Manganese-doped zeolite imidazole framework and application thereof in tumor radiotherapy

Abstract

The invention belongs to the technical field of biological medicine, and particularly relates to a manganese-doped zeolite imidazole framework and application thereof in tumor radiotherapy. According to the present invention, the new use of the manganese-doped zeolite imidazole framework as the tumor radiosensitizer is found, Mn-ZIF-8 has ray responsiveness, can continuously release Mn < 2 + > ions under X-ray irradiation, and can enhance the activation of a cGAS-STING signal channel so as to promote DCs maturation and antigen presentation, and enhance the T cell mediated immune response, such that the tumor treatment effect is enhanced. Furthermore, the invention provides the Mn-ZIF-8 microneedle, the microneedle has the characteristics of rapid dissolution and controlled release, ensures accurate delivery and continuous action of drugs at tumor sites, reduces systemic toxicity, and can significantly amplify local and systemic immune effects caused by radiotherapy and improve the therapeutic effect when used in combination with an immune checkpoint inhibitor.

Description

Technical Field

[0001] The invention belongs to the technical field of biomedicine, and in particular relates to a manganese-doped zeolite imidazole framework and application thereof in tumor radiotherapy. Background Art

[0002] Melanoma is a highly malignant skin tumor that accounts for 72% of skin tumor-related deaths, and its incidence rate is increasing at a rate of 3-5% per year. Although surgical treatment is effective for early melanoma, its invasiveness and high risk of early metastasis lead to poor patient prognosis. Therefore, exploring new treatments and developing effective combination therapies are crucial to improving patient prognosis. In the field of tumor treatment, radiotherapy (RT) is a major treatment method, and its effect is significantly affected by the tumor microenvironment (TME). Physiological barriers in the tumor microenvironment, such as hypoxia, dense extracellular matrix, and immunosuppressive environment, often limit the effect of radiotherapy. Studies have found that radiotherapy (RT) has effective local control of melanoma, and many radiotherapy combined with immunotherapy aims to activate systemic anti-tumor immune responses through radiation-induced in situ tumor vaccines. However, in practice, the synergistic effect of combined therapy is not obvious. Therefore, how to improve the effect of combined therapy has become an urgent problem to be solved in clinical practice.

[0003] The existing technology has the following problems in radiotherapy:

[0004] (1) Limitations of radiotherapy: Although traditional radiotherapy can directly kill tumor cells, it is often unable to effectively eliminate distant micrometastatic lesions, resulting in limited treatment effects.

[0005] (2) Immunosuppression in the tumor microenvironment: Immunosuppressive factors in the tumor microenvironment (TME) limit the immune response activated by radiotherapy and reduce the therapeutic effect.

[0006] Therefore, it is necessary to develop new radiosensitizers to enhance the sensitivity of tumor cells to radiation and activate the body's immune response. Summary of the invention

[0007] The purpose of the first aspect of the present invention is to provide the use of manganese-doped zeolite imidazole framework in the preparation of tumor radiosensitizer products.

[0008] The second aspect of the present invention aims to provide a manganese-doped zeolite imidazole framework.

[0009] The third aspect of the present invention aims to provide a method for preparing a manganese-doped zeolite imidazole framework.

[0010] The fourth aspect of the present invention aims to provide a manganese-doped zeolite imidazole framework microneedle.

[0011] The fifth aspect of the present invention aims to provide a method for preparing manganese-doped zeolite imidazole framework microneedles.

[0012] In order to achieve the above-mentioned purpose of the present invention, the technical solution adopted by the present invention is:

[0013] The first aspect of the present invention provides the use of a manganese-doped zeolite imidazole framework in the preparation of a tumor radiosensitizer product.

[0014] The radiosensitizer means that when radiation is used to treat tumors, there are some tumors that are not very sensitive to radiation, or in other words, these tumors are resistant to radiation. At this time, radiation can be used in combination with a manganese-doped zeolite imidazole framework (as a radiosensitizer) to reverse the tumor's resistance to radiation.

[0015] In some embodiments of the present invention, the mass percentage of Mn in the manganese-doped zeolite imidazole framework is 1 to 30%;

[0016] In some embodiments of the present invention, the mass percentage of Mn in the manganese-doped zeolite imidazole framework is 5-20%.

[0017] In some embodiments of the present invention, the radiosensitizer also includes other substances that improve the effect of tumor radiotherapy; or other tumor treatment drugs, such as immune checkpoint inhibitors (including but not limited to PD-1 antibodies).

[0018] In some embodiments of the present invention, the product further comprises a pharmaceutically acceptable excipient.

[0019] In some embodiments of the present invention, the pharmaceutically acceptable excipients include at least one of solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH regulators, buffers, plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculating agents, filter aids, release retardants, and carriers.

[0020] The above-mentioned pharmaceutically acceptable excipients are generally recognized for this purpose and as inactive ingredients of medicaments. A compilation of pharmaceutically acceptable excipients can be found in reference books such as Handbook of Pharmaceutical Excipients (2nd edition, edited by A. Wade and PJ Weller; published by American Pharmaceutical Association, Washington and The Pharmaceutical 6Gess, London, 1994); Pharmacopoeia - Catalog of Pharmaceutical Excipients.

