CN114767882A - Fluorescence magnetic resonance bimodal imaging nanoprobe of target tumour position - Google Patents
Fluorescence magnetic resonance bimodal imaging nanoprobe of target tumour position Download PDFInfo
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Abstract
The invention discloses a fluorescence magnetic resonance bimodal imaging nanoprobe targeting a tumor part, which is prepared by the following method: 1) preparation of Fe3O4A nanoparticle; 2) preparation of NPAPF-Fe3O4Composite nano-particles: 3) modifying PEG on the surface of the composite nano-particles. The invention utilizes the aggregation state fluorescence enhancement characteristic of the AIE dye NPAPF, and loads Fe used for a magnetic resonance imaging probe in the process of preparing NPAPF nano particles through a simple preparation process3O4Nanoparticles, forming NPAPF-Fe3O4Composite nanoparticles; and further adopts PEG to carry out surface modification to obtain the fluorescence magnetic resonance bimodal imaging nanoprobe which can target the tumor part, and has the fluorescence and MR bimodal imaging functions of magnetic targeting functionThe method also has good biocompatibility, the synthetic process is simple to operate, and no redundant carrier increases the metabolic burden of organisms.
Description
Technical Field
The invention relates to the technical field of nano materials, in particular to a fluorescence magnetic resonance bimodal imaging nano probe for targeting a tumor part.
Background
Sensitive and accurate imaging modalities can advance accurate medical diagnosis and treatment. Multimode imaging probes have become a powerful tool to improve the sensitivity and accuracy of disease detection, and are of great significance in disease diagnosis and treatment. By combining multiple imaging modes, the defects of each imaging method can be overcome, noninvasive imaging with stronger penetrating power and higher resolution can be obtained, and more accurate diagnosis and higher sensitivity can be realized. Wherein fluorescence/magnetic resonance bimodal imaging has gained much attention in research work over the last decades.
Magnetic resonance imaging is one of the most powerful diagnostic tools in medicine at present, and the contrast agent is generally a magnetic substance with strong electron spin, such as ferroferric oxide. It can provide high resolution soft tissue anatomical images, and is a powerful tool in molecular and cellular imaging. Although magnetic resonance imaging itself provides detailed images, diagnosis based purely on the images obtained may not be accurate, since normal and diseased tissue exhibit small differences in relaxation times. MRI contrast agents help to make the image clearer and allow better analysis of the image. It is worth paying attention to that the ferroferric oxide can be used as a contrast agent, and has a magnetic targeting function, and the positioning imaging of a tumor part can be more effectively realized by utilizing the action of an external magnetic field.
Fluorescence imaging is perhaps the most widely used visualization technique in many fields of research. Since some other imaging techniques are based on ionizing radiation, which may have a negative impact on the health of the patient, but fluorescence imaging is non-ionizing radiation, the risk to the patient is low and the analysis process is usually fast, which makes it possible to observe the progression of the disease for a long time or repeatedly. Fluorescence imaging has become more widely used in guided surgery in recent years. In cancer research, fluorescence imaging is mainly used for localization of tumors and detection of their growth or regression. In addition, fluorescence imaging has begun to be widely used as a system for visually tracking drug delivery in vitro and in vivo, and enables in vitro transport and in vivo pharmacokinetics to be easily tracked. The commonly used fluorescent imaging reagents mainly comprise fluorescent protein, inorganic fluorescent quantum dots and organic fluorescent dye. The biocompatibility of the fluorescent protein is good, but the fluorescence quantum yield is not high and the light stability is poor; the inorganic quantum dots have the advantages of high fluorescence quantum yield, good monochromaticity, good light stability and the like, but have poor biological solubility and high toxicity; the organic fluorescent dye has the advantages of various types, convenience in use and the like, however, most of the organic fluorescent dyes contain aromatic groups, the hydrophobic characteristics of the groups enable the organic fluorescent dyes to tend to aggregate in an aqueous medium, so that the fluorescence intensity of the organic fluorescent dyes is greatly reduced and even disappears, namely, a serious aggregate-fluorescent quenching (ACQ) effect exists, and when the organic fluorescent dye is used for biological imaging, the ACQ effect causes the fluorescence signal to be greatly reduced and even disappear, so that the detection is inconvenient.
