Bismuth-based imaging contrast agent and preparation method thereof

Abstract

The invention belongs to the technical field of CT imaging, and relates to a bismuth-based imaging contrast agent and a preparation method thereof. The bismuth-based imaging contrast agent is formed by chelating diethylenetriamine pentaacetic acid (DTPA) modified by sulfamic acid with bismuth ions and then connecting an antibody to the surface. The preparation method comprises the following steps: carrying out first reaction on DTPA and sulfamic acid in the presence of an activating agent to obtain sulfamic acid modified DTPA; carrying out a second reaction with an inorganic bismuth salt in a second solvent, then adjusting the pH value to be neutral, and drying to obtain aminosulfonic acid modified DTPA chelated bismuth ions; and carrying out third reaction on the DTPA chelated bismuth ions modified by sulfamic acid and an antibody, and drying to obtain the product. The CT imaging contrast agent has excellent CT imaging capability, high safety and tumor cell killing capability.

Description

Technical Field

[0001] The invention belongs to the technical field of CT imaging and relates to a bismuth-based imaging contrast agent and a preparation method thereof. Background Art

[0002] CT imaging provides very high spatial resolution, which can provide doctors with detailed information about the patient's anatomical structure and support 3D reconstruction, but for some soft tissues, especially those with similar density, CT has limited resolution and may be difficult to distinguish. In order to improve the imaging effect of CT, contrast agents are widely used in clinical practice. These contrast agents can generally enhance the contrast between soft tissues and other structures, so that doctors can more clearly identify abnormal areas and improve the diagnosis and treatment planning of diseases. The commonly used CT imaging contrast agents are iodine-based contrast agents, but iodine-based contrast agents have the following disadvantages: 1. Iodine-based contrast agents often cause allergic reactions of varying degrees, especially in patients who are allergic to iodine or contrast agent components. The manifestations of allergic reactions may include rash, itching, shortness of breath, and even severe anaphylactic shock. 2. Another significant disadvantage of iodine-based contrast agents is the potential toxicity to the kidneys, especially in patients with renal insufficiency or chronic kidney disease. This side effect is called "contrast-induced nephropathy." 3. The biocompatibility of iodine-based contrast agents is still limited, especially for the metabolism and excretion of organs such as the liver and kidneys, which may bring certain burdens, and long-term and frequent use may lead to cumulative toxicity. 4. Although iodine-based contrast agents can provide better imaging effects, they do not have the targeting ability for tumors or other lesions, and their metabolism rate in the body is relatively fast. For certain types of tumors, conventional CT scans may not provide sufficiently clear contrast or information, limiting the accuracy of their diagnosis and treatment evaluation. 5. The iodine component of iodine-based contrast agents may affect the liver and thyroid gland, especially in patients with thyroid diseases (such as hyperthyroidism). 6. Iodine-based contrast agents are relatively expensive, especially in some low-income countries or regions, which may limit their popularity and application. Therefore, this raises the need to develop new contrast agents.

[0003] The atomic number of bismuth (Bi) is 83, which is much higher than the common CT contrast agent components (such as iodine, barium, etc.). Its high atomic number enables bismuth-based nanomaterials to effectively enhance the absorption capacity of X-rays, thereby providing higher image contrast. This means that the use of bismuth-based nanomaterials can more clearly present the details of low-density structures such as soft tissues and blood vessels, thereby improving the accuracy of diagnosis. The bismuth element itself is considered to be a relatively safe element, and has low toxicity to the human body and is easily excreted from the body through renal metabolism. Compared with traditional iodine-containing contrast agents (such as iodides), bismuth-based nanomaterials may have better biocompatibility. Studies have shown that bismuth nanomaterials have relatively good biodistribution and metabolism in the body, which can reduce the burden of contrast agents on organs such as the kidneys and liver, and reduce the risk of adverse reactions. In addition, its reserves in my country are abundant, and it has a relatively cheap source of raw materials. Summary of the invention

[0004] In order to solve the problems existing in the contrast agents in the prior art, the object of the present invention is to provide a bismuth-based imaging contrast agent and a preparation method thereof, so as to overcome the deficiencies of the prior art.

[0005] The first object of the present invention is to provide a bismuth-based imaging contrast agent, wherein the bismuth-based imaging contrast agent is formed by chelating bismuth ions with DTPA modified with aminosulfonic acid.

