Iron bismuth oxide multimodal imaging probe and preparation method and application thereof

Abstract

The application belongs to the technical field of medicines, and relates to a ferric bismuth oxide multi-modal imaging probe and a preparation method and application thereof. x The ferric bismuth oxide multi-modal imaging probe has a molecular formula of BiFeO x wherein x is 2.5-3.5, the ferric bismuth oxide multi-modal imaging probe has CT imaging and MRI imaging functions, and has POD-like activity, CAT-like activity and GSH-Px-like activity. The preparation method comprises the following steps: dissolving bismuth nitrate in a mannitol solution, then adding a high-molecular polymer to form an A solution; dissolving ferric nitrate in a mannitol solution to form a B solution; dropping the B solution into the A solution, then adding ammonia water, performing high-temperature treatment after reaction, and obtaining the ferric bismuth oxide multi-modal imaging probe after cooling and washing. The ferric bismuth oxide multi-modal imaging probe has significant advantages in multi-modal imaging and tumor treatment, overcomes part of the limitations of single imaging technology and traditional treatment methods, and has important clinical application value.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine, and relates to an iron-bismuth oxide multi-modal imaging probe and a preparation method and application thereof. BACKGROUND

[0002] Computed tomography (CT) is a widely used non-invasive diagnostic tool in clinical practice. However, the small molecule iodinated contrast agents (ICAs) commonly used in clinical CT imaging have limitations such as non-specific in vivo distribution and rapid renal clearance, resulting in a narrow imaging time window. Magnetic resonance imaging (MRI) is a non-invasive medical imaging method that is routinely used in clinical practice, providing anatomical information with micron resolution, soft tissue contrast, and deep penetration. The use of contrast agents to enhance contrast by shortening the longitudinal (T1) or transverse (T2) relaxation time of water protons can significantly improve the resolution of MRI for disease diagnosis. For CT imaging, it can provide excellent spatial resolution and 3D images of tissues without depth limitation, but it cannot be used for targeted imaging and angiography, and it cannot distinguish different soft tissues with very close mass density. While MRI has the advantage of clearly displaying soft tissue structures and the disadvantage of low sensitivity for imaging tumor lesions. Therefore, single CT and MRI imaging has limitations and deficiencies in clinical application, and cannot meet the needs of precise imaging in clinical practice.

[0003] Currently, there is no drug in clinical practice that can simultaneously achieve the effect of enhancing CT and MRI imaging. Multi-modal imaging of CT and MRI is a powerful strategy that can provide complementary and reliable information about the disease site, and has important clinical significance. Inorganic nanoparticles have advantages in multi-modal imaging due to their customizable morphology (size, shape, porosity, etc.) and physical and chemical (optical, magnetic, catalytic, X-ray opacity, etc.) properties.

[0004] The tumor microenvironment (TME) has characteristics such as hypoxia, high levels of hydrogen peroxide and overexpression of glutathione (GSH), which are closely related to the development of tumors: the hypoxic state of the TME hinders many normal physiological processes and treatment-related reactions that rely on oxygen, such as some conventional oxidative reaction-based treatments, which are difficult to fully exert their effects due to the lack of sufficient oxygen as a reactant, greatly reducing the killing effect on tumor cells; the high levels of hydrogen peroxide in TEM can cause DNA damage, oxidative modification of proteins and lipids, and thus promote the survival and proliferation of tumor cells; overexpression of glutathione (GSH) provides a "protective umbrella" for tumor cells, and when it is overexpressed in the tumor microenvironment, whether it is the body's own immune defense mechanism that wants to kill tumor cells by producing some oxidizing substances or exogenous introduction of some treatment drugs based on the principle of oxidation, the process of exerting their effects will be interfered with by glutathione, and these oxidizing substances will be consumed by reacting with glutathione first and thus cannot cause substantial damage to tumor cells. These characteristics of TEM make malignant tumor cells resistant to oxidative stress, thereby exacerbating the challenge of achieving an ideal treatment effect. If appropriate strategies can be developed to cleverly target these characteristics, it may be possible to transform these seemingly "disadvantages" into powerful weapons against tumors, that is, the so-called "turning waste into treasure" strategy.