[0021] In some embodiments of the present invention, the dosage form of the product includes at least one of capsules, tablets, microcapsule preparations, injections, suppositories, sprays, powders, soft capsules, pellets, honey pills, pills, granules, honey pastes, sustained-release preparations, oral liquids, preparations, chewable tablets, buccal tablets, and transdermal microneedles.

[0022] In some embodiments of the present invention, the product is a transdermal microneedle.

[0023] In some embodiments of the present invention, the tumor comprises at least one of a solid tumor and a blood tumor.

[0024] In some embodiments of the present invention, the solid tumor comprises liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal cancer, lung cancer, gastric cancer, adrenal cortical carcinoma, pararenal cortical carcinoma, anal cancer, appendix cancer, astrocytoma, atypical teratoma, rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, bronchial tumor, Burkitt's lymphoma, carcinoid tumor, heart tumor, bile duct epithelial carcinoma, chordoma, colorectal cancer, craniopharyngioma, ductal carcinoma in situ, embryonic tumor, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, intracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fallopian tube cancer, gallbladder cancer, head and neck cancer, hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, Langerhans At least one of: cell histiocytosis, laryngeal cancer, lip cancer, oral cancer, Merkel cell carcinoma, malignant mesothelioma, multiple endocrine neoplasia syndrome, mycosis fungoides, sinonasal cancer, neuroblastoma, non-small cell lung cancer, ovarian cancer, pancreatic neuroendocrine tumors, islet cell tumors, papillomatosis, paraganglioma, sinonasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pituitary tumor, pleuropulmonary blastoma, primary peritoneal cancer, retinoblastoma, salivary gland tumor, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, testicular cancer, thymoma and thymic cancer, thyroid cancer, urethral cancer, uterine cancer, endometrial and uterine sarcoma, vaginal cancer, vascular tumor, vulvar cancer and single myeloma.

[0025] In some embodiments of the present invention, the blood tumor is selected from at least one of B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell or large cell-follicular lymphoma, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia and preleukemia.

[0026] The second aspect of the present invention provides a manganese-doped zeolite imidazole framework.

[0027] In some embodiments of the present invention, the manganese-doped zeolite imidazole framework comprises manganese ions, zinc ions, and 2-methylimidazole.

[0028] In some embodiments of the present invention, the particle size of the manganese-doped zeolite imidazole framework is 113.7-136.9 nm.

[0029] In some embodiments of the present invention, the zeta potential of the manganese-doped zeolite imidazole framework is 21.6-25.7 mV.

[0030] The third aspect of the present invention provides a method for preparing a manganese-doped zeolite imidazole framework.

[0031] Mix zinc salt and manganese salt in a solvent, add the mixed solution dropwise into 2-methylimidazole solution, stir, react at 40-60° C. for 20-120 min, and centrifuge to obtain.

[0032] In some embodiments of the present invention, the zinc salt is Zn(NO 3 ) 2 6H 2 O.

[0033] In some embodiments of the present invention, the manganese salt is Mn(NO 3 ) 2 .

[0034] In some embodiments of the present invention, the molar ratio of zinc to manganese is (5-20):1.

[0035] In some embodiments of the present invention, the solvent comprises an alcohol; preferably methanol.

[0036] A fourth aspect of the present invention provides a manganese-doped zeolite imidazole framework microneedle, comprising a manganese-doped zeolite imidazole framework and a polymerizing agent.

[0037] In some embodiments of the present invention, the polymerizing agent is selected from at least one of polyvinyl pyrrolidone, hyaluronic acid or its salt, polyvinyl alcohol, chitosan, and sodium alginate.

[0038] In some embodiments of the present invention, the mass volume ratio of the polymerization agent to the manganese-doped zeolite imidazole framework is 1:(1-5).

[0039] A fifth aspect of the present invention provides a method for preparing a manganese-doped zeolite imidazole framework microneedle, comprising the following steps:

[0040] 1) mixing a manganese-doped zeolite imidazole framework, a polymerization agent, and a solvent to obtain a needle solution;

[0041] 2) The needle body solution is placed in a microneedle mold and centrifuged to dry to obtain.

[0042] In some embodiments of the present invention, the solvent is methanol.

[0043] In some embodiments of the present invention, the polymerizing agent is selected from at least one of polyvinyl pyrrolidone, hyaluronic acid or its salt, polyvinyl alcohol, chitosan, and sodium alginate.

[0044] In some embodiments of the present invention, the microneedle mold is a conventional device in the art, and those skilled in the art can adjust the size, aperture, spacing and other related parameters of the microneedles according to actual conditions. The microneedle mold is not a limitation of the present invention.

