Iron bismuth oxide multi-mode imaging probe as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicines, and relates to an iron bismuth oxide multi-mode imaging probe as well as a preparation method and application thereof. The molecular formula of the Fe-Bi-O multi-mode imaging probe is BiFeOx, x ranges from 2.5 to 3.5, and the Fe-Bi-O multi-mode imaging probe has CT imaging and MRI imaging functions at the same time and has POD-like activity, CAT-like activity and GSH-Px-like activity at the same time. The preparation method comprises the following steps: dissolving bismuth nitrate in a mannitol solution, and then adding a high-molecular polymer to form a solution A; dissolving ferric nitrate in a mannitol solution to form a solution B; dropwise adding the solution B into the solution A, adding ammonia water, reacting, performing high-temperature treatment, cooling, and washing to obtain the iron bismuth oxide multi-mode imaging probe. The iron bismuth oxide multi-mode imaging probe has remarkable advantages in the aspects of multi-mode imaging and tumor treatment, overcomes part of limitations of a single imaging technology and a traditional treatment method, and has important clinical application value.

Description

Technical Field

[0001] The invention belongs to the field of medical technology and relates to an iron bismuth oxide multimodal imaging probe and a preparation method and application thereof. Background Art

[0002] Computed tomography (CT) is a widely used noninvasive diagnostic tool in clinical practice. However, the small molecule iodinated contrast agents (ICAs) commonly used in clinical CT imaging have limitations such as nonspecific distribution in the body and rapid clearance through the kidneys, resulting in a narrow imaging time window. Magnetic resonance imaging (MRI) is a noninvasive medical imaging modality that is routinely used in clinical practice and provides anatomical information with micron resolution, soft tissue contrast, and depth penetration. The use of contrast agents can significantly improve the resolution of MRI for disease diagnosis by shortening the longitudinal (T1) or transverse (T2) relaxation time of water protons to enhance contrast. For CT imaging, it can provide excellent spatial resolution and three-dimensional (3D) images of tissues without depth restrictions, but it cannot be used for targeted imaging and angiography, and cannot distinguish different soft tissues with very similar mass densities. Magnetic resonance imaging (MRI) has the advantage of being able to clearly display soft tissue structures and the disadvantage of low sensitivity in imaging tumor lesions. Therefore, single CT and MRI imaging have their own limitations and shortcomings in clinical application and cannot meet the needs of clinical precise imaging.

[0003] Currently, there is no drug that can achieve simultaneous CT and MRI imaging enhancement in the clinic. Achieving multimodal 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 the field of multimodal imaging due to their customizable morphological (size, shape, porosity, etc.) and physicochemical (optical, magnetic, catalytic, X-ray opacity, etc.) properties.

[0004] The tumor microenvironment (TME) is characterized by hypoxia, high levels of hydrogen peroxide, and overexpression of glutathione (GSH), which are closely related to the development of tumors. The hypoxic state of TME hinders many normal physiological processes and treatment-related reactions that rely on oxygen. For example, some conventional oxidative reaction-based treatments are difficult to fully function due to the lack of sufficient oxygen as a reactant, which greatly reduces the killing effect on tumor cells. The presence of high levels of hydrogen peroxide in TEM can cause DNA damage, oxidative modification of proteins and lipids, and promote the survival and proliferation of tumor cells. Overexpression of glutathione (GSH) provides a "protective umbrella" for tumor cells. 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 oxidative substances, or some exogenously introduced therapeutic drugs based on the principle of oxidation, the process of their functioning will be interfered by glutathione. These oxidative substances will preferentially react with glutathione and be consumed, making it difficult to cause substantial damage to tumor cells. These characteristics of TEM make malignant tumor cells resistant to oxidative stress, which exacerbates the challenge of achieving ideal therapeutic effects. If we can cleverly formulate corresponding strategies for these characteristics, it is possible to transform these seemingly "disadvantages" into powerful weapons to conquer tumors, which is the so-called "waste to treasure" strategy.