[0005] Nanocatalysts with active sites can catalyze cascade reactions through their active sites to produce reactive oxygen species (ROS) with high toxicity, which have strong oxidizing properties and are a powerful "attack force" against the antioxidant defense mechanisms in tumor cells, and are therefore widely used for targeted tumor therapy. The POD / GSH-Px / CAT-like nanocatalyst has a unique and ingenious function: in an acidic tumor environment, it can function like a peroxidase (POD). The acidic environment of cancer cells provides suitable reaction conditions for this nanocatalyst, allowing it to utilize the hydrogen peroxide and other substances present in the tumor microenvironment to catalyze the generation of products with killing properties. At the same time, the nanocatalyst can also function like glutathione peroxidase (GSH-Px) and catalase (CAT) to protect normal cells. Through this dual function of killing cancer cells and protecting normal cells, the nanocatalyst greatly enhances the overall effectiveness of tumor therapy, making it more precise and efficient, reducing side effects on normal tissues, and having a broad application prospect in the field of tumor therapy. SUMMARY

[0006] To solve the above problems in the prior art, the purpose of the present application is to provide an iron bismuth oxide multi-modal imaging probe and its preparation method and application, to overcome the shortcomings of the prior art.

[0007] The second object of the present application is achieved by the following technical solutions:

[0008] A ferric bismuth oxide multi-modal imaging probe, the molecular formula of the ferric bismuth oxide multi-modal imaging probe is BiFeO x , wherein x is 2.5-3.5, the hydrated particle size is 10-900 nm;

[0009] The ferric bismuth oxide multi-modal imaging probe has CT imaging and MRI imaging functions at the same time.

[0010] The ferric bismuth oxide multi-modal imaging probe has POD-like activity, CAT-like activity and GSH-Px-like activity at the same time.

[0011] The ferric bismuth oxide multi-modal imaging probe has POD-like activity, CAT-like activity and GSH-Px-like activity at the same time, which means that the imaging probe exhibits similar catalytic behavior to natural POD, CAT and GSH-Px. Specifically, natural OD, CAT and GSH-Px can catalyze some specific chemical reactions, and the probe with POD-like activity, CAT-like activity and GSH-Px-like activity can also play a similar catalytic role in similar reactions.

[0012] The second object of the present application is achieved by the following technical solutions:

[0013] A preparation method of a ferric bismuth oxide multi-modal imaging probe, characterized in that it comprises the following steps:

[0014] Dissolve bismuth nitrate in a mannitol solution, then add a high molecular polymer to form an A solution, wherein the high molecular polymer is polyvinylpyrrolidone (PVP) and / or polyacrylic acid (PAA);

[0015] Dissolve ferric nitrate in a mannitol solution to form a B solution;

[0016] Drop the B solution into the A solution to form a C solution, then add ammonia water, after reaction, high-temperature treat the reaction liquid at 130-200 DEG C for 10-30 h, after cooling, wash to obtain the ferric bismuth oxide multi-modal imaging probe.

[0017] Preferably, the bismuth nitrate is hydrated bismuth nitrate, including bismuth nitrate pentahydrate.

[0018] Preferably, the concentration of the mannitol solution is 0.01-1 mol / L, and further preferably 0.05-0.5 mol / L.

[0019] The bismuth nitrate is dissolved in the mannitol solution, and the mass ratio of the bismuth nitrate to the volume of the mannitol solution can be listed as 1g:20-200ml, and preferably 1g:30-100ml.

[0020] Preferably, the mass ratio of the high molecular polymer to bismuth nitrate is 1:1.5-10, further preferably 1:2-8.

[0021] Preferably, the molecular weight of the high molecular polymer is 2000-20000, further preferably 4000-15000.

[0022] After the high molecular polymer is added, stirring is performed at a speed of 100-1000 rpm for 1-30 min to form solution A.

[0023] Preferably, the iron nitrate is hydrated iron nitrate, including one or more of pentahydrate iron nitrate, hexahydrate iron nitrate, nonahydrate iron nitrate, etc.

[0024] The iron nitrate is dissolved in the mannitol solution, and the mass ratio of the iron nitrate to the volume of the mannitol solution can be 1 g:10-200 ml, preferably 1 g:20-100 ml.

