A radionuclide-labeled nanocombined therapeutic agent with radiation sensitization, and its preparation method and application

Abstract

This invention belongs to the field of biomedical nanomedicine technology and discloses a radionuclide-labeled nanocombination therapeutic agent with radiation sensitization, its preparation method, and application. The bismuth oxyiodide nanocombination therapeutic agent comprises a nanoparticle carrier, comprising a negatively charged polyvinylpyrrolidone-coated bismuth oxyiodide nanoparticle, and a radionuclide distributed within the lattice of the nanoparticle carrier. The radionuclide is a short-half-life radionuclide. This invention utilizes BiOI nanoparticles to efficiently load the short-half-life radionuclide, combining radiation sensitization with external irradiation, to provide a new, highly effective and low-toxic radiopharmaceutical strategy for tumor treatment.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedical nanomedicines, and in particular relates to a radionuclide-labeled nano combined therapeutic agent with radiation sensitization, and a preparation method and application thereof. Background Art

[0002] Radioactive drugs, with the highly specific and accurate recognition ability of targeted molecules for lesion tissues and the lethal effect of ionizing radiation produced by radionuclides, are effective against primary tumors and metastatic cancer lesions throughout the body. They even have potential therapeutic effects on tiny hidden lesions that are difficult to detect with traditional diagnostic imaging technologies.

[0003] In the field of tumor treatment using radionuclides, the half-life characteristics of the nuclides have a key impact on their therapeutic effects. Some radionuclides, such as 212 Bi, 211 At 212 Pb, etc., have a relatively short half-life. 212 For example, Bi has a half-life of only about one hour. During drug delivery to the tumor, due to its short half-life, the radioactivity of the nuclide may have been significantly reduced, making it impossible to maintain a radiation dose of sufficient intensity and duration in the tumor tissue. This makes it difficult for tumor cells to receive sufficient radiation damage, and thus may not effectively inhibit tumor growth. Furthermore, the short half-life increases the difficulty of drug preparation and clinical use, as it requires a faster and more efficient preparation and administration process to ensure that the treatment is completed before the radioactivity of the nuclide decays. This places extremely high demands on medical technology and time control in actual clinical applications.

[0004] In recent years, with the increasing research in cancer radiotherapy, new methods have been explored to develop highly effective and low-toxic radiosensitizers. Because the X-ray absorption coefficient (μ) is significantly positively correlated with the atomic number (Z), studies have shown that nanoparticles containing high-Z elements such as hafnium (Hf), gold (Au), tantalum (Ta), and bismuth (Bi) have higher mass-energy absorption coefficients than soft tissue, effectively absorbing X-ray energy and increasing the X-ray deposition dose in tumor tissue. These nanoparticles are widely used for radiosensitization. Bismuth-based nanomaterials, in particular, have attracted attention in the biomedical field due to their high biosafety, strong X-ray absorption, and excellent attenuation properties. Hossain's team found that, under identical physical and chemical conditions, bismuth-based nanoparticles exhibited superior radiosensitization effects compared to nanoparticles doped with gold or platinum. Zhang et al. from the University of Shanghai for Science and Technology detailed the synthesis of a novel heterojunction structure (BiPt-PFA) and its potential application in cancer therapy. Experimental data show that this structure exhibits excellent radiosensitization effects. Through glutathione (GSH)-mediated coordination with bismuth (Bi), it can effectively alleviate the hypoxic tumor microenvironment and exhibit good biocompatibility and low toxicity in vivo. Hamed Nosrati et al. from Zanjan University in Iran, dedicated to the research of nanoradiosensitizers, successfully synthesized the Bi2S3@BSA-Fe3O4-FA nanoradiosensitizer. In animal experiments, five mice were treated with a single dose of nanoparticles combined with 4Gy of X-rays. Results showed that within 15 days, three of the five mice achieved complete tumor ablation. In contrast, tumor growth was not effectively inhibited in the control group receiving only conventional 4Gy of X-ray irradiation, highlighting the significant role of this nanoradiosensitizer in enhancing the efficacy of radiotherapy. Yao et al. from Huazhong University of Science and Technology synthesized Bi2Se3-MnO2@BSA composite nanoparticles. The study found that the Bi2Se3 component can enhance the sensitivity of tumor cells to radiotherapy by increasing local energy deposition at the tumor site and inducing more DNA breaks, revealing the key mechanism of action of this composite nanoparticle in radiosensitization at the molecular level. Li et al. from the First Affiliated Hospital of Sun Yat-sen University constructed a functional nanoplatform, BiOI@M; this nanomaterial has the ability to target tumor sites, significantly improving tumor radiosensitivity and reducing toxicity in vivo through rapid clearance from the kidneys. It also has the ability to image tumors using CT, achieving integrated tumor diagnosis and treatment, and providing a new technological path for precision tumor treatment. Summary of the Invention