[0006] Preferably, the DTPA chelated bismuth ion modified with aminosulfonic acid is obtained by a second reaction of DTPA modified with aminosulfonic acid with an inorganic bismuth salt in a second solvent, followed by adjusting the pH to 7±0.5 and drying.

[0007] Preferably, the molar ratio of aminosulfonic acid-modified DTPA to the inorganic bismuth salt is 1 to 5:1, more preferably 1.5 to 4:1.

[0008] Examples of the second solvent include water and dimethyl sulfoxide (DMSO).

[0009] Preferably, the temperature of the second reaction is 60-120° C., more preferably 70-100° C.; the time of the second reaction is 1-10 h, more preferably 2-6 h, until the solution becomes clear and transparent.

[0010] The second reaction is carried out under vigorous stirring, and the stirring speed can be exemplified as 500 to 2000 rpm.

[0011] Preferably, the inorganic bismuth salt is one or more of bismuth nitrate, bismuth chloride and bismuth sulfate.

[0012] Preferably, the DTPA modified with aminosulfonic acid is obtained by a first reaction of diethylenetriaminepentaacetic acid (DTPA) and aminosulfonic acid in the presence of an activating agent.

[0013] Preferably, the activator is one or more of 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxysuccinimide (NHS), and N,N'-dicyclohexylcarbodiimide (DCC).

[0014] Preferably, the molar ratio of DTPA to aminosulfonic acid is 1:0.1-5, more preferably 1:0.3-3, and even more preferably 1:0.5-2.

[0015] Preferably, the molar ratio of DTPA to the activator is 1:0.1-1, more preferably 1:0.3-0.8.

[0016] Preferably, the temperature of the first reaction is 90 to 160° C., more preferably 100 to 150° C.; the time of the first reaction is 2 to 20 hours, more preferably 5 to 15 hours.

[0017] Preferably, the entire first reaction is carried out in a first solvent, which is any polar solvent that can dissolve the reaction raw materials, and can be listed as one or more of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), acetonitrile, tetrahydrofuran, and acetone.

[0018] The second object of the present invention is to provide another bismuth-based imaging contrast agent, which is formed by chelating bismuth ions with DTPA modified with aminosulfonic acid and then connecting antibodies on the surface.

[0019] The steps of chelating bismuth ions with aminosulfonic acid-modified DTPA are the same as those described in the first object.

[0020] The antibody is an anti-tumor marker antibody, and examples of tumor markers include CEA (carcinoembryonic antigen), CA125, PSA (prostate-specific antigen), AFP (alpha-fetoprotein), CA19-9, EGFR (epidermal growth factor receptor), and the like.

[0021] The bismuth-based imaging contrast agent includes a surface antibody (anti-tumor marker antibody) that can specifically bind to the surface of tumor cells expressing tumor markers, and then locate and evaluate the tumor through CT imaging to achieve high-quality directional CT imaging.

[0022] Preferably, the step of connecting the antibody to the surface comprises: subjecting the antibody to a third reaction with DTPA chelated with bismuth ions modified with aminosulfonic acid.

[0023] Preferably, the mass ratio of aminosulfonic acid-modified DTPA-chelated bismuth ion to the antibody is 5 to 15:1.

[0024] Preferably, the temperature of the third reaction is 20-40° C., and the time of the third reaction is 5-20 h.

[0025] The third reaction is carried out in a third solvent, and the third solvent may be water or dimethyl sulfoxide (DMSO).

[0026] Preferably, the particle size of the bismuth-based imaging contrast agent is 1 to 100 nm, more preferably 1 to 50 nm, more preferably 1 to 20 nm, more preferably 1 to 10 nm, and even more preferably 1 to 8 nm.

[0027] The third object of the present invention is to provide a method for preparing a bismuth-based imaging contrast agent, comprising the following steps:

[0028] S1, DTPA and aminosulfonic acid are dissolved in a first solvent, and then an activator is added to perform a first reaction, and then dried to obtain aminosulfonic acid-modified DTPA;

[0029] S2. Mixing DTPA modified with aminosulfonic acid and an inorganic bismuth salt in a second solvent for a second reaction, then adjusting the pH to 7±0.5, and drying to obtain the bismuth-based imaging contrast agent.

[0030] Preferably, after the drying in step S1, a purification step of the aminosulfonic acid-modified DTPA is further included, and the purification step comprises: dissolving the aminosulfonic acid-modified DTPA in water at 50-90° C., and then cooling to 2-15° C. for recrystallization.