[0025] The dissolution of the bismuth nitrate in the mannitol solution and the dissolution of the iron nitrate in the mannitol solution are preferably performed under ultrasonic assistance.

[0026] Preferably, in solution C, the molar ratio of bismuth nitrate to iron nitrate is 1:0.8-1.2.

[0027] Preferably, in solution C, the molar ratio of bismuth nitrate to iron nitrate is 1:0.9-1.1.

[0028] Further preferably, in solution C, the molar ratio of bismuth nitrate to iron nitrate is 1:1.

[0029] Preferably, the concentration of the ammonia water is 25-28 wt%.

[0030] Preferably, the volume ratio of the ammonia water to solution C is 1:20-100, further preferably 1:30-80.

[0031] Preferably, the ammonia water is added, and the reaction is performed at 15-40°C for 10-60 min.

[0032] Preferably, the molecular formula of the prepared bismuth ferrite multimodal imaging probe is BiFeO x , wherein x is 2.5-3.5. Further preferably, x is 3.

[0033] Preferably, the prepared bismuth ferrite multimodal imaging probe has a hydrated particle size of 10-900 nm, further preferably 20-500 nm, and still further preferably 50-300 nm.

[0034] Preferably, the prepared bismuth ferrite multimodal imaging probe has both CT imaging and MRI imaging functions.

[0035] Preferably, the prepared iron-bismuth ferrite multimodal imaging probe simultaneously possesses POD-like activity, CAT-like activity, and GSH-Px-like activity.

[0036] The third objective of this invention is achieved through the following technical solution:

[0037] The iron-bismuth oxidase multimodal imaging probe is used in the preparation of contrast agents for tumor multimodal imaging or in the preparation of tumor therapeutic drugs.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] 1. The BiFeOx nanoparticles provided by this invention have multimodal imaging effects for CT and MRI. Using BiFeOx nanoparticles for tumor multimodal imaging can achieve complementary advantages between different imaging technologies, provide complementary and reliable information about the disease site, and improve diagnostic reliability.

[0040] 2. The BiFeOx nanoparticles provided by this invention simultaneously possess POD-like activity, CAT-like activity, and GSH-Px-like activity. They can kill cancer cells as POD enzymes in an acidic tumor environment, and at the same time protect normal cells as GSH-Px and CAT enzymes, thereby enhancing the therapeutic effect on tumors. Moreover, this therapeutic effect is significantly enhanced under ultrasound stimulation.

[0041] 3. This invention provides a method for preparing a multimodal imaging probe of iron bismuth ferrite. The method is very simple. BiFeOx nanoparticles with CT / MRI multimodal imaging effect and POD-like, CAT-like and GSH-Px-like activities are synthesized in one step through hydrothermal reaction. The probe has good water dispersibility and is stable under room temperature storage.

[0042] 4. The iron bismuth oxidase multimodal imaging probe provided by this invention has significant advantages in multimodal imaging and tumor treatment, overcomes some limitations of single imaging technology and traditional treatment methods, and has important clinical application value. Attached Figure Description

[0043] Figure 1 This is a DLS image of the BiFeOx nanoparticles prepared in Example 1;

[0044] Figure 2 These are transmission electron microscope (TEM) images and mapping images of the BiFeOx nanoparticles prepared in Example 1.

[0045] Figure 3 This is an in vitro CT image of the BiFeOx nanoparticles prepared in Example 1;

[0046] Figure 4This is an in vitro MRI image of the BiFeOx nanoparticles prepared in Example 1;

[0047] Figure 5 This is a schematic diagram of CT imaging of a subcutaneous tumor in a mouse after intratumoral injection of BiFeOx nanoparticles prepared in Example 1.

[0048] Figure 6 This is a schematic diagram of MR (T1WI) imaging of a subcutaneous tumor in a mouse after intratumoral injection of BiFeOx nanoparticles prepared in Example 1.

[0049] Figure 7 The images show the in vitro POD-like enzyme verification of BiFeOx prepared in Example 1. The left image is a comparison of the generation of hydroxyl radicals via ESR, and the right image is the absorbance after MB dye degradation at different times.