[0005] The purpose of the present invention is to provide a radionuclide-labeled nano-combined therapeutic agent with radiation sensitization, as well as its preparation method and application. By efficiently loading short-half-life radionuclides on bismuth oxyiodide (BiOI) nanocarriers, combined with radiation sensitization and external irradiation, a new strategy for efficient and low-toxic radiopharmaceuticals is provided for tumor treatment.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] A radionuclide-labeled nanocombined therapeutic agent with radiation sensitization, comprising a nanoparticle carrier, and a radionuclide distributed in the crystal lattice of the nanoparticle carrier;

[0008] The nanoparticle carrier refers to bismuth iodide BiOI with negatively charged polyvinylpyrrolidone PVP wrapped on its surface;

[0009] The radioactive nuclides are short half-life nuclides, specifically 212 Bi, 213 Bi, 212 Pb, 211 At 131 I. 125 One or more of I.

[0010] The radioactive nuclide is stably combined with the nanoparticle carrier by direct doping.

[0011] The present invention uses the high atomic number (Z) of bismuth oxyiodide BiOI to enhance X-ray absorption, generate more secondary electrons, and increase the local radiation dose of the tumor; the radioactive nuclides provide internal irradiation and kill, and combine with external irradiation (X-rays) to achieve a synergistic effect.

[0012] The present invention also provides a method for preparing a radionuclide-labeled nanocombination therapeutic agent with radiation sensitization, comprising the following steps:

[0013] Step 1: Dissolve potassium iodide in ethylene glycol at room temperature and ultrasonically dissolve to form a KI solution.

[0014] Dissolve bismuth nitrate pentahydrate and PVP in ethylene glycol and dissolve them under ultrasonic vibration to form Bi(NO3)3-PVP solution;

[0015] Step 2: After thoroughly mixing the KI solution and the radionuclide X solution, add the Bi(NO3)3-PVP solution and deionized water, and ultrasonicate for 10 minutes to allow the radionuclide to be doped into the BiOI nanoparticle carrier lattice;

[0016] Step 3: centrifugation and washing with deionized water for 3-5 times to obtain radionuclide-labeled bismuth iodide nanocombination therapeutic agent.

[0017] In the present invention, ethylene glycol is selected as a solvent to improve reaction uniformity; PVP is used as a dispersant and stabilizer to prevent particle aggregation and enhance biocompatibility; and radioactive nuclides are introduced synchronously during the synthesis process to ensure uniform distribution.

[0018] The radionuclide-labeled bismuth iodide nanocombination therapeutic agent is used in anti-tumor drugs. The radionuclide-labeled bismuth iodide nanocombination therapeutic agent exhibits relatively excellent stability in an in vitro environment and can maintain a high radiochemical purity within a time range of four half-lives. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 for 212 Figure 2 shows the in vitro test results of Bi-BiOI.

[0020] Figure 2 This is the result of the hemolysis experiment of BiOI.

[0021] Figure 3 for 212 Bi-BiOI and 212 Figure 3 shows the cell binding results of BiCl3.

[0022] Figure 4 For BiOI, 212 BiCl3, 212 Bi-BiOI and 212 Cytotoxicity results of Bi-BiOI superimposed with 6Gy of X-rays. DETAILED DESCRIPTION

[0023] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0024] Example 1

[0025] This embodiment provides a 212 Preparation method of Bi-labeled bismuth iodide BiOI; and 212 Bi-BiOI nanocombined therapeutic agents.

[0026] The preparation method comprises the following steps:

[0027] Step 1: Dissolve 3.32 mg of potassium iodide (KI) in 1 mL of ethylene glycol solution and ultrasonicate until dissolved to form a KI solution.

[0028] Take 97.00 mg of bismuth nitrate pentahydrate Bi(NO3)3·5H2O and 4.00 mg of polyvinylpyrrolidone PVP and dissolve them in 1 mL of ethylene glycol solution, and ultrasonically shake them until they dissolve to form a Bi(NO3)3·5H2O-PVP solution.

[0029] Step 2: Add 150 μCi of radioactivity 212 After the Bi aqueous solution and the KI solution were fully mixed, Bi(NO3)3·5H2O-PVP solution was added, ultrasonically shaken for 10 minutes, centrifuged, and the precipitate was washed with deionized water for 3-5 times to obtain 212 The radioactivity yield of Bi-BiOI nanocombined therapeutic agent is about 78.46%.

[0030] Example 2

[0031] This embodiment provides a method for preparing bismuth iodide BiOI, comprising the following steps:

[0032] Step 1: Dissolve 3.32 mg of potassium iodide (KI) in 1 mL of ethylene glycol solution and ultrasonicate until dissolved to form a KI solution.

[0033] Step 2: Mix the KI solution and Bi(NO3)3·5H2O-PVP solution, add 1 mL of deionized water, ultrasonicate for 10 minutes, and centrifuge. Wash the precipitate 3-5 times with deionized water to obtain the nanoparticle carrier BiOI with a yield of about 20%.