[0045] The beneficial effects of the present invention are:

[0046] The present invention has discovered a new use of manganese-doped zeolite imidazole framework as a tumor radiosensitizer. Mn-ZIF-8 has radiation responsiveness and continuously releases Mn under X-ray irradiation. 2+ ions, enhance the activation of the cGAS-STING signaling pathway, thereby promoting DCs maturation and antigen presentation, enhancing T cell-mediated immune responses, and thus enhancing tumor treatment effects. Furthermore, the present invention provides a Mn-ZIF-8 microneedle, which has rapid dissolution and controlled release properties, ensures the precise delivery and sustained action of drugs at the tumor site, reduces systemic toxicity, and when used in combination with immune checkpoint inhibitors, can significantly amplify the local and systemic immune effects caused by radiotherapy and improve the therapeutic effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The present invention will be further described below with reference to the accompanying drawings and embodiments, wherein:

[0048] Figure 1 The structure and characterization of Mn-ZIF-8, including: (A) Transmission electron microscopy image (TEM) of Mn-ZIF-8, scale bar = 10, 20, 50, 100 nm; (B) High angle annular dark field (HAADF) and corresponding element mapping image (TEM) of Mn-ZIF-8, scale bar = 200 nm; (C) The particle size of ZIF-8 and Mn-ZIF-8 measured by Malvern laser particle size analyzer; (D) Zeta potential of ZIF-8 and Mn-ZIF-8; (E) X-ray diffraction patterns (XRD) of ZIF-8 and Mn-ZIF-8; (F) X-ray photoelectron spectroscopy (XPS) curve of Mn-ZIF-8; (G) XPS spectrum of Mn 2p.

[0049] Figure 2The structure and characterization results of Mn-ZIF-8 microneedles, including: (A) Photo of Mn(20%)-ZIF-8 microneedles, scale bar = 1 nm; (B) Scanning electron microscope images (SEM) of Mn(20%)-ZIF-8 (left) and ZIF-8 (right) microneedles, scale bar = 500 μm; (C) High angle annular dark field (HAADF) and corresponding elemental mapping images (TEM) of Mn(20%)-ZIF-8 microneedles, front view and top view. Figure 2. (D) Dissolution of Mn(20%)-ZIF-8 microneedles after being penetrated into the skin for different time periods, scale bar = 200 μm; (E) Force-displacement curves of Mn(20%)-ZIF-8 and ZIF-8 microneedles; (F) Mechanical compression strength of Mn(20%)-ZIF-8 and ZIF-8 microneedles; (G) H&E stained sections of Mn(20%)-ZIF-8 microneedles penetrated into the abdominal skin of rats, scale bar = 100 μm.

[0050] Figure 3 This is the in vivo imaging of melanoma-bearing mice 1, 2, 6, 12, 24, 48, 72, 96 and 120 hours after the application of Mn-ZIF-8 microneedles. A is the image result and B is the data statistical result.

[0051] Figure 4 The effects of Mn-ZIF-8 on melanoma cell proliferation and dsDNA damage, including: (A) Effects of different concentrations of Mn-ZIF-8 and its components combined with radiotherapy (6Gy) on B16 cell viability; (B) CCK8 method analysis of the effects of PBS, ZIF-8 and Mn-ZIF-8 combined with or without radiotherapy (6Gy) on the proliferation of two melanoma cells; (C) Plate cloning analysis of the effects of PBS, ZIF-8 and Mn-ZIF-8 combined with or without different doses of radiotherapy (2, 4, 6Gy) on the proliferation of two melanoma cells; (D) γ-H2AX immunofluorescence was used to evaluate the effects of PBS, ZIF-8 and Mn-ZIF-8 combined with or without radiotherapy (2Gy) on double-stranded DNA damage in two melanoma cells. Scale bar = 10μm; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0052] Figure 5Mn-ZIF-8 enhanced the activation of ICD and STING pathways induced by RT in vitro, where: (A) and (B) CRT fluorescence intensity and representative fluorescence images of melanoma cells in each group were measured. Scale bar = 10 μm; (C) and (D) HMGB1 fluorescence intensity and representative fluorescence images of melanoma cells in each group were measured, scale bar = 10 μm; (E) ELISA analysis of ATP secretion levels of melanoma cells in each group; (F) Western blot analysis of the activation of cGAS-STING signaling pathway in melanoma cells with different treatments; (G) ELISA analysis of IFN-β secretion levels in melanoma cells with different treatments; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0053] Figure 6 The results of the anti-tumor effect of Mn-ZIF-8 microneedles in the B16 melanoma xenograft mouse model, including: (A) Treatment experiment timeline of C57BL / 6J mice bearing B16 melanoma; (B) Mouse weight change curve during treatment; (C) Photo of B16 tumor isolated from the subcutaneous tissue of mice on the 18th day; (D) Tumor growth curve of mice treated with different treatments; (E) and (F) and (G) Tumor growth curves of each mouse after different treatments; (H) Tumor weight isolated from the subcutaneous tissue of mice on the 18th day; (I) Ki67, CD4+ Tgp1, Tgp2, Tgp3, Tgp4+ Tgp5, Tgp6+ Tgp6+ Tgp7+ Tgp8+ Tgp9+ Tgp10+ Tgp11+ Tgp12+ Tgp13+ Tgp14+ Tgp15+ Tgp16+ Tgp17+ Tgp18+ Tgp19+ Tgp20+ Tgp10+ Tgp10+ Tgp11+ Tgp12+ Tgp13+ Tgp14+ Tgp15+ Tgp16+ Tgp2 ...6+ Tgp11+ Tgp12+ Tgp13+ Tgp14+ Tgp16+ Tgp1 + T and CD8 + T cell infiltration and Foxp3 expression; (J) Mature DCs (CD11c + CD80 in cells + CD86 + ) Quantitative analysis of (K), (L) and (M) tumor infiltrating CD4 + T, CD8 + Percentages of T and Treg cells; (N) and (O) percentages of spleen infiltrating CD4+T and CD8+T cells; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0054] Figure 7Figure 3. Mn-ZIF-8 microneedles combined with RT+ICB induce systemic antitumor immunity, including: (A) Treatment experiment schedule of C57BL / 6J mice bearing bilateral B16 melanoma; (B) Photos of bilateral B16 tumors isolated from mice subcutaneously on day 16; (C) and (D) Weights of primary tumors and metastatic tumors isolated from mice subcutaneously on day 16; (E) and (F) Tumor growth curves of primary tumors and metastatic tumors of mice after different treatments; (G) Mature DCs (CD11c + CD80 in cells + CD86 + ) Quantitative analysis of primary tumor infiltrating CD4 + T, CD8 + Percentages of T and Treg cells; (K), (L) and (M) metastatic tumor infiltrating CD4 + T, CD8 + (N) H&E staining (bar = 100 nm) and immunohistochemical images (bar = 50 nm) of bilateral tumor tissues showing Ki67, CD4 + T and CD8 + T cell infiltration and Foxp3 expression; *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[0055] Figure 8 This is the complete blood cell analysis and blood biochemistry data of mice 18 days after Mn-ZIF-8 microneedle combined with radiotherapy.