[0050] Figure 8 The BiFeOx prepared in Example 1 and the BiFe prepared in Comparative Example 1 are examples of BiFeOx prepared in Example 1. 0.5 Comparison of in vitro POD-like enzyme performance of BiFe2Ox prepared in Comparative Example 1 and BiFe2Ox prepared in Comparative Example 2, from left to right: BiFe2Ox prepared in Comparative Example 1, BiFe2Ox prepared in Comparative Example 2, and BiFe2Ox prepared in Comparative Example 2. 0.5 Ox, BiFeOx prepared in Example 1, and BiFe2Ox prepared in Comparative Example 2;

[0051] Figure 9 This is an in vitro CAT-like enzyme performance verification diagram of the BiFeOx nanoparticles prepared in Example 1;

[0052] Figure 10 This is an in vitro GSH-Px enzyme performance verification diagram of the BiFeOx nanoparticles prepared in Example 1;

[0053] Figure 11 This is a diagram illustrating the therapeutic effects of BiFeOx nanoparticles prepared in Example 1 at the cellular level.

[0054] Figure 12 This is an in vitro POD-like enzyme performance verification diagram of the BiFeOx nanoparticles prepared in Example 2;

[0055] Figure 13 This is a graph showing the in vitro POD-like enzyme performance verification of BiFeOx nanoparticles prepared in Comparative Example 3. Detailed Implementation

[0056] The technical solution of the present invention will be further described and illustrated below with reference to specific embodiments and accompanying drawings. It should be understood that the specific embodiments described herein are only for the purpose of helping to understand the present invention and are not intended to limit the specific scope of the present invention. Furthermore, the accompanying drawings used herein are merely for better illustrating the content disclosed in the present invention and do not limit the scope of protection. Unless otherwise specified, the raw materials used in the embodiments of the present invention are all commonly used in the art, and the methods used in the embodiments are all conventional methods in the art.

[0057] Example 1

[0058] The iron-bismuth ferrite multimodal imaging probe of this embodiment was prepared by the following method:

[0059] S1. Dissolve 485 mg of bismuth nitrate pentahydrate (Bi(NO3)3·5H2O) in a mannitol aqueous solution (0.1 M, 30 mL), sonicate to dissolve, then add 0.1 g of polyvinylpyrrolidone (molecular weight approximately 10,000), and magnetically stir at 500 rpm for 10 min to form solution A; weigh 404 mg of ferric nitrate nonahydrate (Fe(NO3)3·9H2O) and dissolve in a mannitol aqueous solution (0.1 M, 20 mL), sonicate to dissolve, to form solution B.

[0060] S2. Slowly add solution B dropwise to solution A while stirring at 500 rpm to form solution C.

[0061] S3. Add 0.8 mL of concentrated ammonia (25-28 wt%) to solution C and continue magnetic stirring at room temperature for 30 min.

[0062] S4. Subsequently, the above solution was transferred to a 100 mL polytetrafluoroethylene-lined reactor and reacted at 160 °C for 24 h. After the reaction was completed and cooled to room temperature, the solution was washed four times using anhydrous ethanol-deionized water-anhydrous ethanol-deionized water to obtain BiFeO. x (Theoretically, x is 3 here) A multimodal imaging probe of iron-bismuth ferrite was dispersed in deionized water to obtain BiFeO. x Aqueous dispersion.

[0063] BiFeO from Example 1 x After dilution of the aqueous dispersion, the particle size and distribution of the nanoparticles were measured using dynamic light scattering (DLS) measurement, such as... Figure 1 As shown, the nanoparticles have a water content and a particle size of approximately 142 ± 1.5 nm, with a PDI value of 0.1, indicating that they have good water dispersibility and stability.

[0064] BiFeO from Example 1 xThe diluted aqueous dispersion was dropped onto a copper grid and placed in a 45°C oven for 24 hours. Its size and morphology were observed using a Talos transmission electron microscope, and its characterization was performed using elemental mapping. Figure 2 As shown, the nanoparticles are observed to be a polymer composed of small particles of about 10 nm in size, and elemental characterization results indicate the presence of iron and bismuth.