Unlike a general fluorescent dye always having a phenomenon of fluorescence quenching in an aggregated state, an Aggregation-Induced Emission (AIE) dye exhibits a phenomenon of fluorescence enhancement in an aggregated state. And because the inorganic metal material has a strong quenching effect on the organic fluorescent dye, the problem can be just overcome by adopting the AIE dye, the normal fluorescent imaging is ensured, the magnetic resonance imaging is combined, the defects are made up, the accuracy and the reliability of diagnosis are improved, and the support and the guidance effect are provided for the early treatment of the diseases. However, no reliable scheme for using AIE dyes for the preparation of fluorescent magnetic resonance bimodal imaging probes is known.
Disclosure of Invention
The invention aims to solve the technical problem of providing a fluorescence magnetic resonance bimodal imaging nanoprobe for targeting a tumor part aiming at the defects in the prior art. The invention designs a polyethylene glycol surface modified di- (4- (N- (2-naphthyl) benzylamino) benzeneYl) fumaric dinitrile (NPAPF) and ferroferric oxide composite nanoparticles (NPAPF-Fe)3O4) In which the AIE dye NPAPF is used for fluorescence imaging, Fe3O4The magnetic resonance imaging (MR) contrast agent can be used for scanning in any selected direction, and has full three-dimensional function, excellent soft tissue contrast and higher spatial resolution. Therefore, the NPAPF-Fe3O4 composite nanoparticle composite nanoprobe can theoretically realize fluorescence and MR bimodal imaging simultaneously, can integrate the advantages of the two imaging means and acquire more accurate and reliable diagnostic information.
In order to realize the purpose, the invention adopts the technical scheme that: a fluorescence magnetic resonance bimodal imaging nanoprobe targeting a tumor part is prepared by the following method:
1) preparation of Fe3O4A nanoparticle;
2) preparation of NPAPF-Fe3O4Composite nanoparticles:
2-1) dissolving NPAPF in acetone to prepare NPAPF solution;
2-2) taking the Fe prepared in the step 1)3O4Uniformly dispersing the nano particles in an NPAPF solution to obtain a mixed solution;
2-3) dropwise adding the mixed solution obtained in the step 2-2) into deionized water uniformly stirred by a mechanical stirrer, and continuously stirring to obtain monodisperse NPAPF-Fe3O4An aqueous suspension of composite nanoparticles;
3) in NPAPF-Fe3O4Modifying PEG on the surface of the composite nano-particles to obtain a final product: a bimodal imaging nanoprobe.
Preferably, the step 1) specifically includes:
1-1) taking 2-3 mmol of ferric triacetylacetone Fe (acac)3Sequentially adding 10-20 mmol of 1, 2-hexadecanediol, 6-10 mmol of oleylamine, 6-10 mmol of oleic acid and 20-30 mL of dibenzyl ether into a 250mL three-necked bottle;
1-2) stirring under the protection of nitrogen, gradually heating to 200 ℃, and reacting for 2-3 h at constant temperature under the condition of the temperature;
1-3) then heating to 300 ℃ for refluxing, and preserving heat for 1-2 h;
1-4) removing the heating device and the heat preservation device, and cooling the reaction system to room temperature;
1-5) after the reaction is finished, adding ethanol into the obtained product, performing ultrasonic dispersion, centrifuging for 5-10 min at the rotating speed of 6000rad/min, and discarding the upper liquid to remove the solution which is not centrifuged and ferroferric oxide with too small size;
1-6) dispersing the precipitate obtained by centrifugation in n-hexane, then adding ethanol for centrifugation, dispersing in n-hexane again, and repeating for a plurality of times; finally obtaining Fe with uniform grain diameter3O4And (3) nanoparticles.
Preferably, the step 1) specifically includes:
1-1) taking 2.5mmol of ferric triacetylacetone Fe (acac)315mmol of 1, 2-hexadecanediol, 8mmol of oleylamine, 8mmol of oleic acid and 25mL of dibenzyl ether are sequentially added into a 250mL three-necked bottle;
1-2) stirring under the protection of nitrogen, gradually heating to 200 ℃, and reacting for 2.5 hours at constant temperature under the condition of the temperature;
1-3) then heating to 300 ℃ for refluxing, and preserving heat for 1 h;
1-4) removing the heating device and the heat preservation device to cool the reaction system to room temperature;
1-5) after the reaction is finished, adding ethanol into the obtained product, performing ultrasonic dispersion, then centrifuging for 6min at the rotating speed of 6000rad/min, and discarding the upper liquid to remove the solution which is not centrifuged and ferroferric oxide with too small size;
1-6) dispersing the precipitate obtained by centrifugation in n-hexane, adding ethanol for centrifugation, dispersing in n-hexane again and again for a plurality of times; finally obtaining Fe with uniform grain diameter3O4And (3) nanoparticles.
