A bismuth-based imaging contrast agent and its preparation method

Abstract

This invention belongs to the field of CT imaging technology and relates to a bismuth-based imaging contrast agent and its preparation method. The bismuth-based imaging contrast agent is formed by chelating bismuth ions with DTPA modified with aminosulfonic acid, followed by surface-linking with an antibody. The preparation method includes: a first reaction of DTPA and aminosulfonic acid in the presence of an activator to obtain aminosulfonic acid-modified DTPA; a second reaction of DTPA with an inorganic bismuth salt in a second solvent, followed by pH adjustment to neutral and drying to obtain aminosulfonic acid-modified DTPA chelated with bismuth ions; and a third reaction of the aminosulfonic acid-modified DTPA chelated with bismuth ions with an antibody, followed by drying. The CT imaging contrast agent exhibits excellent CT imaging capabilities, high safety, and tumor cell killing ability.

Description

Technical Field

[0001] This invention belongs to the field of CT imaging technology and relates to a bismuth-based imaging contrast agent and its preparation method. Background Technology

[0002] CT imaging offers very high spatial resolution, providing doctors with detailed information about a patient's anatomy and supporting 3D reconstruction. However, for certain soft tissues, especially those with similar densities, CT resolution is limited and may be difficult to distinguish. To improve CT imaging, contrast agents are widely used in clinical practice. These contrast agents typically enhance the contrast between soft tissues and other structures, allowing doctors to more clearly identify abnormal areas and improve disease diagnosis and treatment planning. Currently, the most commonly used CT contrast agent is iodine-based. However, iodine-based contrast agents have the following drawbacks: 1. Iodine-based contrast agents often trigger allergic reactions of varying degrees, especially in patients allergic to iodine or contrast agent components. Allergic reactions may manifest as rashes, itching, shortness of breath, or even severe anaphylactic shock. 2. Another significant drawback of iodine-based contrast agents is their potential nephrotoxicity, especially in patients with renal insufficiency or chronic kidney disease. This side effect is known as "contrast-induced nephropathy." 3. Iodine-based contrast agents still have limited biocompatibility, particularly regarding their metabolism and excretion by organs such as the liver and kidneys, which may impose a burden. Long-term, frequent use may lead to cumulative toxicity. 4. Although iodine-based contrast agents provide good imaging results, they lack targeting specific tumors or other lesions and are metabolized rapidly in vivo. For certain types of tumors, conventional CT scans may not provide sufficient contrast or information, limiting the accuracy of their diagnosis and treatment assessment. 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, particularly in some low-income countries or regions, which may limit their widespread use. Therefore, there is a need to develop novel contrast agents.

[0003] Bismuth (Bi) has an atomic number of 83, significantly higher than common CT contrast agents (such as iodine and barium). This high atomic number allows bismuth-based nanomaterials to effectively enhance X-ray absorption, thus providing higher image contrast. This means that bismuth-based nanomaterials can more clearly reveal details of low-density structures such as soft tissues and blood vessels, improving diagnostic accuracy. Bismuth itself is considered a relatively safe element with low toxicity to humans and is easily metabolized and excreted through the kidneys. Compared to 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 vivo, reducing the burden of contrast agents on organs such as the kidneys and liver, and lowering the risk of adverse reactions. Furthermore, bismuth is abundant in my country, providing a relatively inexpensive source of raw materials. Summary of the Invention

[0004] To address the problems existing in contrast agents in the prior art, the present invention aims to provide a bismuth-based imaging contrast agent and its preparation method, thereby overcoming the shortcomings of the prior art.

[0005] The first objective of this invention is to provide a bismuth-based imaging contrast agent formed by bismuth ions chelated by DTPA modified with aminosulfonic acid.

[0006] Preferably, the aminosulfonic acid-modified DTPA chelates bismuth ions by a second reaction between aminosulfonic acid-modified DTPA and 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 inorganic bismuth salt is 1 to 5:1, more preferably 1.5 to 4:1.

