofuran solution. After 12 hours of reaction, 45m was addedAnd centrifuging for 5 minutes by cyclohexane at 5000r/min to obtain a precipitate, adding 4ml of tetrahydrofuran, shaking for dispersion, and repeating the centrifugation and shaking for 3 times. Vacuum drying, adding water, transferring to a ultrafiltration tube with molecular weight cut-off of 100k, centrifuging at 5000r/min, ultrafiltering for 10min, transferring the liquid in the filter element to sample bottle, and storing in 4deg.C refrigerator to obtain FePt@Fe 3 O 4 A multi-modal nano-contrast agent.
The obtained FePt@Fe 3 O 4 The TEM image of the multi-modal nanocontrast agent is shown in fig. 3, with a distinct core-shell structure, with shell side lengths and core diameters of 12.5nm and 3.3nm, respectively, and therefore labeled herein as c3.3s12.5. The X-ray diffraction diagram is shown in figure 6, and FePt standard card (04-0326, blue) and Fe appear 3 O 4 Mixed diffraction peaks of standard cards (19-0629, black). The hydrodynamic radius of c3.3s12.5 is shown in FIG. 8, showing good aqueous stability. The hysteresis loop of c3.3s12.5 is shown in FIG. 9, MRI T1 and T2 weighted imaging is shown in FIGS. 10 and 11, and the longitudinal relaxation rate r1 and the transverse relaxation rate r2 are shown in Table 1. The contrast agents of comparative examples 2 and 4, c3.3s12.5, due to their moderate overall size, have balanced r1 and r2 values. The method can increase the size of the inner core and adjust the interface effect of the core-shell structure under the condition of controlling the whole size of the nano crystal by optimizing the concentration and the proportion of reactants, thereby obtaining better T1-T2 dual-mode imaging effect.
Example 4 Synthesis of FePt@Fe 3 O 4 Multi-modal nano contrast agent (c3.3s16.5)
Into a 50ml three-necked flask, 0.1mmol of platinum acetylacetonate, 2mmol of iron acetylacetonate, 5mmol of oleic acid, 5mmol of oleylamine, 0.3mmol of 1, 2-hexadecanediol and 20ml (62.5 mmol) of octadecene were charged, and vacuum-pumping was carried out under stirring at 80℃for 60 minutes, followed by high-temperature reflux at 300℃under nitrogen for 30 minutes. Cooling to room temperature after the reaction is finished, adding ethanol 6000r/min for centrifugal separation for 10 minutes, adding cyclohexane for centrifugal separation, taking supernatant, repeating the centrifugal separation operation for 2 times, dispersing the product into cyclohexane, and placing the cyclohexane in a refrigerator at 4 ℃ for standby. Adding 40ml acetone 6000r/min into the 2ml oil phase sample (mass concentration about 8 mg/ml), centrifuging for 10min to obtain precipitate, adding 4ml tetrahydrofuran, stirring at 40deg.C, and slowly dripping 30mg/ml PEG tetrahydrofuran3ml of the solution. After the reaction for 12 hours, 45ml cyclohexane 5000r/min is added for centrifugal separation for 5 minutes, sediment is taken, 4ml tetrahydrofuran is added for shaking dispersion, and centrifugal shaking is repeated for 3 times. Vacuum drying, adding water, transferring to a ultrafiltration tube with molecular weight cut-off of 100k, centrifuging at 5000r/min, ultrafiltering for 10min, transferring the liquid in the filter element to sample bottle, and storing in 4deg.C refrigerator to obtain FePt@Fe 3 O 4 A multi-modal nano-contrast agent.
The obtained FePt@Fe 3 O 4 The TEM image of the multi-modal nanocontrast agent is shown in fig. 4, with a distinct core-shell structure, with shell side lengths and core diameters of 16.5nm and 3.3nm, respectively, and therefore labeled herein as c3.3s16.5. The X-ray diffraction diagram is shown in figure 6, and FePt standard card (04-0326, blue) and Fe appear 3 O 4 Mixed diffraction peaks of standard cards (19-0629, black). The hydrodynamic radius of c3.3s16.5 is shown in FIG. 8, showing good aqueous stability. The hysteresis loop of c3.3s16.5 is shown in FIG. 9, MRI T1 and T2 weighted imaging is shown in FIGS. 10 and 11, and the longitudinal relaxation rate r1 and the transverse relaxation rate r2 are shown in Table 1. The contrast agents of comparative examples 2 and 3, c3.3s16.5, have larger r2 values due to their larger overall size, and the T2 weighted imaging effect is better.