[0005] Nanozymes with active sites can catalyze cascade reactions with the help of their active sites to produce highly toxic reactive oxygen species (ROS). ROS are highly oxidizing and are a very destructive "attack force" for the antioxidant defense mechanism in tumor cells. Therefore, they are widely used in targeted tumor treatment. POD / GSH-Px / CAT-like nanozymes have unique and exquisite functions. In the acidic tumor environment, they can act like peroxidase (POD). The acidic environment in which cancer cells are located provides suitable reaction conditions for this nanozyme, enabling it to utilize substances such as hydrogen peroxide present in the tumor microenvironment to catalyze the generation of lethal products. At the same time, the nanozyme can also act like glutathione peroxidase (GSH-Px) and catalase (CAT), and play a protective role for normal cells. Through this dual role of both killing cancer cells and protecting normal cells, the nanozyme greatly enhances the overall effect of tumor treatment, making tumor treatment more accurate and efficient, reducing side effects on normal tissues, and has broad application prospects in the field of tumor treatment. Summary of the invention

[0006] In order to solve the above problems existing in the prior art, the purpose of the present invention is to provide a bismuth iron oxide multimodal imaging probe and a preparation method and application thereof, so as to overcome the shortcomings of the prior art.

[0007] One object of the present invention is achieved by the following technical solutions:

[0008] A bismuth iron oxide multimodal imaging probe, wherein the molecular formula of the bismuth iron oxide multimodal imaging probe is BiFeO x , where x is 2.5 to 3.5 and the hydrated particle size is 10 to 900 nm;

[0009] The iron bismuth oxide multimodal imaging probe has both CT imaging and MRI imaging functions;

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

[0011] The iron bismuth oxide multimodal 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 catalytic behavior similar to that of natural POD, CAT, and GSH-Px. Specifically, natural OD, CAT, and GSH-Px can catalyze some specific chemical reactions, and probes 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 invention is achieved by the following technical solutions:

[0013] A method for preparing a bismuth iron oxide multimodal imaging probe, characterized in that it comprises the following steps:

[0014] Dissolving bismuth nitrate in a mannitol solution, and then adding a polymer to form a solution A, wherein the polymer is polyvinyl pyrrolidone (PVP) and / or polyacrylic acid (PAA);

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

[0016] Solution B is dropped into solution A to form solution C, and then ammonia water is added. After the reaction, the reaction solution is treated at a high temperature of 130 to 200° C. for 10 to 30 hours. After cooling, the solution is washed to obtain an iron bismuth oxide multimodal 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 to 1 mol / L, more preferably 0.05 to 0.5 mol / L.

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

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

[0021] Preferably, the molecular weight of the high molecular weight polymer is 2,000 to 20,000, more preferably 4,000 to 15,000.

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

[0023] Preferably, the ferric nitrate is hydrated ferric nitrate, including one or more of ferric nitrate pentahydrate, ferric nitrate hexahydrate, ferric nitrate nonahydrate and the like.

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

[0025] The dissolution of bismuth nitrate in mannitol solution and the dissolution of ferric nitrate in mannitol solution are preferably carried out with the assistance of ultrasound.

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

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

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

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

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

[0031] Preferably, aqueous ammonia is added and the reaction is carried out at 15 to 40° C. for 10 to 60 minutes.

[0032] Preferably, the molecular formula of the prepared bismuth iron oxide multimodal imaging probe is BiFeO x , wherein x is 2.5 to 3.5. More preferably, x is 3.

[0033] Preferably, the hydrated particle size of the prepared iron bismuth oxide multimodal imaging probe is 10 to 900 nm, more preferably 20 to 500 nm, and even more preferably 50 to 300 nm.

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

[0035] Preferably, the prepared iron bismuth oxide multimodal imaging probe has POD-like activity, CAT-like activity and GSH-Px-like activity at the same time.

[0036] The third object of the present invention is achieved by the following technical solutions:

[0037] The bismuth iron oxide multimodal imaging probe is used in the preparation of a contrast agent for multimodal tumor imaging, or in the preparation of a tumor therapeutic drug.

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

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

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

[0041] 3. The present invention provides a method for preparing a bismuth iron oxide multimodal imaging probe. The method is very simple. BiFeOx nanoparticles having CT / MRI multimodal imaging effects and POD-like activity, CAT-like activity and GSH-Px-like activity are synthesized in one step through a hydrothermal reaction. The nanoparticles have good water dispersibility and are stable when stored at room temperature.