[0056] Fig. 9 H&E staining of the main organs of mice 18 days after treatment with Mn-ZIF-8 microneedles combined with radiotherapy; scale bar = 100 μm. DETAILED DESCRIPTION

[0057] The following will be combined with the embodiments to clearly and completely describe the concept of the present invention and the technical effects produced, so as to fully understand the purpose, characteristics and effects of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative work are all within the scope of protection of the present invention.

[0058] The present invention aims to develop a microneedle (MNs) system loaded with manganese-based nanoparticles (Mn-ZIF-8NPs), which can change the tumor microenvironment (TME) to overcome radioresistance and reduce immunosuppression, and the transdermal administration route of microneedles as carriers is expected to improve the transdermal delivery efficiency of drugs and increase the accumulation of drugs in superficial tumor lesions such as melanoma.2+ As an effective activator of the cGAS-STING pathway, it is expected to further activate local and systemic immune responses, improve the anti-tumor efficacy of combined radioimmunotherapy, and provide a new solution for clinical tumor treatment.

[0059] Example 1 Synthesis and Characterization of Mn-ZIF-8 Nanoparticles

[0060] 1. Preparation method

[0061] Weigh 0.5 mM Mn(NO 3 ) 2 ·4H 2 O, 2mmol Zn(NO 3 ) 2 6H 2 O, dissolved in 20mL methanol to obtain mixed solution 1. Weigh 40mM 2-methylimidazole and dissolve it in 80mL methanol. Under magnetic stirring at room temperature, use a pipette to drop the mixed solution 1 drop by drop into the methanol solution of 2-methylimidazole. After the addition is completed, stir at room temperature for 4h, and then keep at 50℃ for 1 hour. 10000rpm, room temperature, centrifuge for 10 minutes, wash the methanol solution twice, and enrich to obtain 20mL of Mn (20%)-ZIF-8 (mass percentage) methanol solution.

[0062] Based on the same preparation method, the Mn(NO 3 ) 2 ·4H 2 O was used to obtain methanol solutions of Mn(5%)-ZIF-8 and Mn(10%)-ZIF-8.

[0063] Contrast combination:

[0064] ZIF-8 nanoparticles: weigh 2.5 mmol of Zn(NO 3 ) 2 6H 2 O, dissolved in 20 mL of methanol to obtain mixed solution 1. Weigh 40 mmol of 2-methylimidazole and dissolve it in 80 mL of methanol. Under magnetic stirring at room temperature, use a pipette to drop the mixed solution 1 drop by drop into the methanol solution of 2-methylimidazole. After the addition is complete, stir at room temperature for 4 hours, and then keep at 50°C for 1 hour. Centrifuge at 10000 rpm, room temperature for 10 minutes, wash the methanol solution twice, and enrich to obtain 20 mL of ZIF-8 methanol solution.

[0065] 2. Structural characterization

[0066] Transmission electron microscopy (TEM) was used to show the morphology and particle size; elemental mapping was used to detect the characteristic elements of Zn, O and Mn; Malvern laser particle size analyzer was used to detect the particle size of NAs; zeta potential analyzer was used to verify the zeta potential of NAs; X-ray diffraction (XRD) diagrams showed the crystal structure of NAs; X-ray photoelectron spectroscopy (XPS) showed the chemical composition, valence state and electronic structure of NAs.