[0065] Based on the bismuth concentration, different concentrations of BiFeO were prepared using 5ml centrifuge tubes. x Aqueous dispersions (0.5, 1.5, 2.5, 3.5 mg / mL) were arranged in ascending order of concentration on centrifuge tube racks. Plain scans were performed using a clinical computed tomography scanner with a scan width of 2 cm to obtain the corresponding BiFeO concentrations. x X-ray CT images of aqueous dispersions, such as Figure 3 As shown, it can be observed that with the increase of BiFeO x As the concentration increases, the CT signal gradually strengthens.

[0066] Based on the iron concentration, BiFeO solutions of different concentrations were prepared. x Aqueous dispersions (0, 0.06, 0.125, 0.25, 0.5, 1, 2, 4 mM) were filled into 5 ml centrifuge tubes and fixed in centrifuge tube racks in order of increasing concentration. Plain MRI scans were performed using a clinical 3.0T MRI scanner, with T-weighted MRI scan parameters set, to capture images of different concentrations of BiFeO. x T1-MR images of aqueous dispersions, such as Figure 4 As shown, it can be observed that with the increase of BiFeO x As the concentration increases, the bright signal on MRI T1 imaging gradually increases.

[0067] Balb / c nude mice with relatively large tumor volumes were selected as the animal model for in vivo imaging evaluation. After anesthetizing the mice with an intraperitoneal injection of 5% chloral hydrate solution, 50 μL of BiFeO was injected in situ through the tumor site. x (Dispersed in PBS, bismuth concentration 4 mg / mL), tumor-bearing mice were CT scanned using Micro-CT, and tumor CT images were recorded before and after injection, as follows: Figure 5 As shown, a significant increase in CT signal at the tumor site can be observed after injection.

[0068] Balb / c nude mice with relatively large tumor volumes were selected as the animal model for in vivo imaging evaluation. After anesthetizing the mice with an intraperitoneal injection of 5% chloral hydrate solution, 50 μL of BiFeO was injected in situ through the tumor site. x(Dispersed in PBS, bismuth concentration 4 mg / mL), then T1 imaging scans were performed on tumor-bearing mice using a 0.5T MRI scanner, and tumor T1 imaging images were recorded before and after injection, as shown below. Figure 6 As shown, a significant increase in T1 signal can be observed at the tumor site after injection.

[0069] BiFeO x Enzyme activity verification

[0070] (1) Validation of POD-like enzyme activity in vitro

[0071] The generation of hydroxyl radicals was detected using electron paramagnetic resonance (ESR). 10 μL of H₂O₂ (1M) solution and 100 μL of BiFeO₂ from Example 1 were used. x An aqueous dispersion (Fe: 0.25 mg / mL) and 880 μL of deionized water were prepared, with 10 μL of DMPO scavenging agent added. (Other groups were ensured to have BiFeO in 1 mL of solution.) x H₂O₂ and DMPO were at the same concentration. Different reagents were added, and the mixture was adjusted to equilibrium with deionized water. The mixture was reacted for 5 minutes, and a certain amount of the above mixed solution was loaded into a capillary tube. Finally, it was analyzed using an electron paramagnetic resonance spectrometer. The results are shown below. Figure 7 The left image.

[0072] Add 10 μL of H2O2 (1M), 10 μL of methylene blue (MB) solution, and 100 μL of BiFeO from Example 1 to a 1.5 mL centrifuge tube. x An aqueous dispersion (Fe: 0.25 mg / mL) and 880 μL of deionized water were mixed. The absorbance at 664 nm was measured using UV-Vis absorption spectroscopy at different time points (0, 5, 10, and 20 min). The results are shown in the table below. Figure 7 The image on the right.

[0073] Experimental results show that BiFeO x It exhibits strong POD-like enzyme activity. In the presence of H2O2, it can undergo a Fenton-like reaction to generate hydroxyl radicals (·OH) with tumor-killing effects. Furthermore, ESR experiments in the presence of US have demonstrated that US enhances the POD-like enzyme activity.

[0074] (2) In vitro CAT enzyme performance verification

[0075] Add 100 μL of H2O2 (1M) and 1 mL of BiFeO from Example 1 to a 25 mL reagent bottle. xAn aqueous dispersion (Fe: 0.25 mg / mL) and 8.9 mL of deionized water were prepared. In a separate 25 mL reagent bottle, 100 μL of 1 M H₂O₂ and 9.9 mL of deionized water were added. The dissolved oxygen levels in both solutions were measured using a portable dissolved oxygen analyzer. The experimental results are shown below. Figure 9 BiFeO can be observed. x The dissolved oxygen content in the reagent bottle increased significantly. This indicates that BiFeO x It possesses ideal CAT-like enzyme activity.