[0042] 4. The iron bismuth oxide multimodal imaging probe provided by the present 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. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 is a DLS graph of BiFeOx nanoparticles prepared in Example 1;

[0044] Figure 2 It is the transmission electron microscope and mapping image of BiFeOx nanoparticles prepared in Example 1;

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

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

[0047] Figure 5 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 is a schematic diagram of MR (T1WI) imaging of a subcutaneous tumor in a mouse after intratumoral injection of the BiFeOx nanoparticles prepared in Example 1;

[0049] Figure 7 The figure is a verification diagram of the in vitro POD-like enzyme of BiFeOx prepared in Example 1. The left figure is a comparison diagram of hydroxyl radical generation through ESR, and the right figure is an absorbance diagram 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 0.5 Ox, and the comparison diagram of the in vitro POD-like enzyme performance of BiFe2Ox prepared in comparative example 2. From left to right, BiFe2Ox prepared in comparative example 1 0.5 Ox, BiFeOx prepared in Example 1, and BiFe2Ox prepared in Comparative Example 2;

[0051] Fig. 9 This is a diagram for verifying the in vitro CAT enzyme-like performance of the BiFeOx nanoparticles prepared in Example 1;

[0052] Fig.10 This is a graph verifying the in vitro GSH-Px-like enzyme performance of the BiFeOx nanoparticles prepared in Example 1;

[0053] Fig.11 is a diagram of the therapeutic effect of BiFeOx nanoparticles prepared in Example 1 at the cellular level;

[0054] Fig.12 This is a graph verifying the in vitro POD enzyme performance of the BiFeOx nanoparticles prepared in Example 2;

[0055] Fig.13 This is a graph verifying the in vitro POD enzyme performance of the BiFeOx nanoparticles prepared in Example 3. DETAILED DESCRIPTION

[0056] The technical scheme of the present invention is further described below by specific examples and accompanying drawings. It should be understood that the specific examples described herein are only used to help understand the present invention and are not intended for specific limitations of the present invention. The accompanying drawings used herein are only for better illustrating the disclosure of the present invention and do not have a limiting effect on the scope of protection. If not otherwise specified, the raw materials used in the embodiments of the present invention are all commonly used raw materials in the art, and the methods used in the embodiments are all conventional methods in the art.

[0057] Example 1

[0058] The iron bismuth oxide multimodal imaging probe of this embodiment is 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), add 0.1 g of polyvinyl pyrrolidone (molecular weight of about 10,000) after ultrasonic dissolution, and stir magnetically at 500 rpm for 10 min to form solution A; weigh 404 mg of ferric nitrate nonahydrate (Fe(NO3)3·9H2O) and dissolve it in a mannitol aqueous solution (0.1 M, 20 mL), and dissolve it by ultrasonication to form solution B.

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

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

[0062] S4, then transfer the above solution to a 100 mL polytetrafluoroethylene liner reactor, react at 160°C for 24 hours, wait for the reaction to end and cool to room temperature, then wash 4 times according to the steps of anhydrous ethanol-deionized water-anhydrous ethanol-deionized water to obtain BiFeO x (Theoretically, x is 3 here) Iron bismuth oxide multimodal imaging probe, dispersed in deionized water to obtain BiFeO x Aqueous dispersion.

[0063] The BiFeO x After dilution of the aqueous dispersion, the particle size and distribution of the nanoparticles were measured using a dynamic light scattering (DLS) instrument, such as Figure 1 As shown, it can be observed that the particle size of the nanoparticles is about 142±1.5 nm and the PDI value is 0.1, indicating that it has good water dispersibility and stability.

[0064] The BiFeO xThe aqueous dispersion was diluted and dripped onto the copper grid, placed in an oven at 45 °C for 24 h, and its size and morphology were observed using a Talos transmission electron microscope, and the mapping element diagram was characterized, such as Figure 2 It can be observed that the nanoparticles are aggregates of small particles of about 10 nm, and the element characterization results show the presence of iron and bismuth.

[0065] Based on the concentration of bismuth, different concentrations of BiFeO were prepared using 5 ml centrifuge tubes. x The aqueous dispersions (0.5, 1.5, 2.5, and 3.5 mg / mL) were arranged in a centrifuge tube rack in order of concentration from low to high, and scanned using a clinical computed tomography scanner with a scanning width of 2 cm to obtain the corresponding concentrations of BiFeO x X-ray CT images of aqueous dispersions, such as Figure 3 As shown. It can be observed that as BiFeO x As the concentration increases, the CT signal gradually increases.