[0067] The results are as follows Figure 1 Transmission electron microscopy (TEM) images show that when Mn 2+ and Mn 4+ After modification, ZIF-8 maintained its original structure of rhombic dodecahedron shape ( Figure 1 (A). Manganese and zinc are distributed throughout the nanoparticles ( Figure 1 The area of ​​manganese is equivalent to a doping rate of 20%, which is consistent with the theoretical value. The hydrodynamic diameters of ZIF-8 and Mn-ZIF-8 ( Figure 1 C) and zeta potential ( Figure 1 D) are almost the same, with average particle sizes of 124.5, 136.9, 113.7, and 123.3 nanometers, and average potentials of 22.7, 24.8, 22.3, and 23.2 mV, respectively. This shows that manganese ion doping does not change the basic properties of ZIF-8 nanoparticles. The X-ray diffraction (XRD) diagrams of ZIF-8 and Mn-ZIF-8 show characteristic diffraction peaks ( Figure 1 In addition, with the increase of Mn doping rate, the main peak (011) of Mn-ZIF-8 gradually shifts to the right, which may be because the zinc ions in the ZIF-8 framework are replaced by manganese ions. The chemical composition and valence state of manganese were analyzed by X-ray photoelectron spectroscopy (XPS). Figure 1 Figure F shows the main corresponding peaks of Zn, Mn and O. Figure 1 Figure G shows the Mn 2p XPS spectrum. The Mn 2p3 / 2 peak can be divided into two characteristic peaks (640.7 and 642.8 eV), which are respectively related to the Mn 2+ and Mn 4+ This indicates that there is Mn in the structure of Mn-ZIF-8. 2+ and Mn 4+ :Mn 2+ The proportion of Mn is 50.05%, 4+ The ratio is 49.95%.

[0068] Example 2 Synthesis and Characterization of Mn-ZIF-8 Microneedles

[0069] 1. Preparation method

[0070] Take 1mL of Mn (20%)-ZIF-8 methanol solution as the needle tip solution. Accurately weigh a certain amount of polyvinylpyrrolidone PVP K90, dissolve it in anhydrous ethanol at a ratio of 1:3.2 (w / v), stir evenly, and swell overnight to obtain a microneedle substrate solution. Place an appropriate amount of needle tip solution on the negative mold, and prepare Mn (20%)-ZIF-8 microneedles using a three-step centrifugation method. Add 200μL / well of needle tip solution to the negative mold, place the negative mold in the cradle of the centrifuge, and centrifuge at 4000rpm at 4-10℃ for 5 minutes to fill the needle tip solution with the microchannels of the negative mold. Then take out the negative mold, use an aluminum spatula to fully scrape off the remaining needle tip solution on the surface of the negative mold, put the negative mold back into the centrifuge, and centrifuge at 4000rpm at 4-10℃ for 30 minutes to fully compress the needle tip solution and dry it to a certain extent. Finally, take an appropriate amount of microneedle substrate solution (300 μL / well) on the negative mold, place it in a centrifuge at 4000 rpm at 4-10°C for 5 minutes, so that the substrate solution evenly covers the microchannels. The negative mold is placed in a desiccator and dried at room temperature for 48 hours. After the microneedles are completely dry, use tweezers to gently remove the Mn (20%)-ZIF-8 microneedles and store them in a desiccator.

[0071] Based on the same preparation method, different needle tip solutions such as Mn (5%)-ZIF-8 and Mn (10%)-ZIF-8 methanol solutions were selected to prepare microneedles with different mass proportions of Mn.

[0072] Contrast combination:

[0073] ZIF-8 microneedles: Take 1 mL of ZIF-8 methanol solution as the needle tip solution. Accurately weigh a certain amount of polyvinylpyrrolidone PVP K90, dissolve it in anhydrous ethanol at a ratio of 1:3.2 (w / v), stir evenly, and swell overnight to obtain the microneedle base solution. Place an appropriate amount of needle tip solution on the negative mold, and prepare ZIF-8 microneedles using a three-step centrifugation method. Add 200 μL / well of needle tip solution to the negative mold, place the negative mold in the cradle of the centrifuge, and centrifuge at 4000 rpm at 4-10 ° C for 5 minutes to fill the needle tip solution with the microchannels of the negative mold. Then take out the negative mold, use an aluminum spatula to fully scrape off the remaining needle tip solution on the surface of the negative mold, put the negative mold back into the centrifuge, and centrifuge at 4000 rpm at 4-10 ° C for 30 minutes to fully compress the needle tip solution and dry it to a certain extent. Finally, take an appropriate amount of microneedle substrate solution (300 μL / well) on the negative mold and centrifuge it at 4000 rpm at 4-10°C for 5 minutes to make the substrate solution evenly cover the microchannels. Place the negative mold in a desiccator and dry it at room temperature for 48 hours. After the microneedles are completely dry, use tweezers to gently remove the ZIF-8 microneedles and store them in a desiccator. 2. Structural characterization