[0076] (3) In vitro performance verification of GSH-Px enzyme

[0077] Add 15 μL of DTNB (1 x 10⁻⁶) to a 1.5 mL centrifuge tube. -3 M), 200 μL of reduced glutathione solution (10 mM), 100 μL of BiFeO from Example 1 x An aqueous dispersion (Fe: 0.25 mg / mL) and 685 μL of deionized water were mixed. After mixing, the absorbance at 410 nm was measured using UV-Vis absorption spectroscopy at different time points (0, 0.5, 1, 2, 6, and 10 h). The results are as follows: Figure 10 As shown, it can be observed that the UV absorption peak of DTNB at 410 nm gradually decreases with increasing reaction time, indicating that BiFeO x It possesses ideal GSH-Px-like enzyme activity.

[0078] Validation of therapeutic effects at the cellular level

[0079] Cell status was assessed using a Calcein-AM / PI double staining kit. HT29 cells were dispersed in 1 mL of complete culture medium at a density of 10,000 cells per well and incubated in confocal dishes for 24 hours to allow cell adhesion. Then, the cells were subjected to different treatments, forming different groups.

[0080] (1) Control, do not perform any treatment, continue incubation for 24 hours;

[0081] (2) US group, using a sonodynamic therapy device at 0.5W / cm 2 At the specified intensity, sonicate for 1 minute, then continue incubation for 24 hours;

[0082] (3) H2O2 group: After adding complete culture medium containing 200 μM H2O2, continue incubation for 24 h;

[0083] (4)BiFeO x Add BiFeO containing the sample from Example 1 x Continue incubation in the complete culture medium for 24 hours;

[0084] (5)BiFeO x +US group, with added BiFeO from Example 1 x After incubation in complete culture medium for 18 hours, the sample was treated with a sonodynamic therapy device at 0.5 W / cm². 2 At the specified intensity, sonicate for 1 minute, then continue incubation for 6 hours;

[0085] (6)BiFeO x +H2O2 group, adding BiFeO x Incubate with complete culture medium containing H2O2 for another 24 hours;

[0086] (7)BiFeO x +H2O2+US group, adding BiFeO x Incubate with complete culture medium containing H2O2 for 18 hours, then use a sonodynamic therapy device at 0.5 W / cm². 2 At the specified intensity, sonicate for 1 minute, then continue incubation for 6 hours;

[0087] Above BiFeO x The concentrations of all were Bi 3+ The concentration of H2O2 was 200 μg / mL. All HT29 cells in all experimental groups were stained with Calcein-AM / PI working solution at 37℃ for 30 min. Finally, the fluorescence signal of the cells was observed using a laser confocal microscope to assess cell viability. Cell viability in each group is shown below. Figure 11 As shown. Green represents live cells, and red represents dead cells. BiFeO can be observed. x The +H2O2+US group showed significant tumor cell killing ability.

[0088] Example 2

[0089] The iron-bismuth ferrite multimodal imaging probe of this embodiment was prepared by the following method:

[0090] S1. Dissolve 485 mg of bismuth nitrate pentahydrate (Bi(NO3)3·5H2O) in a mannitol aqueous solution (0.1M, 50 mL), sonicate to dissolve, then add 0.2 g of polyacrylic acid (molecular weight approximately 5000), and magnetically stir at 300 rpm for 15 min to form solution A; weigh 404 mg of ferric nitrate nonahydrate (Fe(NO3)3·9H2O) and dissolve in a mannitol aqueous solution (0.1M, 40 mL), sonicate to dissolve, to form solution B.

[0091] S2. Slowly add solution B dropwise to solution A while stirring at 600 rpm to form solution C.

[0092] S3. Add 1 mL of concentrated ammonia (25-28 wt%) to solution C and continue magnetic stirring at room temperature for 40 min.