[0066] Based on the concentration of iron, different concentrations of BiFeO were prepared. x The aqueous dispersions (0, 0.06, 0.125, 0.25, 0.5, 1, 2, 4 mM) were filled in 5 ml centrifuge tubes and fixed in the centrifuge tube rack in the order of concentration from low to high. The clinical 3.0T magnetic resonance imaging was used for plain scanning, and the T-weighted MRI scanning parameters were set to take pictures of different concentrations of BiFeO x T1-MR imaging images of aqueous dispersions, such as Figure 4 As shown. It can be observed that as BiFeO x As the concentration increases, the bright signal of 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 intraperitoneal injection of 5% chloral hydrate solution, 50 μL BiFeO x (PBS dispersion, bismuth concentration 4 mg / mL), and used Micro-CT to perform CT scans on tumor-bearing mice, and recorded the tumor CT images before and after injection, such as Figure 5 As shown in Figure 2, it can be observed that the CT signal at the tumor site was significantly enhanced after injection.

[0068] Balb / c nude mice with relatively large tumor volumes were selected as the animal model for in vivo imaging evaluation. After intraperitoneal injection of 5% chloral hydrate solution for anesthesia, 50 μL BiFeO x(PBS dispersion, bismuth concentration 4 mg / mL), and then a 0.5T magnetic resonance imaging device was used to perform T1 imaging scans on the tumor-bearing mice, and the T1 imaging images of the tumors before and after injection were recorded, such as Figure 6 As shown in Figure 2, it can be observed that the T1 signal at the tumor site was significantly enhanced after injection.

[0069] BiFeO x Enzyme-like activity verification

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

[0071] The generation of hydroxyl radicals was detected by electron paramagnetic resonance (ESR). 10 μL H2O2 (1M) solution and 100 μL BiFeO prepared in Example 1 were taken. x aqueous dispersion (Fe: 0.25 mg / mL) and 880 μL deionized water, add 10 μL DMPO capture agent. (Other groups ensure that BiFeO x , H2O2, and DMPO have the same concentration, and after adding different reagents, use deionized water to adjust the balance. ) Mix and react for 5 minutes, use a capillary to fill a certain amount of the above mixed solution, and finally use an electron paramagnetic resonance instrument to test and analyze. The results are shown in Figure 7 Left picture.

[0072] To a 1.5 mL centrifuge tube, add 10 μL H2O2 (1 M), 10 μL methylene blue (MB) solution, 100 μL BiFeO x The aqueous dispersion (Fe: 0.25 mg / mL) and 880 μL of deionized water were mixed and the changes in the absorbance at a wavelength of 664 nm were observed using UV-visible absorption spectroscopy at different time points of 0, 5, 10, and 20 min. The results are shown in Figure 7 Right picture.

[0073] The experimental results show that BiFeO x It has strong POD-like enzyme activity. In the presence of H2O2, a Fenton-like reaction can occur to produce hydroxyl radicals (·OH) with tumor-killing effects. In the presence of US, ESR experimental results prove that US has the effect of enhancing POD-like enzymes.

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

[0075] Add 100 μL H2O2 (1M), 1 mL BiFeO xAqueous dispersion (Fe: 0.25 mg / mL) and 8.9 mL of deionized water. In another 25 mL reagent bottle, add 100 μL of H2O2 (1M) and 9.9 mL of deionized water. Use a portable dissolved oxygen detector to measure the dissolved oxygen in the two solutions. The experimental results are shown in Fig. 9 It can be observed that BiFeO x The dissolved oxygen content in the reagent bottle increased significantly. x It has ideal CAT-like enzyme activity.

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

[0077] To a 1.5 mL centrifuge tube, add 15 μL DTNB (1x10 -3 M), 200 μL reduced glutathione solution (10 mM), 100 μL BiFeO x After mixing the above solutions, the changes in the absorbance at a wavelength of 410 nm were observed using UV-visible absorption spectroscopy at different time points of 0, 0.5, 1, 2, 6, and 10 h. The results are as follows: Fig.10 It can be observed that as the reaction time increases, the UV absorption peak of DTNB at 410 nm gradually decreases, indicating that BiFeO x It has ideal GSH-Px-like enzyme activity.

[0078] Verification of therapeutic effects at the cellular level

[0079] The cell status was determined using the Calcein-AM / PI double staining kit. HT29 cells were dispersed in 1 mL of complete medium at a density of 10,000 cells per well and incubated in a confocal dish for 24 hours to allow the cells to adhere to the wall. Then, the cells were treated differently and different groups were set up.

