CN-121554767-B - Metal organic framework material for chelating alpha nuclide, preparation method thereof and application thereof in antitumor drugs

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a metal organic framework material for chelating alpha nuclide, a preparation method thereof and application thereof in antitumor drugs, wherein the preparation method of the metal organic framework material comprises the steps of dissolving ferric chloride tetrahydrate and 2, 5-dihydroxyl-1, 4-benzenedicarboxylic acid in an organic solvent according to a molar ratio of 2:3, and reacting for 24 hours at 105 ℃. The key of the invention is that the metal organic framework material is used as a novel 223 Ra chelating platform, the efficient capture and stable loading of 223 Ra can be realized without depending on a traditional chelating mechanism, the chelating difficulty caused by the intrinsic property of Ra < 2+ > ions is effectively solved, the stability and targeting of 223 Ra radiopharmaceuticals are improved, and the radiation exposure risk of non-target organs is remarkably reduced.

Inventors

• YU FEI
• JIN YAO
• XIE YUNFEI
• ZHANG JIAJIA
• ZHANG WEI
• LU KEYI
• WANG KAITAO
• He Limeng
• QIN SHANSHAN
• SONG ZHILING
• LUAN XIAOHUI

Assignees

• 四川省医学科学院·四川省人民医院
• 上海市第十人民医院

Dates

Publication Date

20260505

Application Date

20260122

Claims (8)

1. 1. A 223 Ra radioactive nano-drug is characterized by comprising a metal-organic framework material and 223 Ra nuclide chelated on the metal-organic framework material; The metal organic framework material comprises ferric chloride tetrahydrate and 2, 5-dihydroxyl-1, 4-benzene dicarboxylic acid which are dissolved in an organic solvent according to a molar ratio of 2:3, and is heated to 105 ℃ by an oil bath heating method, reacted for 24 hours, and centrifugally separated to obtain the dark brown metal organic framework material.
2. 2. The 223 Ra radiopharmaceutical of claim 1, wherein said organic solvent is a mixed solution of N, N-dimethylformamide, 2-propanol and water.
3. 3. A method for preparing 223 Ra radiopharmaceuticals according to claim 1, comprising contacting a metal organic framework material with a solution containing 223Ra2+ ions, and separating to obtain said 223 Ra radiopharmaceuticals.
4. 4. The method according to claim 3, wherein the contact reaction is stirring or shaking at a temperature of room temperature to 60 ℃ for 1 to 48 hours.
5. 5. The method of claim 4, wherein the metal organic framework material is present in the solution at a concentration of 0.1-10 mg/mL.
6. 6. A method according to claim 3, wherein the solution is ethanol.
7. 7. Use of 223 Ra radiopharmaceuticals as claimed in claim 1 in the preparation of antitumor drugs.
8. 8. A pharmaceutical composition for treating tumors comprising a therapeutically effective amount of the 223 Ra radiopharmaceutical of claim 1 and an anti-PD-L1 antibody.

Description

Metal organic framework material for chelating alpha nuclide, preparation method thereof and application thereof in antitumor drugs Technical Field The invention belongs to the technical field of biological medicine, and in particular relates to a metal organic framework material for chelating alpha nuclide, a preparation method thereof and application thereof in antitumor drugs. Background Radium-223 (223 Ra) is the first alpha nuclide radiopharmaceutical obtained worldwide and has remarkable curative effect in the bone metastasis treatment of the prostate cancer. The characteristics of high Linear Energy Transfer (LET), short range, hypoxia tolerance and the like can efficiently induce tumor cells to generate irreparable DNA Double Strand Breaks (DSBs), thereby realizing precise killing and protecting surrounding normal tissues. However, the Ra 2+ ion radius is larger, the charge density is low, the electrostatic combination effect between the Ra 2+ ion and the chelating agent is weakened, the in vivo stability of the compound is insufficient, and the expansion of clinical application and the improvement of curative effect are severely limited. To advance the 223 Ra targeted alpha therapy, the us oak-ridge national laboratory developed a novel 21-membered macrocyclic ligand macropa-XL for chelation 223Ra2+. However, the affinity to 223Ra2+ is still low due to free energy loss, and the stability of the complex is poor. The "chelation problem" caused by the intrinsic nature of ions is to be broken through, and development of a novel efficient carrier independent of the traditional strong electrostatic action is needed. Disclosure of Invention The invention aims to provide a metal organic framework material for chelating alpha nuclide, a preparation method thereof and application thereof in anti-tumor drugs, and the metal organic framework material realizes high-efficiency capturing and stable loading of Ra 2+ through unique structural characteristics, provides a carrier foundation for tumor targeted therapy and effectively reduces radiation exposure risk of non-target organs. In order to achieve the above purpose, the invention adopts the following technical scheme: A process for preparing the metallic-organic frame material used to chelate alpha nuclide includes such steps as dissolving ferrous chloride tetrahydrate and 2, 5-dihydroxy-1, 4-benzenedicarboxylic acid in organic solvent according to mole ratio of 2:3, heating to 105 deg.C by oil bath heating, reacting for 24 hr, and centrifugal separation. The metal organic framework material prepared by the invention has a highly adjustable nano pore canal structure, is used for precisely matching specific ion sizes, is rich in negative charge sites on the surface, generates strong electrostatic attraction to target ions, has high-density Fe 3+ coordination unsaturated sites, enhances adsorption capacity through an ion exchange mechanism, has a high specific surface area, and provides a structural basis for multi-active site distribution. The efficient capturing and stable loading of 223Ra2+ can be realized without depending on a traditional strong electrostatic chelating mechanism, the multiple action mechanism overcomes the chelating difficulty caused by the intrinsic property of 223 Ra, improves the stability and the targeting performance of the radioactive drug, and obviously reduces the radiation exposure risk of non-target organs. By utilizing the height-adjustable nano pore channel structure, the surface negative charge site and the high-density Fe 3+ coordination unsaturated site of the metal organic framework material, the efficient capturing and stable loading of 223Ra2+ is realized through ion exchange adsorption, namely the metal organic framework material is contacted with a solution containing 223Ra2+ ions, and the 223 Ra radioactive nano-drug can be obtained. Combining 223 Ra alpha particle radiation and Fe 3+ to catalyze the chemo-dynamic therapy (CDT) effect of H 2O2 to generate hydroxyl radical (OH) forms a synergistic mechanism of 'alpha radiation-chemical kinetics' dual action, the two effects synergistically act to remarkably amplify DNA damage and oxidative stress level of tumor cells and overcome the efficiency bottleneck of monotherapy. The combination of 223 Ra radioactive nano-drug and PD-L1 resistant drug can obviously improve the intensity and the persistence of anti-tumor immune response. The anti-PD-L1 medicine can block PD-1/PD-L1 passage, reduce the immune escape of tumor cells and make the immune response induced by the 223Ra radioactive nano medicine more effective. The apoptosis induced by the 223Ra radioactive nano-drug releases a large amount of tumor antigens, while the PD-L1 resisting drug enhances the activation of T cells, and the synergistic effect of the two can obviously improve the treatment effect. Experiments show that the traditional Chinese medicine composition not only can effectively inhibit primary tumors, b