[0031] A fourth object of the present invention is to provide a method for preparing another bismuth-based imaging contrast agent, comprising the following steps:

[0032] S1, DTPA and aminosulfonic acid are dissolved in a first solvent, and then an activator is added to perform a first reaction, and then dried to obtain aminosulfonic acid-modified DTPA;

[0033] S2, mixing the aminosulfonic acid-modified DTPA and the inorganic bismuth salt in a second solvent, performing a second reaction, then adjusting the pH to 7±0.5, and drying to obtain the aminosulfonic acid-modified DTPA chelated bismuth ion;

[0034] S3, dissolving the aminosulfonic acid-modified DTPA-chelated bismuth ions and the antibody in a third solvent, performing a third reaction, and drying to obtain the bismuth-based imaging contrast agent.

[0035] Preferably, after the drying in step S1, a purification step of the aminosulfonic acid-modified DTPA is further included, and the purification step comprises: dissolving the aminosulfonic acid-modified DTPA in water at 50-90° C., and then cooling to 2-15° C. for recrystallization.

[0036] Preferably, the mass ratio of aminosulfonic acid-modified DTPA-chelated bismuth ion to the antibody is 5 to 15:1.

[0037] Compared with the prior art, the present invention has the following beneficial effects:

[0038] 1. The present invention modifies DTPA with aminosulfonic acid and then chelates bismuth ions to form a CT imaging contrast agent Bi-DTPA-NH-SO3H, which has a superior CT imaging capability than Bi-DTPA that is not modified with aminosulfonic acid, and realizes low-dose, high-quality CT imaging.

[0039] 2. After Bi-DTPA-NH-SO3H is formed in the present invention, an antibody is further connected to the surface to form a CT imaging contrast agent of antibody-Bi-DTPA-NH-SO3H. The antibody can specifically bind to the surface of tumor cells expressing tumor markers. Therefore, the CT imaging contrast agent can achieve directional imaging. The tumor is then located and evaluated through CT imaging to achieve high-quality directional CT imaging.

[0040] 3. The particle size of the CT contrast agent provided by the present invention can be controlled within the range of 1 to 100 nm, preferably 1 to 10 nm. This smaller particle size helps to improve the dispersibility and targeting of the contrast agent in the body, enabling it to better reach the target tissue or cells, thereby further improving the imaging effect.

[0041] 4. The antibody-targeted CT contrast agent (antibody-Bi-DTPA-NH-SO3H) provided by the present invention has better tumor cell killing ability than Bi-DTPA-NH-SO3H without antibody targeting, which makes the contrast agent not only useful for imaging diagnosis, but also has potential application value in tumor treatment, providing new ideas and methods for the comprehensive treatment of tumors.

[0042] 5. The CT contrast agent formed by the present invention has good biocompatibility and low toxicity because Bi itself has good biocompatibility and low toxicity. In the form of small molecule chelates, it is easier to exist stably in the body and is not easy to have harmful interactions with other molecules, reducing potential damage to tissues. At the same time, the bismuth element is relatively mild in the body and is not easy to accumulate in the kidneys or other organs. It may become a safer contrast agent choice for patients with renal insufficiency. Since it does not contain iodine, the contrast agent will not have a direct effect on thyroid function, avoiding iodine-related thyroid risks, and is suitable for more types of patients, especially those with thyroid diseases. Therefore, the CT contrast agent provided by the present invention is safer. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 is the infrared spectrum of Bi-DTPA-NH-SO3H prepared in Example 1;

[0044] Figure 2 The in vitro CT images of Bi-DTPA-NH-SO3H prepared in Example 1 and Bi-DTPA prepared in Comparative Example 1 are shown, wherein (A) is the CT images of the two at different concentrations, and (B) is the trend diagram of the CT signal values ​​of the two as a function of concentration;

[0045] Figure 3 This is a transmission electron microscopy image of Anti-CEA-Bi-DTPA-NH-SO3H prepared in Example 2;

[0046] Figure 4 Mapping diagram of Anti-CEA-Bi-DTPA-NH-SO3H prepared in Example 2;

[0047] Figure 5 This is the in vivo CT imaging image of the Anti-CEA-Bi-DTPA-NH-SO3H prepared in Example 2;

[0048] Figure 6 Cell therapy images (live-dead staining images) of Bi-DTPA-NH-SO3H prepared in Example 1 and Anti-CEA-Bi-DTPA-NH-SO3H prepared in Example 2. DETAILED DESCRIPTION

[0049] 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.