[0080] (1) Control, no treatment, continued incubation for 24 h;

[0081] (2) US group, using sonodynamic therapy device at 0.5 W / cm 2 At the intensity of , ultrasonicate for 1 min and continue incubation for 24 h;

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

[0083] (4)BiFeO x , add BiFeO containing Example 1 x Complete culture medium, continue incubation for 24h;

[0084] (5)BiFeO x +US group, adding BiFeO containing Example 1 x After incubation in complete culture medium for 18 h, the sonodynamic therapy device was used at 0.5 W / cm 2 At the intensity of , ultrasonicate for 1 min and continue incubation for 6 h;

[0085] (6)BiFeO x +H2O2 group, adding BiFeO x and complete medium containing H2O2, and incubate for another 24 h;

[0086] (7)BiFeO x +H2O2+US group, adding BiFeO x and H2O2 complete medium, incubated for 18 h, and treated with sonodynamic therapy at 0.5 W / cm 2 At the intensity of , ultrasonicate for 1 min and continue incubation for 6 h;

[0087] Above BiFeO x The concentration of Bi 3+ : 200μg / mL, H2O2 concentration was 200μM. HT29 cells in all experimental groups were stained with Calcein-AM / PI working solution at 37°C for 30min, and then the fluorescence signal of cells was observed using a laser confocal microscope to evaluate the survival status of cells. The survival status of cells in each group is shown in Fig.11 Green represents live cells, red represents dead cells, and BiFeO x The +H2O2+US group had significant tumor cell killing ability.

[0088] Example 2

[0089] The iron bismuth oxide multimodal imaging probe of this embodiment is prepared by the following method:

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

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

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

[0093] S4, then transfer the above solution to a 150mL polytetrafluoroethylene-lined reactor, react at 180°C for 20h, wait for the reaction to end and cool to room temperature, then wash 4 times according to the steps of anhydrous ethanol-deionized water-anhydrous ethanol-deionized water to obtain BiFeO x BiFeO multimodal imaging probe dispersed in deionized water x Aqueous dispersion.

[0094] To a 1.5 mL centrifuge tube, add 10 μL H2O2 (1 M), 10 μL methylene blue (MB) solution, 100 μL BiFeO x The aqueous dispersion (Fe: 0.25 mg / mL) and 880 μL of deionized water were mixed and the changes in the absorbance at a wavelength of 664 nm were observed using UV-visible absorption spectroscopy at different time points of 0, 5, 10, and 20 min. The results are shown in Fig.12 . It shows 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 step S1 of Comparative Example 1 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 polyvinyl pyrrolidone (molecular weight of about 10,000) is added, and magnetic stirring is performed 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, and BiFe 0.5 O x .

[0097] Comparative Example 2

[0098] The difference between Comparative Example 1 and Example 1 is that step S1 of Comparative Example 1 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 polyvinyl pyrrolidone (molecular weight of about 10,000) is added, and magnetic stirring is performed 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 (0.1M, 20 mL), and after ultrasonic dissolution, solution B is formed. The rest is the same as in Example 1 to obtain BiFe2Ox .

[0099] The BiFeO x , BiFe of Comparative Example 1 0.5 O x , BiFe2O of Comparative Example 2 x Dilute to an aqueous dispersion with an iron ion concentration of 0.25 mg / mL. Add 10 μL of H2O2 (1M) and 10 μL of methylene blue (MB) solution to a 1.5 mL centrifuge tube, and then add 100 μL of BiFeO prepared in Example 1 to the mixed solution in the centrifuge tube. x , BiFe of Comparative Example 1 0.5 O x , BiFe2O of Comparative Example 2 x After mixing, the absorbance at 664 nm was measured by UV-visible absorption spectroscopy at different time points of 0, 5, 10, and 20 min. The results are shown in Figure 8 It can be observed that within 20 minutes, the absorbance value change difference of BiFeOx in Example 1 at a wavelength of 664 nm is the largest, more ·OH is generated, and it has a stronger POD-like enzyme activity.

[0100] Comparative Example 3

[0101] The iron bismuth oxide 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, add 0.1 g of polyvinyl pyrrolidone (molecular weight of about 10,000) after ultrasonic dissolution, and stir magnetically at 500 rpm for 10 min to form solution A; weigh 404 mg of ferric nitrate nonahydrate (Fe(NO3)3·9H2O) and dissolve it in water to form solution B.