Preferably, the step 2) specifically includes:
2-1) dissolving NPAPF in acetone to prepare NPAPF solution with the concentration of 1 mg/mL;
2-2) taking 1-2 mg of Fe prepared in the step 1)3O4The nanoparticles are uniformly dispersed in 10mL of NPAPFIn solution, making Fe3O4The final concentration is 100-200 mu g/mL, and a mixed solution is obtained;
2-3) taking 150 mu L of mixed liquid obtained in the step 2-2) by a microinjector at each time, dropwise adding the mixed liquid into 5mL of deionized water uniformly stirred by a mechanical stirrer, and continuously stirring for 5-10 min to obtain monodisperse NPAPF-Fe3O4An aqueous suspension of composite nanoparticles.
Preferably, the step 2) specifically includes:
2-1) dissolving NPAPF in acetone to prepare NPAPF solution with the concentration of 1 mg/mL;
2-2) taking 1mg of Fe obtained in step 1)3O4The nanoparticles were uniformly dispersed in 10mL of NPAPF solution to make Fe3O4The final concentration is 100 mug/mL, and mixed liquor is obtained;
2-3) taking 150 mu L of mixed solution obtained in the step 2-2) by a microinjector at each time, dropwise adding the mixed solution into 5mL of deionized water uniformly stirred by a mechanical stirrer, and continuously stirring for 5min to obtain monodisperse NPAPF-Fe3O4An aqueous suspension of composite nanoparticles.
Preferably, the step 3) specifically includes:
3-1) preparing a C18PMH-PEG aqueous solution with the concentration of 1 mg/mL;
3-2) then adding 200-300 mu LC18PMH-PEG aqueous solution into 5mL NPAPF-Fe3O4In the composite nanoparticle water suspension, ultrasonic dispersion is carried out to ensure that the modifying agent is fully modified on the surfaces of the nanoparticles;
3-3) PEG-modified NPAPF-Fe3O4The composite nanoparticle aqueous suspension was stored at 4 ℃ in the dark.
Preferably, the step 3) specifically includes:
3-1) preparing a C18PMH-PEG aqueous solution with the concentration of 1 mg/mL;
3-2) then 200. mu.L of 18PMH-PEG aqueous solution was added to 5mL of NPAPF-Fe3O4In the composite nanoparticle water suspension, ultrasonic dispersion is carried out to ensure that the modifying agent is fully modified on the surfaces of the nanoparticles;
3-3) PEG-modified NPAPF-Fe3O4The composite nanoparticle aqueous suspension was stored at 4 ℃ in the dark.
The beneficial effects of the invention are:
the invention utilizes the aggregation state fluorescence enhancement characteristic of the AIE dye NPAPF, and loads Fe used for a magnetic resonance imaging probe in the process of preparing NPAPF nano particles through a simple preparation process3O4Nanoparticles, forming NPAPF-Fe3O4Composite nanoparticles; the surface of the probe is further modified by PEG to obtain a fluorescence magnetic resonance bimodal imaging nanoprobe which can target a tumor part, and the probe has good biocompatibility, simple synthetic process operation and no redundant carrier to increase the metabolic burden of an organism while having the fluorescence and MR bimodal imaging functions of a magnetic targeting function; the fluorescence magnetic resonance bimodal imaging nanoprobe can be used for tumor position positioning and growth or regression detection in cancer research, thereby providing reference basis for clinical monitoring and treatment schemes.
Drawings
FIG. 1 shows Fe obtained in example of the present invention3O4Nanoparticles and NPAPF-Fe3O4The performance detection result of the composite nano-particles;
FIG. 2 shows NPAPF nanoparticles and NPAPF-Fe prepared in examples of the present invention3O4Particle size and fluorescence analysis results of the composite nanoparticles;
FIG. 3 is a graph of NPAPF-Fe prepared in an example of the present invention3O4The in vivo fluorescence imaging result of the mouse compounded with the nano particles;
FIG. 4 is a graph of NPAPF-Fe prepared in an example of the present invention3O4Results of in vitro imaging studies of composite nanoparticles.