[0093] S4. Subsequently, the above solution was transferred to a 150 mL polytetrafluoroethylene-lined reactor and reacted at 180 °C for 20 h. After the reaction was completed and cooled to room temperature, the solution was washed four times using anhydrous ethanol-deionized water-anhydrous ethanol-deionized water to obtain BiFeO. x A multimodal imaging probe for iron-bismuth oxidases was dispersed in deionized water to obtain BiFeO. x Aqueous dispersion.

[0094] Add 10 μL of H2O2 (1M), 10 μL of methylene blue (MB) solution, and 100 μL of BiFeO from Example 2 to a 1.5 mL centrifuge tube. x An aqueous dispersion (Fe: 0.25 mg / mL) and 880 μL of deionized water were mixed. The absorbance at 664 nm was measured using UV-Vis absorption spectroscopy at different time points (0, 5, 10, and 20 min). The results are shown in the table below. Figure 12 This indicates that the BiFeO in Example 2... x It has strong POD-like enzyme activity.

[0095] Comparative Example 1

[0096] The difference between Comparative Example 1 and Example 1 is that in Comparative Example 1, step S1 is as follows: 485 mg of bismuth nitrate pentahydrate (Bi(NO3)3·5H2O) is dissolved in a mannitol aqueous solution (0.1M, 30 mL), and after ultrasonic dissolution, 0.1 g of polyvinylpyrrolidone (molecular weight approximately 10000) is added, and the mixture is magnetically stirred at 500 rpm for 10 min to form solution A; 202 mg of ferric nitrate nonahydrate (Fe(NO3)3·9H2O) is weighed and dissolved in a mannitol aqueous solution (0.1M, 20 mL), and after ultrasonic dissolution, solution B is formed. The rest is the same as in Example 1, yielding BiFe 0.5 O x .

[0097] Comparative Example 2

[0098] The difference between Comparative Example 1 and Example 1 is that in Comparative Example 1, step S1 is as follows: 485 mg of bismuth nitrate pentahydrate (Bi(NO3)3·5H2O) is dissolved in a mannitol aqueous solution (0.1 M, 30 mL), and after ultrasonic dissolution, 0.1 g of polyvinylpyrrolidone (molecular weight approximately 10,000) is added, and the mixture is magnetically stirred at 500 rpm for 10 min to form solution A; 808 mg of ferric nitrate nonahydrate (Fe(NO3)3·9H2O) is weighed and dissolved in a mannitol aqueous solution (0.1 M, 20 mL), and after ultrasonic dissolution, solution B is formed. The rest is the same as in Example 1, yielding BiFe2Ox .

[0099] BiFeO from Example 1 x BiFe , Comparative Example 1 0.5 O x BiFe2O (Comparative Example 2) x The solution was diluted to an aqueous dispersion with an iron ion concentration of 0.25 mg / mL. 10 μL of 1M H₂O₂ and 10 μL of methylene blue (MB) solution were added to a 1.5 mL centrifuge tube. Then, 100 μL of BiFeO₂ from Example 1 was added to the mixture in the centrifuge tube. x BiFe , Comparative Example 1 0.5 O x BiFe2O (Comparative Example 2) x An aqueous dispersion was prepared, and 880 μL of deionized water was added to each dispersion. After mixing, the absorbance at 664 nm was measured using UV-Vis absorption spectroscopy at different time points of 0, 5, 10, and 20 min. The results are shown in the figure. Figure 8 It can be observed that within 20 minutes, the BiFeOx of Example 1 showed the largest difference in absorbance value at a wavelength of 664 nm, producing more ·OH and exhibiting stronger POD-like enzyme activity.

[0100] Comparative Example 3

[0101] The iron-bismuth ferrite multimodal imaging probe of Comparative Example 3 was prepared by the following method:

[0102] S1. Dissolve 485 mg of bismuth nitrate pentahydrate (Bi(NO3)3·5H2O) in water, sonicate to dissolve, then add 0.1 g of polyvinylpyrrolidone (molecular weight approximately 10,000), and magnetically stir at 500 rpm for 10 min to form solution A; weigh 404 mg of ferric nitrate nonahydrate (Fe(NO3)3·9H2O) and dissolve in water to form solution B.

[0103] Steps S2-S4 are the same as in Example 1. BiFeO is obtained. x .