[0050] Example 1

[0051] The CT contrast agent of this embodiment is prepared by the following steps:

[0052] S1. Weigh DTPA (5 mmol) and aminosulfonic acid (5 mmol), mix the two and dissolve them in 100 mL DMSO, add 0.5 g EDC thereto, condense and reflux at 120° C. for 12 h, and after the reaction is completed, obtain the product aminosulfonic acid-modified DTPA (DTPA-NH-SO3H). After freeze-drying the obtained product, dissolve it in 15 mL water, dissolve it under heating at 80° C., recrystallize it at 5° C. after dissolution, and purify DTPA-NH-SO3H.

[0053] S2. Mix Bi(NO3)3 (1 mmol) and DTPA-NH-SO3H (2 mmol) in 30 mL H2O, and react at 80°C with vigorous stirring (1000 rpm) for 4 hours until the solution gradually becomes clear and transparent, indicating that Bi-DTPA-NH-SO3H has been formed. Adjust the pH value of the reaction solution to neutral (about 7) with ammonia water, and freeze-dry the Bi-DTPA-NH-SO3H product.

[0054] The Bi-DTPA-NH-SO3H product was freeze-dried into powder by freeze drying, and some pure DTPA was taken and tested by infrared spectrometer. The infrared spectrum is shown in Figure 1 By comparing the infrared absorption peaks of the two, it can be proved that Bi-DTPA-NH-SO3H was successfully prepared.

[0055] Comparative Example 1

[0056] The CT contrast agent of Comparative Example 1 is prepared by the following steps:

[0057] S1. Mix Bi(NO3)3 (1 mmol) and DTPA (2 mmol) in 30 mL H2O, and react at 80°C with vigorous stirring (1000 rpm) for 4 hours until the solution gradually becomes clear and transparent, indicating that Bi-DTPA has been formed. Adjust the pH value of the reaction solution to neutral (about 7) with ammonia water, and freeze-dry the product to obtain Bi-DTPA CT contrast agent.

[0058] Based on the concentration of bismuth, 5 ml centrifuge tubes were used to prepare different concentrations of Bi-DTPA-NH-SO3H aqueous dispersions (0, 1, 2, 4, 8, 16, 32, 64 mM) provided in Example 1 and Bi-DTPA aqueous dispersions provided in Comparative Example 1 with the same concentration gradient, and arranged in a centrifuge tube rack in order from low to high concentrations. A clinical computed tomography scanner was used for plain scanning with a scanning width of 2 cm to obtain X-ray CI images of Bi-DTPA-NH-SO3H and Bi-DTPA aqueous dispersions of corresponding concentrations. CT intensity measurements and analysis of CT images of different concentrations were performed using professional software to obtain CT images of Bi-DTPA-NH-SO3H and Bi-DTPA at different concentrations, such as Figure 2 As shown in (A). It can be observed that the CT signals of both are enhanced with the increase of bismuth ion concentration. When the bismuth ion concentration reaches 7.5mM, the CT signal enhancement ability of Bi-DTPA-NH-SO3H is significantly stronger than that of Bi-DTPA. After analysis and processing, the trend graph of the CT signal value of Bi-DTPA-NH-SO3H and Bi-DTPA with the concentration change is obtained, as shown in Figure 2As shown in (B), it can be seen that the slope of the straight line of the CT signal of Bi-DTPA-NH-SO3H changing with concentration is significantly stronger than that of Bi-DTPA, indicating that Bi-DTPA-NH-SO3H has superior CT imaging ability than Bi-DTPA.

[0059] Example 2

[0060] The CT contrast agent of this embodiment is prepared by the following steps:

[0061] S1. Weigh DTPA (5 mmol) and aminosulfonic acid (5 mmol), mix the two and dissolve them in 100 mL DMSO, add 0.5 g EDC thereto, condense and reflux at 120° C. for 12 h, and after the reaction is completed, obtain the product aminosulfonic acid-modified DTPA (DTPA-NH-SO3H). After freeze-drying the obtained product, dissolve it in 15 mL water, dissolve it under heating at 80° C., recrystallize it at 5° C. after dissolution, and purify DTPA-NH-SO3H.