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

[0009] Preferably, the temperature of the second reaction is 60–120°C, more preferably 70–100°C; the reaction time 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, with stirring speeds ranging from 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 aminosulfonic acid-modified DTPA is obtained by a first reaction of diethylenetriaminepentaacetic acid (DTPA) and aminosulfonic acid in the presence of an activator.

[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 to 5, more preferably 1:0.3 to 3, and even more preferably 1:0.5 to 2.

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

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

[0017] Preferably, the entire first reaction is carried out in a first solvent, which is any polar solvent capable of dissolving the reactants, such as one or more of dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), acetonitrile, tetrahydrofuran, and acetone.

[0018] A second objective of this 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 attaching an antibody to its surface.

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

[0020] Antibodies are anti-tumor markers. Tumor markers can include CEA (carcinoembryonic antigen), CA125, PSA (prostate-specific antigen), AFP (alpha-fetoprotein), CA19-9, EGFR (epidermal growth factor receptor), etc.

[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. The tumor can then be located and assessed using CT imaging, achieving high-quality directional CT imaging.

[0022] Preferably, the surface-linked antibody step includes: a third reaction in which DTPA-chelated bismuth ions modified with aminosulfonic acid are reacted with the antibody.

[0023] Preferably, the mass ratio of bismuth ions chelated by DTPA modified with aminosulfonic acid to the antibody is 5–15:1.

[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 takes place in a third solvent, such as water or dimethyl sulfoxide (DMSO).

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

[0027] A third objective of this 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 the first solvent, and then an activator is added to carry out the first reaction. After drying, aminosulfonic acid modified DTPA is obtained.

[0029] S2. The aminosulfonic acid-modified DTPA and inorganic bismuth salt are mixed in a second solvent to carry out a second reaction. Then the pH is adjusted to 7±0.5 and dried to obtain the bismuth-based imaging contrast agent.

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

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

[0032] S1, DTPA and aminosulfonic acid are dissolved in the first solvent, and then an activator is added to carry out the first reaction. After drying, aminosulfonic acid modified DTPA is obtained.

[0033] S2. The aminosulfonic acid-modified DTPA and inorganic bismuth salt are mixed in the second solvent to carry out the second reaction. Then the pH is adjusted to 7±0.5 and dried to obtain aminosulfonic acid-modified DTPA chelating bismuth ions.

[0034] S3. The aminosulfonic acid-modified DTPA chelated bismuth ions and the antibody are dissolved in a third solvent to carry out a third reaction, and then dried to obtain the bismuth-based imaging contrast agent.

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

[0036] Preferably, the mass ratio of bismuth ions chelated by DTPA modified with aminosulfonic acid to the antibody is 5–15:1.

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

[0038] 1. This invention modifies DTPA with aminosulfonic acid and then chelates bismuth ions to form a CT imaging contrast agent Bi-DTPA-NH-SO3H, which has superior CT imaging capabilities compared to Bi-DTPA without aminosulfonic acid modification, achieving low-dose, high-quality CT imaging.

[0039] 2. In this invention, after forming Bi-DTPA-NH-SO3H, an antibody is further attached to its surface to form an antibody-Bi-DTPA-NH-SO3H CT imaging contrast agent. The antibody can specifically bind to the surface of tumor cells expressing tumor markers; therefore, this CT imaging contrast agent can achieve directional imaging. The tumor can then be located and assessed using CT imaging, achieving 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 dispersion and targeting of the contrast agent in vivo, enabling it to reach the target tissue or cells better, thereby further improving the imaging effect.

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

[0042] 5. The CT contrast agent formed by this invention has good biocompatibility and low toxicity due to Bi content. In its small molecule chelate form, it is more stable in vivo and less prone to harmful interactions with other molecules, reducing potential tissue damage. Simultaneously, bismuth is metabolized mildly in vivo and is less likely to accumulate in the kidneys or other organs, potentially making it a safer contrast agent option for patients with renal insufficiency. Since it does not contain iodine, this contrast agent does not directly affect thyroid function, avoiding iodine-related thyroid risks and making it suitable for a wider range of patients, especially those with thyroid disease. Therefore, the CT contrast agent provided by this invention has higher safety. Attached Figure Description

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

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

[0045] Figure 3 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 In vivo CT images of Anti-CEA-Bi-DTPA-NH-SO3H prepared in Example 2;

[0048] Figure 6 Cell therapy diagrams (live / dead staining diagrams) of Bi-DTPA-NH-SO3H prepared in Example 1 and Anti-CEA-Bi-DTPA-NH-SO3H prepared in Example 2. Detailed Implementation

[0049] 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.