Detailed Description
The present invention is further described in detail below with reference to examples so that those skilled in the art can practice the invention with reference to the description. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
It will be understood that terms such as "having," "including," and "comprising," as used herein, do not preclude the presence or addition of one or more other elements or combinations thereof.
Example 1
The embodiment provides a fluorescence magnetic resonance bimodal imaging nanoprobe targeting a tumor part, which is prepared by the following method:
1) preparation of Fe3O4Nano-particles:
1-1) taking 2.5mmol of ferric triacetylacetone Fe (acac)315mmol of 1, 2-hexadecanediol, 8mmol of oleylamine, 8mmol of oleic acid and 25mL of dibenzyl ether are sequentially added into a 250mL three-necked bottle;
1-2) stirring under the protection of nitrogen, gradually heating to 200 ℃, and reacting for 2.5 hours at constant temperature under the condition of the temperature;
1-3) then heating to 300 ℃ for reflux, and preserving heat for 1 h;
1-4) removing the heating device and the heat preservation device, and cooling the reaction system to room temperature;
1-5) after the reaction is finished, adding ethanol into the obtained product, performing ultrasonic dispersion, then centrifuging for 6min at the rotating speed of 6000rad/min, and discarding the upper liquid to remove the solution which is not centrifuged and ferroferric oxide with too small size;
1-6) dispersing the precipitate obtained by centrifugation in n-hexane, then adding ethanol for centrifugation, dispersing in n-hexane again, and repeating for a plurality of times; finally obtaining Fe with uniform grain diameter3O4And (3) nanoparticles.
2) Preparation of NPAPF-Fe3O4Composite nano-particles:
2-1) dissolving NPAPF in acetone to prepare NPAPF solution with the concentration of 1 mg/mL;
2-2) taking 1mg of Fe prepared in step 1)3O4The nanoparticles were uniformly dispersed in 10mL of NPAPF solution to make Fe3O4The final concentration is 100 mug/mL, and mixed liquor is obtained;
2-3) taking 150 mu L of the extract each time by using a micro-syringe, and obtaining the extract obtained in the step 2-2)Dropwise adding the obtained mixed solution into 5mL of deionized water uniformly stirred by a mechanical stirrer, and continuously stirring for 5min to obtain monodisperse NPAPF-Fe3O4Aqueous suspensions of composite nanoparticles.
3) In NPAPF-Fe3O4Surface modification of composite nanoparticles PEG:
3-1) preparing a C18PMH-PEG aqueous solution with the concentration of 1 mg/mL;
3-2) then 200. mu.L of 18PMH-PEG aqueous solution was added to 5mL of NPAPF-Fe3O4In the composite nanoparticle water suspension, ultrasonic dispersion is carried out to ensure that the modifying agent is fully modified on the surfaces of the nanoparticles;
3-3) PEG-modified NPAPF-Fe3O4The composite nanoparticle aqueous suspension was stored at 4 ℃ in the dark.
Referring to FIG. 1, the Fe obtained in this example3O4Nanoparticles and NPAPF-Fe3O4The results of the property measurement of the composite nanoparticles are shown in FIG. 1(a) as Fe3O4TEM images of the nanoparticles; FIG. 1(b) is NPAPF-Fe3O4Photographs of aqueous dispersions of composite nanoparticles without (left) and with (right) magnets show the NPAPF-Fe3O4The composite nano-particles have a magnetic targeting function; FIG. 1(c) is NPAPF-Fe3O4SEM image (TEM image at upper left corner) of composite nanoparticle, and NPAPF-Fe in FIG. 1(d)3O4Elemental analysis spectra of the composite nanoparticles.
With reference to FIG. 2, NPAPF nanoparticles and NPAPF-Fe prepared in this example3O4The particle size and fluorescence analysis results of the composite nanoparticles are shown in FIG. 2(a) as NPAPF-Fe3O4Particle size distribution of composite nanoparticles, NPAPF-Fe in FIG. 2(b)3O4The change curve of the particle size of the composite nano-particles within 72 hours shows that the particle size is stable; FIG. 2(c) shows the result doped with Fe3O4The UV-Vis absorption spectrum after the nano particles has no mixed peak, which indicates that NPAPF-Fe3O4The composite preparation of the composite nano-particles is more successful. FIG. 2(d) is NPAPF nanoparticles and NPAPF-Fe3O4The fluorescence emission spectrum of the composite nanoparticle is excited at 488nm, and the emission peaks are about 675nm, which is a wavelength favorable for non-dumping imaging because light with longer wavelength has deeper tissue penetrability and weaker background fluorescence. In addition, the Stokes shift of the material reaches about 180nm, which is beneficial to reducing the optical interference of an excitation light source, and shows that NPAPF-Fe3O4The composite nano-particles have better fluorescence luminescence property.