[0074] The morphology of the microneedles was determined using a stereo microscope and a scanning electron microscope (SEM); the corresponding element mapping (TEM) images showed the presence of characteristic elements of Zn and Mn in the microneedles. The Mn-ZIF-8 microneedles were applied to pig skin to dissolve the encapsulated Mn-ZIF-8 nanoparticles, and the micropore insertion and dissolution abilities were examined using a confocal microscope (CLSM); the mechanical properties of the Mn-ZIF-8 microneedles and ZIF-8 microneedles were evaluated using a force measurement system; the Mn-ZIF-8 microneedles were inserted into the abdominal skin of rats, and the skin was sampled and fixed with 4% paraformaldehyde and then stained with H&E to evaluate the insertion ability of the Mn-ZIF-8 microneedles; the drug metabolism time was detected using a small animal in vivo imaging system.

[0075] The results are as follows Figure 2 , 3 As shown. MNs were prepared by a three-step centrifugal casting method. The generated Mn-ZIF-8 microneedles were pyramid-shaped and regularly arranged in a 12×12 array ( Figure 2 Middle A). MNs with a needle height of 1200 μm, a base width of 300 μm, and a tip-to-tip gap of 800 μm were located on a 1 × 1 cm patch ( Figure 2 In addition, the element maps of the front and top views of the microneedles were scanned to study the distribution of Mn and Zn ions in the microneedles. It was observed that most of the Mn and Zn ions were distributed in the needle tip, which may be due to the aggregation of Mn-ZIF-8 in the needle tip under the action of centrifugal force ( Figure 2 The solubility of the microneedles facilitates the release and diffusion of drugs from MNs, thereby improving the drug delivery efficiency. The morphological changes of ZIF-8 and Mn-ZIF-8 microneedles were recorded using optical microscopy, which showed that the microneedles were completely dissolved 8 minutes after application ( Figure 2 (D). The mechanical properties of microneedles are the key factor determining their skin insertion ability. The average breaking forces of Mn-ZIF-8MNs and ZIF-8MNs were 0.3305 N / needle and 0.3285 N / needle, respectively, and the breaking forces of both microneedles were greater than the minimum force required to pierce the stratum corneum (0.1 N / needle) ( Figure 2 E, F). Hematoxylin and eosin (H&E) staining was performed on the rat skin that underwent Mn-ZIF-8 microneedle puncture. Obvious micropores with a depth of 300-340 μm were observed in the H&E-stained skin tissue, indicating that the prepared MNs have good skin penetration ability and can successfully deliver drugs to the dermis ( Figure 2 G). At different times after the Mn-ZIF-8 microneedle was inserted into the subcutaneous tumor, the present embodiment captured the fluorescence images of the IR780-labeled Mn-ZIF-8 ( Figure 3 A) and constructed a fluorescence intensity curve ( Figure 3 The results showed that Mn-ZIF-8 was slowly released, reaching a peak in 1 to 6 hours, and remained in the body for more than 120 hours.

[0076] Example 3: Mn-ZIF-8 nanoparticles can enhance the inhibition of tumor cell growth by radiation

[0077] 1. Experimental methods

[0078] Cell viability assay: B16 and A375 cells (1×10 3 / well) were inoculated in a 96-well plate, 100 μL / well of 1640 / DMEM containing 10% fetal bovine serum was added to support cell growth, and the cells were incubated in a cell incubator at 37°C for 6-8 hours. ZIF-8 / Mn(5%)-ZIF-8 / Mn(10%)-ZIF-8 / Mn(20%)-ZIF-8 nanoparticle stock solutions (the corresponding mass concentrations were 99.5, 78.74, 80.88, and 124.98 mg / ml, respectively) were added to each well, and the nanoparticle concentration in each well of the 96-well plate was prepared to be 10 or 20 μg / ml. An equal volume of PBS was added to the control group, and the cells were incubated for 16 hours, irradiated with X-rays (0 / 2 / 4 / 6 Gy), and after culturing for another 24 hours, 10 μL of CCK (5 mg / mL) stock solution was added to each well, and the cells were incubated at 37°C for 2 hours, and then the absorbance was detected at a wavelength of 450 nm using a multifunctional enzyme marker (TECAN). The relative percentage of untreated cells was adjusted to represent 100% cell viability, and the cell survival curve was calculated and plotted by GraphPad Prism.

[0079] Cell proliferation activity assay: B16 and A375 cells (2×10 3 / well) were inoculated in a six-well plate, 2 mL of 1640 / DMEM containing 10% fetal bovine serum was added to support cell growth, and incubated in a cell incubator at 37°C for 6-8 hours. ZIF-8 / Mn-ZIF-8 (specifically Mn (20%)-ZIF-8 in subsequent experiments) nanoparticle stock solution (the corresponding mass concentrations were 99.5 and 124.98 mg / ml, respectively) was added to each well, and the nanoparticle concentration in each well of the six-well plate was prepared to be 10 or 20 μg / ml. An equal volume of PBS was added to the control group, and the cells were incubated for another 16 hours, irradiated with X-rays (0 / 2 / 4 / 6 Gy), and then further cultured for 10 days. Subsequently, the cells were gently soaked in PBS three times, fixed with 4% paraformaldehyde for 15 minutes at room temperature, and stained with 0.1% crystal violet for 30 minutes. The colonies were imaged under a stereo microscope and analyzed with Image J software, and then the cell clone formation rate histogram was drawn with GraphPad Prism.