[0050] Example 1

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

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

[0053] S2. Mix Bi(NO3)3 (1 mmol) and DTPA-NH-SO3H (2 mmol) in 30 mL of H2O and stir vigorously at 80 °C (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 of the reaction solution to neutral (around 7) with ammonia water and freeze-dry the Bi-DTPA-NH-SO3H product.

[0054] The Bi-DTPA-NH-SO3H product was freeze-dried into a powder. A separate sample of pure DTPA was taken, and both were analyzed using an infrared spectrometer. The infrared spectra are shown below. Figure 1 As shown in the figure. By comparing the infrared absorption peaks of the two, the successful preparation of Bi-DTPA-NH-SO3H can be confirmed.

[0055] Comparative Example 1

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

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

[0058] Based on the bismuth concentration, 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 with the same concentration gradient were prepared using 5 ml centrifuge tubes. The tubes were arranged in ascending order of concentration in a centrifuge rack, and plain X-ray computed tomography (CT) images of Bi-DTPA-NH-SO3H and Bi-DTPA aqueous dispersions were obtained using a clinical computed tomography scanner with a scan width of 2 cm. CT intensity measurements and analyses of the CT images at different concentrations were performed using specialized software to obtain CT images of Bi-DTPA-NH-SO3H and Bi-DTPA at different concentrations, as shown below. Figure 2 As shown in (A), it can be observed that the CT signals of both increased with increasing bismuth ion concentration. When the bismuth ion concentration reached 7.5 mM, the CT signal enhancement ability of Bi-DTPA-NH-SO3H was significantly stronger than that of Bi-DTPA. Furthermore, after analysis, the trend graphs of the CT signal values ​​of Bi-DTPA-NH-SO3H and Bi-DTPA as a function of concentration are obtained, as shown in (A). Figure 2As shown in (B), it can be seen that the slope of the linear change of CT signal of Bi-DTPA-NH-SO3H with concentration is significantly stronger than that of Bi-DTPA, indicating that Bi-DTPA-NH-SO3H has a superior CT imaging capability compared to Bi-DTPA.

[0059] Example 2

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

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

[0062] S2. Mix Bi(NO3)3 (1 mmol) and DTPA-NH-SO3H (2 mmol) in 30 mL of H2O and stir vigorously at 80 °C (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 of the reaction solution to neutral (around 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 and dissolve it in 10 mL of water. Sonicate until the sample is completely dissolved. Add 1 mg of anti-CEA antibody to the solution and stir magnetically at 37°C for 12 hours. Freeze-dry the sample for later use to obtain Anti-CEA-Bi-DTPA-NH-SO3H.

[0064] The Anti-CEA-Bi-DTPA-NH-SO3H nanoparticles from Example 2, diluted 10-fold, were dropped onto a copper grid and placed in an oven at 45°C for 24 hours. Their size and morphology were then observed using a transmission electron microscope. Figure 3 As shown, the nanoparticles are uniformly dispersed and have a size of approximately 3–5 nm.

[0065] The Anti-CEA-Bi-DTPA-NH-SO3H nanoparticles from Example 2, diluted 10-fold, were dropped onto a copper grid and placed in an oven at 45°C for 24 hours. The elemental mapping was then performed using a Talos transmission electron microscope. Figure 4 As shown, elemental characterization results confirm 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 anesthetizing the mice with a 5% chloral hydrate solution via intraperitoneal injection, 100 μL of Anti-CEA-Bi-DTPA-NH-SO3H (dispersed in PBS, bismuth concentration 30 mg / kg) from Example 2 was injected via the tail vein. Six hours after injection, CT scans were performed on the tumor-bearing mice using Micro-CT, and tumor CT images were recorded before and after injection, as shown below. Figure 5 As shown, a significant enhancement of CT signal at the tumor site can be observed after injection.