Referring to FIG. 3, NPAPF-Fe prepared in this example3O4According to the in vivo fluorescence imaging result of the mice with the composite nanoparticles, NPAPF-Fe3O4 composite nanoparticles are injected into the mice with 4T1 tumors through tail veins, a blank mouse with PBS injected into the tail veins is used as a control group in fig. 3a, the blank mouse with PBS injected into the tail veins is used as a control group in fig. 3b, 3c and 3d, the mice are anesthetized after 6h, 12h and 24h respectively, then an animal multispectral imaging system is used for imaging, and then the mice are sacrificed and dissected to perform tissue organ imaging. The imaging result shows that the tumor part of the control group of mice has almost no fluorescence, and the fluorescence intensity of the tumor part of the experimental group of mice gradually increases along with the increase of the circulation action time, which is attributed to the passive targeting action of the nano-probe at the tumor part.
FIG. 4 shows NPAPF-Fe prepared in this example3O4In vitro imaging studies of composite nanoparticles, it can be seen from the figure that the brightness shows a significant darkening trend with increasing Fe concentration, indicating NPAPF-Fe3O4The composite nano-particles have obvious negative contrast effect. Although NPAPF-Fe3O4The r2 value of the composite nano-particle is smaller than that of the traditional commercial T2 contrast agent, but we believe that the targeted magnetic resonance imaging in vivo of small animals can be finally realized through later surface modification and structural performance optimization, and the composite nano-particle has great potential research and application values.
While embodiments of the invention have been disclosed above, it is not limited to the applications listed in the description and the embodiments, which are fully applicable in all kinds of fields of application of the invention, and further modifications may readily be effected by those skilled in the art, so that the invention is not limited to the specific details without departing from the general concept defined by the claims and the scope of equivalents.
Claims (7)
1. A fluorescence magnetic resonance bimodal imaging nanoprobe targeting a tumor part is characterized in that the fluorescence magnetic resonance bimodal imaging nanoprobe is prepared by the following method:
1) preparation of Fe3O4A nanoparticle;
2) preparation of NPAPF-Fe3O4Composite nanoparticles:
2-1) dissolving NPAPF in acetone to prepare NPAPF solution;
2-2) taking the Fe prepared in the step 1)3O4Uniformly dispersing the nano particles in an NPAPF solution to obtain a mixed solution;
2-3) dropwise adding the mixed solution obtained in the step 2-2) into deionized water uniformly stirred by a mechanical stirrer, and continuously stirring to obtain monodisperse NPAPF-Fe3O4An aqueous composite nanoparticle suspension;
3) in NPAPF-Fe3O4Modifying PEG on the surface of the composite nano-particles to obtain a final product: a bimodal imaging nanoprobe.
2. The tumor site targeted fluorescence magnetic resonance bimodal imaging nanoprobe according to claim 1, wherein the step 1) specifically comprises:
1-1) taking 2-3 mmol of ferric triacetylacetone Fe (acac)3Sequentially adding 10-20 mmol of 1, 2-hexadecanediol, 6-10 mmol of oleylamine, 6-10 mmol of oleic acid and 20-30 mL of dibenzyl ether into a 250mL three-necked bottle;
1-2) stirring under the protection of nitrogen, gradually heating to 200 ℃, and reacting for 2-3 h at constant temperature under the condition of the temperature;
1-3) then heating to 300 ℃ for refluxing, and preserving heat for 1-2 h;
1-4) removing the heating device and the heat preservation device, and cooling the reaction system to room temperature;
1-5) after the reaction is finished, adding ethanol into the obtained product, performing ultrasonic dispersion, then centrifuging for 5-10 min at the rotating speed of 6000rad/min, and discarding the upper-layer liquid to remove the solution which is not centrifuged and ferroferric oxide with too small size;
1-6) dispersing the precipitate obtained by centrifugation in n-hexane, adding ethanol for centrifugation, dispersing in n-hexane again and again for a plurality of times; finally obtaining Fe with uniform grain diameter3O4And (3) nanoparticles.