[0062] S2. Mix Bi(NO3)3 (1 mmol) and DTPA-NH-SO3H (2 mmol) in 30 mL H2O, and react at 80°C with vigorous stirring (1000 rpm) for 4 hours until the solution gradually becomes clear and transparent, indicating that Bi-DTPA-NH-SO3H has been formed. Adjust the pH value of the reaction solution to neutral (about 7) with ammonia water, and freeze-dry the Bi-DTPA-NH-SO3H product.

[0063] S3. Weigh 10 mg of the prepared Bi-DTPA-NH-SO3H product, dissolve it in 10 mL of water, and sonicate until the sample is completely dissolved; add 1 mg of anti-CEA antibody to the above solution, stir magnetically at 37°C for 12 hours, and freeze-dry the sample for later use to obtain Anti-CEA-Bi-DTPA-NH-SO3H.

[0064] The Anti-CEA-Bi-DTPA-NH-SO3H nanoparticles of Example 2 diluted 10 times were dropped onto a copper mesh and placed in an oven at 45°C for 24 hours. The size and morphology of the nanoparticles were observed using a transmission electron microscope. Figure 3 As shown, it can be observed that the nanoparticles are evenly dispersed and have a size of about 3 to 5 nm.

[0065] The Anti-CEA-Bi-DTPA-NH-SO3H nanoparticles of Example 2 diluted 10 times were dropped onto a copper mesh and placed in an oven at 45°C for 24 hours. The mapping element map was characterized using a Talos transmission electron microscope. Figure 4 As shown. The element characterization results show the presence of bismuth.

[0066] Balb / c nude mice with relatively large tumor volumes were selected as the animal model for in vivo imaging evaluation. After anesthesia with 5% chloral hydrate solution injected into the peritoneal cavity of the mice, 100 μL of Anti-CEA-Bi-DTPA-NH-SO3H (PBS dispersion, bismuth concentration 30 mg / kg) of Example 2 was injected through the tail vein. 6 hours after the injection, the tumor-bearing mice were scanned using Micro-CT, and the tumor CT images before and after the injection were recorded, as shown in FIG. Figure 5 As shown, it can be observed that the CT signal at the tumor site is significantly enhanced after injection.

[0067] Cell therapy experiments:

[0068] The cell status was measured 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 a confocal dish for 24 hours to allow the cells to adhere. Then, the cells were treated differently and divided into different groups: (1) Control, no treatment, and continued incubation for 24 hours; (2) Bi-DTPA-NH-SO3H group, after adding the complete culture medium containing Bi-DTPA-NH-SO3H of Example 1, continued incubation for 24 hours; (3) Anti-CEA-Bi-DTPA-NH-SO3H group, after adding the complete culture medium containing Anti-CEA-Bi-DTPA-NH-SO3H, continued incubation for 24 hours;

[0069] The concentration of Bi was 200 μg / mL. HT29 cells in all experimental groups were stained with Calcein-AM / PI working solution at 3°C ​​for 30 min, and then the fluorescence signal of cells was observed using a laser confocal microscope to evaluate the survival status of cells. Figure 6 Green represents live cells and red represents dead cells. It can be observed that the Anti-CEA-Bi-DTPA-NH-SO3H group has a significant tumor cell killing ability.

[0070] Example 3

[0071] The CT contrast agent of this embodiment is prepared by the following steps:

[0072] S1. Weigh DTPA (5 mmol) and aminosulfonic acid (4 mmol), mix the two and dissolve them in 120 mL DMSO, add 0.3 g NHS thereto, condense and reflux at 110° C. for 15 h, and after the reaction is completed, obtain the product aminosulfonic acid-modified DTPA (DTPA-NH-SO3H). After freeze-drying the obtained product, dissolve it in 20 mL water, dissolve it under heating at 80° C., recrystallize it at 5° C. after dissolution, and purify DTPA-NH-SO3H.

[0073] S2. Mix BiCl3 (1 mmol) and DTPA-NH-SO3H (2.5 mmol) in 40 mL H2O, and react at 90°C with vigorous stirring (1000 rpm) for 5 hours until the solution gradually becomes clear and transparent, indicating that Bi-DTPA-NH-SO3H has been formed. Adjust the pH value of the reaction solution to neutral (about 7) with ammonia water, and freeze-dry the Bi-DTPA-NH-SO3H product.

[0074] S3. Weigh 10 mg of the prepared Bi-DTPA-NH-SO3H product, dissolve it in 20 mL of water, and sonicate until the sample is completely dissolved; add 1.5 mg of anti-EGFR antibody to the above solution, stir magnetically at 37°C for 10 hours, and freeze-dry the sample for later use to obtain Anti-EGFR-Bi-DTPA-NH-SO3H.