TABLE 1 FePt@Fe prepared in examples 1-4 3 O 4 Longitudinal relaxation rate r of nano contrast agent 1 And transverse relaxation rate r 2
Comparative example, fePt@Fe with poor multimodal imaging effect 3 O 4 Nanometer contrast agent (c4.5s20)
Into a 50ml three-necked flask, 0.3mmol of platinum acetylacetonate, 2mmol of iron acetylacetonate, 15mmol of oleic acid, 15mmol of oleylamine, 1.8mmol of 1, 2-hexadecanediol and 10ml (35 mmol) of hexadecene were charged, and stirring and vacuum-pumping were carried out at 80℃for 30 minutes, followed by high-temperature reflux at 300℃under nitrogen for 45 minutes. Cooling to room temperature after the reaction is finished, adding ethanol 6000r/min for centrifugal separation for 10 minutes to precipitate, adding cyclohexane for centrifugal separation to obtain supernatant, repeating the centrifugal separation operation for 2 times,the product was dispersed to cyclohexane and placed in a refrigerator at 4 ℃ for use. To the above-mentioned 2ml oil phase sample (mass concentration about 18 mg/ml), 40ml of acetone 6000r/min was added, and the precipitate was obtained by centrifugation for 10 minutes, and then 4ml of tetrahydrofuran was added, followed by stirring at a low temperature of 40℃and slowly dropwise addition of 3ml of a 30mg/ml PEG tetrahydrofuran solution. After the reaction for 12 hours, 45ml cyclohexane 5000r/min is added for centrifugal separation for 5 minutes, sediment is taken, 4ml tetrahydrofuran is added for shaking dispersion, and centrifugal shaking is repeated for 3 times. Vacuum drying, adding water, transferring to a ultrafiltration tube with molecular weight cut-off of 100k, centrifuging at 5000r/min, ultrafiltering for 10min, transferring the liquid in the filter element to sample bottle, and storing in 4deg.C refrigerator to obtain FePt@Fe 3 O 4 A multi-modal nano-contrast agent.
The obtained FePt@Fe 3 O 4 The TEM image of the multi-modal nanocontrast agent is shown in fig. 5, with a distinct core-shell structure, with a shell side length and a core diameter of 20nm and 4.5nm, respectively, and therefore is labeled herein as c4.5s20. As shown in fig. 12, the contrast agent of comparative example 1, c4.5s20, has a strong T2 weighted imaging effect but the T1 weighted imaging effect is significantly poor due to its overall size.
Claims (4)
1. Multimode FePt@Fe 3 O 4 The application of the nano contrast agent in preparing the T1-T2-ULF multi-mode nano contrast agent for magnetic resonance imaging/ultra-low field magnetic imaging;
the multimode FePt@Fe 3 O 4 The nanometer contrast agent is FePt@Fe with polyethylene glycol modified on the surface 3 O 4 An inorganic nanoparticle; the FePt@Fe 3 O 4 The inorganic nano particles take FePt alloy as a core and Fe 3 O 4 Is a shell nanocrystal, the multimode FePt@Fe 3 O 4 The overall size of the nano contrast agent is 8.5-16.5 nm based on the side length of the shell, and the size of the nuclear area is 3.3-4.5 nm based on the diameter of the inner core;
the multi-mode FePt@Fe 3 O 4 The 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 returning the system in an inert atmosphereFlow, obtaining the FePt@Fe 3 O 4 An inorganic nanoparticle;
(2) At the FePt@Fe 3 O 4 The surface of the inorganic nano particle is modified with polyethylene glycol to obtain the FePt@Fe 3 O 4 A nano-contrast agent;
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 ferric oleate;
the stabilizer is one or more of oleylamine, oleic acid and capric acid;
the reducing agent is 1, 2-hexadecane diol or 1, 10-decanediol;
the solvent is octadecene, hexadecene, dibenzyl ether or squalane.
2. The use according to claim 1, characterized in that: the temperature of stirring and vacuumizing is 30-80 ℃ and the time is 15-60 minutes;
the temperature of the reflux is 250-350 ℃ and the time is 0.5-4 hours.
3. The use according to claim 1, characterized in that: the FePt@Fe 3 O 4 The mass ratio of the inorganic nano particles to the polyethylene glycol is (1.5-4.0): 1, a step of;
the polyethylene glycol is polyethylene glycol modified with biphosphoric acid, 2, 3-dimercaptosuccinic acid dicarboxyl or dopamine;
the molecular weight of the polyethylene glycol is 2K-5K.
4. A use according to claim 3, characterized in that: the polyethylene glycol is polyethylene glycol modified with biphosphoric acid;
the temperature of the modification is 30-50 ℃ and the time is 8-24 hours.
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