[0080] 2. Experimental results

[0081] The results are as follows Figure 4First, the cell survival rate of B16 cells (epithelial cells isolated from the skin of mice with melanoma) treated with 10 or 20 μg / ml of ZIF-8 / Mn(5%)-ZIF-8 / Mn(10%)-ZIF-8 / Mn(20%)-ZIF-8 nanoparticles, or an equal volume of PBS, after 6 Gy X-ray irradiation was evaluated. The analysis of this example found that the cell survival rate was negatively correlated with the drug concentration. The group in which Mn (20%)-ZIF-8 was added, especially at a concentration of 20 μg / mL, had the most obvious inhibitory effect on cell viability, with a cell viability of only 60% of that in the PBS group, and significantly lower than that in the ZIF-8 / Mn (5%)-ZIF-8 / Mn (10%)-ZIF-8 group at a concentration of 20 μg / ml (81.8%, 79.8%, and 64.7%, respectively), indicating that Mn (20%)-ZIF-8 significantly enhanced the cytotoxic effect of radiotherapy ( Figure 4 A). Therefore, ZIF-8 and Mn-ZIF-8 (hereinafter referred to as Mn (20%)-ZIF-8) at a concentration of 20 μg / ml were selected for subsequent studies. Cell counting kit 8 (CCK8) assay showed that Mn-ZIF-8 combined with 6Gy radiotherapy showed significant cytotoxicity to B16 and A375 melanoma cells, and the cell number was only 26.3% and 35.6% of that in the blank control group ( Figure 4 In addition, the colony numbers of B16 and A375 melanoma cells in the ZIF-8 combined with 6Gy radiotherapy group were 5.28% and 5.82% of those in the blank control group, and Mn-ZIF-8 combined with 6Gy radiotherapy had the most significant inhibitory effect on the colony formation of B16 and A375 melanoma cells, with the colony numbers being only 2.75% and 2.3% of those in the blank control group ( Figure 4 In summary, these results suggest that Mn-ZIF-8 can increase the sensitivity of melanoma cells to radiotherapy.

[0082] Example 4 Mn-ZIF-8 nanoparticles can promote radiation-induced DNA damage

[0083] 1. Experimental methods

[0084] B16 and A375 cells (5×10 4 / well) were inoculated in a 24-well plate and incubated in a cell incubator at 37°C for 6-8 hours. 0.5 mL of 1640 / DMEM containing 10% fetal bovine serum was added to each well to support cell growth. They were incubated with Mn-ZIF-8 and ZIF-8 nanoparticles at a concentration of 20 μg / ml for 16 hours, irradiated with X-rays (2Gy), and cultured for another hour. Subsequently, the cells were gently soaked in PBS three times and fixed with 4% paraformaldehyde at room temperature for 15 minutes. Then, they were washed with PBS three times, incubated at room temperature with 0.5% TritonX-100 for 15 minutes, washed with PBS twice, blocked with 5% BSA sealing solution for 1 hour, and anti-γ-H 2 The AX antibody was incubated at 4°C overnight, washed 3 times with PBST, incubated with Alexa fluorescent conjugated secondary antibody at room temperature for 1 hour, washed 3 times with PBST, stained with DAPI for 10 minutes, washed 3 times with PBST, and sealed with mounting medium, observed and photographed under a confocal microscope (Zeiss). Image J was then used for analysis, and GraphPadPrism was used to draw the cell average fluorescence intensity histogram.

[0085] 2. Experimental results

[0086] The results are as follows Figure 4 Immunofluorescence detection of γ-H 2 γ-H2AX foci were used to evaluate DNA damage in melanoma cells. The average number of γ-H2AX foci induced by PBS, ZIF-8, and Mn-ZIF-8 combined with 2 Gy radiotherapy in B16 cell line was 38, 42, and 98, respectively, and the average number of γ-H2AX foci in A375 cell line was 37, 39, and 79, respectively. Figure 4 D). These results suggest that Mn-ZIF-8 can increase radiotherapy-induced DNA damage in melanoma cells.