[0034] The prepared in Example 1 212 The Bi-BiOI nanocomposite therapeutic agent was added to PBS buffer and 20% fetal bovine serum to test its in vitro stability. Figure 1 As shown, the results showed that the in vitro stability in PBS buffer and fetal bovine serum remained at 96.57% and 96.16%, respectively.

[0035] The nanoparticle carrier BiOI prepared in Example 2 was added into a PBS buffer solution containing 4% red blood cells in a gradient concentration order. Figure 2 As shown, the results showed that BiOI at each concentration exhibited no significant hemolytic activity, and the hemolysis rate was less than 5%, indicating that it is highly safe in biomedical applications and meets the safety requirements of injections.

[0036] Will 212 Bi-BiOI nanocomposite therapeutics 212 BiCl3 was added to the pre-seeded 1×10 6Mouse breast cancer 4T1 cells were incubated in a six-well plate for 12 hours. After the drug incubation process was completed, sample collection and analysis were carried out in an orderly manner at time points such as 10, 30, 60, 120, and 240 minutes. Figure 3 As shown in the results, after 4 hours of incubation, the cells 212 The binding rate of Bi-BiOI reached 12.74%; compared with 212 BiCl3, 212 Bi-BiOI showed a more significant effect in cell binding, highlighting 212 Cell affinity properties of Bi-BiOI.

[0037] Will 212 Bi-BiOI, BiOI and 212 BiCl3 was added in gradient concentrations to pre-seeded 1×10 4 Mouse breast cancer cells 4T1 were cultured in 96-well plates for 24 hours and then incubated for another 24 hours after drug treatment. 212 The Bi-BiOI experimental group received X-ray irradiation with a total dose of 6 Gy and a dose rate of 0.75 Gy / min. Figure 4 As shown in the figure, cytotoxicity analysis shows that when treated with 60μg / mL of non-labeled BiOI nanomaterials, the survival rate of 4T1 cells after 24 hours of incubation is still over 95%, indicating that the material has extremely low cytotoxicity under the current dose gradient. This is significantly different from: 212 Bi-BiOI showed concentration-dependent cytotoxicity to 4T1 cells. When the drug concentration increased to 40 μg / mL, the cell viability tended to plateau. Quantitative detection showed that exposure to 22.20 KBq 212 The 24-hour cell survival rate of Bi-BiOI was 58.07±1.03%, and after superimposing 6Gy of X-ray irradiation, the cell survival rate decreased significantly compared with the single-drug group, reaching a minimum of 24.23±2.37%. The above results indicate that BiOI nanomaterials have a clear radiosensitization effect on X-ray irradiation and can synergistically enhance 212 The killing effect of Bi radionuclide on tumor cells.

[0038] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A radionuclide-labeled nanocombination therapeutic agent with radiation sensitization, characterized in that: comprising a nanoparticle carrier, and a radionuclide distributed in a lattice of the nanoparticle carrier; The nanoparticle carrier refers to bismuth iodide with negatively charged polyvinyl pyrrolidone coated on its surface; The radioactive nuclide is a short half-life nuclide. 212 Bi, 213 Bi, 212 Pb, 211 At 131 I. 125 One or more of I; The nano-combined therapeutic agent uses the high atomic number of bismuth iodide to enhance X-ray absorption, generate more secondary electrons, and increase the local radiation dose of the tumor; the radioactive nuclides provide internal irradiation and kill, and combined with external irradiation to achieve a synergistic effect.

2. The radionuclide-labeled nanocombination therapeutic agent with radiation sensitization according to claim 1, characterized in that: The radioactive nuclide is stably combined with the nanoparticle carrier by direct doping.

3. A method for preparing the radionuclide-labeled nanocombination therapeutic agent with radiation sensitization according to claim 1 or 2, characterized in that: include: Potassium iodide is dissolved in ethylene glycol to form a KI solution, and bismuth nitrate pentahydrate and polyvinyl pyrrolidone are dissolved in ethylene glycol to form a Bi(NO3)3-PVP solution. The radionuclide X aqueous solution and the KI solution are thoroughly mixed, and then the Bi(NO3)3-PVP solution is added. The mixture is ultrasonically shaken for 10 minutes, and then centrifuged to obtain a BiOI-X nanocombination therapeutic agent. The mass ratio of potassium iodide, bismuth nitrate pentahydrate, and polyvinyl pyrrolidone is 3.32:97:

4. The radioactivity of the radionuclide solution is 150 μCi; The radionuclide X is 212 Bi, 213 Bi, 212 Pb, 211 At 131 I. 125 One or more of I.

4. Use of the radionuclide-labeled nano-combination therapeutic agent with radiation sensitization prepared according to the preparation method of claim 3 in the preparation of anti-breast cancer drugs.

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