3. The tumor site targeted fluorescence magnetic resonance bimodal imaging nanoprobe according to claim 2, wherein the step 1) specifically comprises:
1-1) taking 2.5mmol of ferric triacetylacetone Fe (acac)315mmol of 1, 2-hexadecanediol, 8mmol of oleylamine, 8mmol of oleic acid and 25mL of benzyl ether are sequentially added into a 250mL three-necked bottle;
1-2) stirring under the protection of nitrogen, gradually heating to 200 ℃, and reacting for 2.5 hours at constant temperature under the condition of the temperature;
1-3) then heating to 300 ℃ for refluxing, and preserving heat for 1;
1-4) removing the heating device and the heat preservation device, and cooling the reaction system to room temperature;
1-5) after the reaction is finished, adding ethanol into the obtained product, performing ultrasonic dispersion, then centrifuging for 6min at the rotating speed of 6000rad/min, and discarding the upper-layer liquid to remove the solution which is not centrifuged and ferroferric oxide with too small size;
1-6) dispersing the precipitate obtained by centrifugation in n-hexane, adding ethanol for centrifugation, dispersing in n-hexane again and again for a plurality of times; finally obtaining Fe with uniform grain diameter3O4And (3) nanoparticles.
4. The tumor site targeted fluorescence magnetic resonance bimodal imaging nanoprobe of claim 3, wherein the step 2) specifically comprises:
2-1) dissolving NPAPF in acetone to prepare NPAPF solution with the concentration of 1 mg/mL;
2-2) taking 1-2 mg of Fe prepared in the step 1)3O4The nanoparticles were uniformly dispersed in 10mL of NPAPF solution to make Fe3O4The final concentration is 100-200 mug/mL, and a mixed solution is obtained;
2-3) dropwise adding 150 mu L of the mixed solution obtained in the step 2-2) into 5mL of deionized water uniformly stirred by a mechanical stirrer by using a micro-injector each time, and continuously stirring for 5-10 min to obtain monodisperse NPAPF-Fe3O4An aqueous suspension of composite nanoparticles.
5. The tumor site targeted fluorescence magnetic resonance bimodal imaging nanoprobe according to claim 4, wherein the step 2) specifically comprises:
2-1) dissolving NPAPF in acetone to prepare NPAPF solution with the concentration of 1 mg/mL;
2-2) taking 1mg of Fe prepared in step 1)3O4The nanoparticles were uniformly dispersed in 10mL of NPAPF solution to make Fe3O4The final concentration is 100 mug/mL, and mixed liquor is obtained;
2-3) taking 150 mu L of mixed liquid obtained in the step 2-2) by a micro-injector each time, dropwise adding the mixed liquid into 5mL of deionized water uniformly stirred by a mechanical stirrer, and continuously stirring for 5min to obtain monodisperse NPAPF-Fe3O4An aqueous suspension of composite nanoparticles.
6. The tumor site targeted fluorescence magnetic resonance bimodal imaging nanoprobe according to claim 5, wherein the step 3) specifically comprises:
3-1) preparing a C18PMH-PEG aqueous solution with the concentration of 1 mg/mL;
3-2) then adding 200-300 mu LC18PMH-PEG aqueous solution into 5mL of NPAPF-Fe3O4In the composite nanoparticle water suspension, ultrasonic dispersion is carried out to ensure that the modifying agent is fully modified on the surfaces of the nanoparticles;
3-3) PEG-modified NPAPF-Fe3O4The composite nanoparticle aqueous suspension was stored at 4 ℃ in the dark.
7. The tumor site targeted fluorescence magnetic resonance bimodal imaging nanoprobe according to claim 6, wherein the step 3) specifically comprises:
3-1) preparing a C18PMH-PEG aqueous solution with the concentration of 1 mg/mL;
3-2) then 200. mu.L of 18PMH-PEG aqueous solution was added to 5mL of NPAPF-Fe3O4In the composite nanoparticle water suspension, ultrasonic dispersion is carried out to ensure that the modifying agent is fully modified on the surfaces of the nanoparticles;
3-3) PEG-modified NPAPF-Fe3O4The composite nanoparticle aqueous suspension was stored at 4 ℃ in the dark.
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