[0104] Add 10 μL of 1M H2O2, 10 μL of methylene blue (MB) solution, and 100 μL of BiFeO from Comparative Example 3 to a 1.5 mL centrifuge tube. x An aqueous dispersion (Fe: 0.25 mg / mL) and 880 μL of deionized water were mixed. After mixing, the absorbance at 664 nm was measured using UV-Vis absorption spectroscopy at different time points of 0, 5, 10, and 20 min. The results are shown in the figure. Figure 13It can be observed that within 20 minutes, the difference in absorbance value of BiFeOx in Comparative Example 3 at a wavelength of 664 nm is smaller than that in Example 1, and less ·OH is generated. The POD-like enzyme activity of BiFeOx in Comparative Example 3 is not as good as that in Example 1.

[0105] All aspects, embodiments, and features of this invention should be considered illustrative in all respects and not limiting of the invention; the scope of the invention is defined only by the claims. Other embodiments, modifications, and uses will become apparent to those skilled in the art without departing from the spirit and scope of the invention as claimed.

[0106] In the preparation method of this invention, the order of the steps is not limited to the listed order. For those skilled in the art, variations in the order of the steps without creative effort are also within the scope of protection of this invention. Furthermore, two or more steps or actions can be performed simultaneously.

[0107] Finally, it should be noted that the specific embodiments described herein are merely illustrative examples of the invention and are not intended to limit the implementation of the invention. Those skilled in the art can make various modifications or additions to the described specific embodiments or use similar methods to replace them; it is neither necessary nor possible to exemplify all embodiments here. However, these obvious variations or modifications derived from the essential spirit of the invention still fall within the scope of protection of the invention, and interpreting them as any additional limitation would contradict the spirit of the invention.

Claims

1. A method for preparing an iron-bismuth-oxide multimodal imaging probe, characterized in that, The method comprises the following steps: dissolving bismuth nitrate in a mannitol solution, then adding a high molecular polymer, polyvinylpyrrolidone and / or polyacrylic acid, to form an A solution; dissolving ferric nitrate in a mannitol solution to form a B solution; adding the B solution dropwise into the A solution to form a C solution, then adding ammonia water, and after reaction, treating the reaction liquid at a high temperature of 130-200 DEG C for 10-30 h, and after cooling, washing to obtain a ferric bismuth oxide multi-modal imaging probe.

2. The production method according to claim 1, characterized by, The concentration of the mannitol solution is 0.01-1 mol / L; and / or, the bismuth nitrate is dissolved in the mannitol solution, and the mass ratio of the bismuth nitrate to the volume of the mannitol solution is 1 g:20-200 ml; and / or, the ferric nitrate is dissolved in the mannitol solution, and the mass ratio of the ferric nitrate to the volume of the mannitol solution is 1 g:10-200 ml.

3. The preparation method according to claim 1, characterized in that, The mass ratio of the high molecular polymer to the bismuth nitrate is 1:1.5-10; and / or, the molecular weight of the high molecular polymer is 2000-20000.

4. The method of claim 1, wherein, In the C solution, the molar ratio of the bismuth nitrate to the ferric nitrate is 1:0.8-1.

2.

5. The preparation method according to claim 1, characterized in that, In the C solution, the molar ratio of the bismuth nitrate to the ferric nitrate is 1:

1.

6. The method of claim 1, wherein, The concentration of the ammonia water is 25-28 wt%; and / or, the volume ratio of the ammonia water to the C solution is 1:20-100.

7. The preparation method according to claim 1, characterized in that, After adding the ammonia water, the reaction is carried out at 15-40 DEG C for 10-60 min.

8. The preparation method according to claim 1, characterized in that, The molecular formula of the prepared iron bismuth oxide multimodal imaging probe is BiFeO x wherein x is 2.5-3.5; and / or, the prepared ferric bismuth oxide multi-modal imaging probe has a hydration particle size of 10-900 nm; and / or, the prepared ferric bismuth oxide multi-modal imaging probe has CT imaging and MRI imaging functions simultaneously; and / or, the prepared ferric bismuth oxide multi-modal imaging probe has POD-like activity, CAT-like activity and GSH-Px-like activity simultaneously.

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