[0067] Cell therapy experiments:

[0068] Cell status was determined 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 and different groups were set up: (1) Control, no treatment was performed and incubation continued for 24 h; (2) Bi-DTPA-NH-SO3H group, after adding complete culture medium containing Bi-DTPA-NH-SO3H from Example 1, incubation continued for 24 h; (3) Anti-CEA-Bi-DTPA-NH-SO3H group, after adding complete culture medium containing Anti-CEA-Bi-DTPA-NH-SO3H, incubation continued for 24 h.

[0069] The concentration of Bi was 200 μg / mL for all experiments. All HT29 cells in all experimental groups were stained with Calcein-AM / PI working solution at 3°C ​​for 30 min. Finally, the fluorescence signal of the cells was observed using a laser confocal microscope to assess cell viability. Figure 6 As shown in the figure, 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 in this embodiment is prepared by the following steps:

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

[0073] S2. Mix BiCl3 (1 mmol) and DTPA-NH-SO3H (2.5 mmol) in 40 mL of H2O and stir vigorously at 90 °C (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 of the reaction solution to neutral (around 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 and dissolve it in 20 mL of water. Sonicate until the sample is completely dissolved. Add 1.5 mg of anti-EGFR antibody to the solution and stir magnetically at 37 °C for 10 hours. Freeze-dry the sample for later use to obtain Anti-EGFR-Bi-DTPA-NH-SO3H.

[0075] 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.

[0076] 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.

[0077] 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 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.

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 attaching antibodies to the surface.

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

4. The 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 to 5, and the molar ratio of DTPA to activator is 1:0.1 to 1; And / or, the temperature of the first reaction is 90–160°C, and the time of the first reaction is 2–20 h; And / or, the first reaction is carried out in a first solvent, which is a polar solvent capable of dissolving the reactants; And / or, the molar ratio of aminosulfonic acid-modified DTPA to inorganic bismuth salt is 1 to 5:1; And / or, the temperature of the second reaction is 60–120°C, and the time of the second reaction is 1–10 h; 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 surface-linked antibody step includes a third reaction in which bismuth ions chelated with aminosulfonic acid-modified DTPA are reacted with the antibody.

6. The bismuth-based imaging contrast agent according to claim 5, characterized in that, Antibodies are anti-tumor markers. And / or, the mass ratio of aminosulfonic acid-modified DTPA-chelated bismuth ions to antibodies is 5–15:1; And / or, the temperature of the third reaction is 20–40°C, and the time of the third reaction is 5–20 h; And / or, the third reaction is carried out in a third solvent, which 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 1–100 nm.

8. A method for preparing a bismuth-based imaging contrast agent, characterized in that, Includes the following steps: S1, DTPA and aminosulfonic acid are dissolved in the first solvent, and then an activator is added to carry out the first reaction. After drying, aminosulfonic acid-modified DTPA is obtained. S2. The aminosulfonic acid-modified DTPA and inorganic bismuth salt are mixed in a second solvent to carry out a second reaction. Then the pH is adjusted to 7±0.5 and dried to obtain the bismuth-based imaging contrast agent.

9. A method for preparing a bismuth-based imaging contrast agent, characterized in that, Includes the following steps: S1, DTPA and aminosulfonic acid are dissolved in the first solvent, and then an activator is added to carry out the first reaction. After drying, aminosulfonic acid-modified DTPA is obtained. S2. The aminosulfonic acid-modified DTPA and inorganic bismuth salt are mixed in the second solvent to carry out the second reaction. Then the pH is adjusted to 7±0.5 and dried to obtain aminosulfonic acid-modified DTPA chelating bismuth ions. S3. The aminosulfonic acid-modified DTPA chelated bismuth ions and the antibody are dissolved in a third solvent to carry out a third reaction, and then dried to obtain the bismuth-based imaging contrast agent.

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

Images