[0075] 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.

[0076] 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.

[0077] 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-based imaging contrast agent, characterized in that: The bismuth-based imaging contrast agent is formed by DTPA modified with aminosulfonic acid to chelate bismuth ions.

2. A bismuth-based imaging contrast agent, characterized in that: The bismuth-based imaging contrast agent is formed by chelating bismuth ions with DTPA modified with aminosulfonic acid and then connecting antibodies on the surface.

3. A bismuth-based imaging contrast agent according to claim 1 or 2, characterized in that: The DTPA modified with aminosulfonic acid to chelate bismuth ions is obtained by a second reaction of the DTPA modified with aminosulfonic acid with an inorganic bismuth salt in a second solvent, followed by adjusting the pH to 7±0.5 and drying; The DTPA modified with aminosulfonic acid is obtained by a first reaction of DTPA with aminosulfonic acid in the presence of an activating agent.

4. A bismuth-based imaging contrast agent according to claim 3, characterized in that: The activator is one or more of 1-ethyl-(3-dimethylaminopropyl)carbodiimide, N-hydroxysuccinimide, and N,N'-dicyclohexylcarbodiimide; and / or, the molar ratio of DTPA to aminosulfonic acid is 1:0.1-5, and the molar ratio of DTPA to the activator is 1:0.1-1; And / or, the temperature of the first reaction is 90 to 160° C., and the time of the first reaction is 2 to 20 hours; And / or, the first reaction is carried out in a first solvent, wherein the first solvent is a polar solvent capable of dissolving the reaction raw materials; and / or, the molar ratio of aminosulfonic acid-modified DTPA to the inorganic bismuth salt is 1 to 5:1; And / or, the temperature of the second reaction is 60 to 120° C., and the time of the second reaction is 1 to 10 hours; And / or, the inorganic bismuth salt is one or more of bismuth nitrate, bismuth chloride, and bismuth sulfate; And / or, the second solvent is water and / or dimethyl sulfoxide.

5. A bismuth-based imaging contrast agent according to claim 2, characterized in that: The step of connecting the antibody to the surface comprises: performing a third reaction between the DTPA-chelated bismuth ions modified with aminosulfonic acid and the antibody.

6. A bismuth-based imaging contrast agent according to claim 5, characterized in that: The antibody is an anti-tumor marker antibody; and / or, the mass ratio of aminosulfonic acid-modified DTPA-chelated bismuth ion to the antibody is 5 to 15:1; and / or, the temperature of the third reaction is 20 to 40° C., and the time of the third reaction is 5 to 20 hours; And / or, the third reaction is carried out in a third solvent, and the third solvent is water and / or dimethyl sulfoxide.

7. A bismuth-based imaging contrast agent according to claim 1 or 2, characterized in that: The particle size of the bismuth-based imaging contrast agent is 1 to 100 nm.

8. A method for preparing a bismuth-based imaging contrast agent, characterized in that: The following steps are involved: S1, DTPA and aminosulfonic acid are dissolved in a first solvent, and then an activator is added to perform a first reaction, and then dried to obtain aminosulfonic acid-modified DTPA; S2. Mixing DTPA modified with aminosulfonic acid and an inorganic bismuth salt in a second solvent for a second reaction, then adjusting the pH to 7±0.5, and drying to obtain the bismuth-based imaging contrast agent.

9. A method for preparing a bismuth-based imaging contrast agent, characterized in that: The following steps are involved: S1, DTPA and aminosulfonic acid are dissolved in a first solvent, and then an activator is added to perform a first reaction, and then dried to obtain aminosulfonic acid-modified DTPA; S2, mixing the aminosulfonic acid-modified DTPA and the inorganic bismuth salt in a second solvent, performing a second reaction, then adjusting the pH to 7±0.5, and drying to obtain the aminosulfonic acid-modified DTPA chelated bismuth ion; S3, dissolving the aminosulfonic acid-modified DTPA-chelated bismuth ions and the antibody in a third solvent, performing a third reaction, and drying to obtain the bismuth-based imaging contrast agent.

10. The preparation method according to claim 8 or 9, characterized in that: After the drying in step S1, a purification step of the aminosulfonic acid-modified DTPA is also included, and the purification step includes: dissolving the aminosulfonic acid-modified DTPA in water at 50-90° C., and then cooling to 2-15° C. for recrystallization.

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