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

[0104] To a 1.5 mL centrifuge tube, add 10 μL H2O2 (1M), 10 μL methylene blue (MB) solution, 100 μL BiFeO x Water dispersion (Fe: 0.25 mg / mL), 880 μL deionized water. After mixing, the changes in the absorbance value at a wavelength of 664 nm were observed using UV-visible absorption spectroscopy at different time points of 0, 5, 10, and 20 min. The results are shown in Fig.13It can be observed that within 20 minutes, the difference in absorbance value change at 664 nm of BiFeOx in Comparative Example 3 is smaller than that in Example 1, and less ·OH is generated. The POD-like enzyme activity of BiFeOx in Comparative Example 3 is inferior to that in Example 1.

[0105] The various aspects, embodiments, and features of the present invention should be considered to be illustrative in all aspects and not limiting of the present invention, the scope of which is defined solely by the claims. Other embodiments, modifications, and uses will be apparent to those skilled in the art without departing from the spirit and scope of the claimed invention.

[0106] In the preparation method of the present invention, the order of each step is not limited to the order listed. For those skilled in the art, without creative work, the order of each step is also within the protection scope of the present invention. In addition, two or more steps or actions can be performed simultaneously.

[0107] Finally, it should be noted that the specific embodiments described herein are merely examples of the present invention, and are not intended to limit the implementation methods of the present invention. A person skilled in the art of the present invention may make various modifications or supplements to the specific embodiments described, or replace them in a similar manner. It is not necessary and impossible to provide all examples of all implementation methods here. However, these obvious changes or modifications derived from the essential spirit of the present invention still fall within the scope of protection of the present invention, and interpreting them as any additional limitation is contrary to the spirit of the present invention.

Claims

1. A bismuth iron oxide multimodal imaging probe, characterized in that: The molecular formula of the bismuth iron oxide multimodal imaging probe is BiFeO x , wherein x is 2.5 to 3.5, and its hydrated particle size is 10 to 900 nm; The iron bismuth oxide multimodal imaging probe has both CT imaging and MRI imaging functions; The iron bismuth oxide multimodal imaging probe has POD-like activity, CAT-like activity and GSH-Px-like activity at the same time.

2. A method for preparing a bismuth iron oxide multimodal imaging probe, characterized in that: The following steps are involved: Dissolving bismuth nitrate in a mannitol solution, and then adding a polymer to form a solution A, wherein the polymer is polyvinyl pyrrolidone and / or polyacrylic acid; Dissolve ferric nitrate in mannitol solution to form solution B; Solution B is dropped into solution A to form solution C, and then ammonia water is added. After the reaction, the reaction solution is treated at a high temperature of 130 to 200° C. for 10 to 30 hours. After cooling, the solution is washed to obtain an iron bismuth oxide multimodal imaging probe.

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

4. The preparation method according to claim 2, characterized in that: The mass ratio of the high molecular polymer to bismuth nitrate is 1:1.5-10; And / or, the molecular weight of the high molecular weight polymer is 2,000 to 20,000.

5. The preparation method according to claim 2, characterized in that: In solution C, the molar ratio of bismuth nitrate to ferric nitrate is 1:0.8-1.

2.

6. The preparation method according to claim 2, characterized in that: In solution C, the molar ratio of bismuth nitrate to ferric nitrate is 1:

1.

7. The preparation method according to claim 2, characterized in that: The concentration of ammonia water is 25-28 wt%; And / or, the volume ratio of ammonia water to C solution is 1:20-100.

8. The preparation method according to claim 2, characterized in that: After adding ammonia water, react at 15-40°C for 10-60 minutes.

9. The preparation method according to claim 2, characterized in that: The molecular formula of the prepared iron bismuth oxide multimodal imaging probe is BiFeO x , where x is 2.5 to 3.5; And / or, the hydrated particle size of the prepared iron bismuth oxide multimodal imaging probe is 10 to 900 nm; And / or, the prepared iron bismuth oxide multimodal imaging probe has both CT imaging and MRI imaging functions; And / or, the prepared iron bismuth oxide multimodal imaging probe simultaneously has POD-like activity, CAT-like activity and GSH-Px-like activity.

10. Use of the bismuth iron oxide multimodal imaging probe according to claim 1 or the bismuth iron oxide multimodal imaging probe prepared by the preparation method of claim 2 in preparing a contrast agent for multimodal imaging of tumors, or in preparing a drug for treating tumors.

Images