[0087] Example 5 Mn-ZIF-8 nanoparticles can promote radiation-induced immunogenic cell death and activation of the cGAS-STING pathway to enhance radiation-induced anti-tumor immunity

[0088] 1. Experimental methods

[0089] CRT exposure, HMGB1 release and ATP secretion assays: B16 and A375 cells (5 × 10 4) were inoculated into 24-well plates and incubated in a cell incubator at 37°C for 6-8 hours. 0.5 mL of 1640 / DMEM containing 10% fetal bovine serum was added to each well to support cell growth. They were co-incubated with Mn-ZIF-8 and ZIF-8 nanoparticles at a concentration of 20 μg / ml for 16 hours, irradiated with X-rays (6 Gy), and then further cultured for 24 or 8 hours. Subsequently, the cells were gently soaked 3 times with PBS and fixed with 4% paraformaldehyde at room temperature for 15 minutes. Then, they were washed 3 times with PBS, incubated with anti-HMGB1 / anti-CRT antibodies at 4°C overnight, washed 3 times with PBST, incubated with fluorescently labeled secondary antibodies at room temperature for 1 hour, washed 3 times with PBST, stained with DAPI for 10 minutes, washed 3 times with PBST, and sealed with a sealing agent. They were observed and photographed under a confocal microscope (Zeiss), and then analyzed with Image J, and the cell mean fluorescence intensity histogram was drawn with GraphPadPrism. After irradiation, the cells were cultured for 18 hours, and the cell culture medium was collected and the dead cells in the culture medium were removed by centrifugation. The supernatant was used to quantify the ATP content using an ATP assay kit (Beyotime), and the ATP content histogram was plotted using GraphPad Prism.

[0090] GAS-STING pathway protein expression detection: B16 and A375 cells (1×10 5 ) were inoculated into 6-well plates and incubated in a cell incubator at 37°C for 6-8 hours. 2 mL of 1640 / DMEM containing 10% fetal bovine serum was added to each well to support cell growth. They were incubated with Mn-ZIF-8 and ZIF-8 at a concentration of 20 μg / ml for 16 hours, irradiated with X-rays (6 Gy), and then further cultured for 24 hours. Total protein extracts from cells were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to polyvinylidene fluoride membranes. After blocking with 5% BSA, the membrane was incubated with the primary antibody at 4°C overnight. The membrane was then incubated with the secondary antibody for 60 minutes. The bands were incubated with an ECL kit and analyzed with a luminescent imaging system.

[0091] Cytokine detection: B16 cells (1×10 5 The cells were inoculated with 20 μg / ml Mn-ZIF-8 and ZIF-8 nanoparticles (100 μg / well) into a 6-well plate containing complete medium and incubated in a cell incubator at 37°C for 6-8 hours. 2 mL of 1640 containing 10% fetal bovine serum was added to each well to support cell growth. The cells were incubated with Mn-ZIF-8 and ZIF-8 nanoparticles at a concentration of 20 μg / ml for 16 hours, irradiated with X-rays (6 Gy), and then further cultured for 48 hours. The supernatant was collected and IFN-β was detected using an ELISA kit (enzyme-immunoassay, catalog number: 4107). A histogram of IFN-β content was drawn using GraphPad Prism.

[0092] 2. Experimental results

[0093] The results are as follows Figure 5 This example investigated the effect of Mn-ZIF-8 on RT-induced ICD by detecting CRT exposure, HMGB1 release, and ATP secretion. Significant expression of CRT was observed after treatment with Mn-ZIF-8 combined with IR (6 Gy), in sharp contrast to the other groups ( Figure 5 In addition, treatment with Mn-ZIF-8 combined with IR (6 Gy) enhanced the release of HMGB1 from the nucleus and ATP production in B16 and A375 melanoma cells ( Figure 5 These results suggest that treatment with Mn-ZIF-8 combined with RT will significantly promote ICD of tumor cells, which is a prerequisite for subsequent antitumor immune response. Next, Western blotting was used to detect STING pathway-related proteins. Figure 5 As shown in Figure F, after treatment with Mn-ZIF-8 combined with IR (6 Gy), increased levels of pSTING and pIRF3 were observed, indicating that Mn-ZIF-8 contributes to RT-induced activation of the STING pathway in melanoma cells. In addition, Mn-ZIF-8 significantly promoted IFN-β secretion after IR treatment, further indicating that Mn-ZIF-8 effectively activated the STING pathway ( Figure 5 Middle G).

[0094] Example 6 Mn-ZIF-8 microneedles can enhance the efficacy of combined therapy

[0095] 1. Experimental methods

[0096] The 6-week-old female C57BL / 6 mice used were purchased from Guangdong Zhiyuan Biopharmaceutical Company. The mice were raised under specific pathogen-free conditions in the Laboratory Animal Center of Nanfang Hospital of Southern Medical University. All animal experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals and approved by the Laboratory Animal Protection, Welfare and Ethics Committee of Nanfang Hospital of Southern Medical University (IACUC-LAC-20231022-001). B16 cells (5×10 5 ) were injected subcutaneously into the right thigh of C57BL / 6 mice. On day 7, when the right tumor volume was approximately 100 mm 3At the same time, the animals were randomly assigned to: i. irradiation group; ii. irradiation + ZIF-8 microneedle group; iii. irradiation + Mn-ZIF-8 microneedle group. On the 7th day after tumor implantation, one microneedle patch was applied to the tumor site for each mouse in groups ii and iii. On the 8th day, all mice were anesthetized by intraperitoneal injection of sodium pentobarbital (20 mg / kg) and subjected to X-ray irradiation (12 Gy) using the small animal radiation research platform of the Radiotherapy Department of Nanfang Hospital (512 cGy / min, 6-MeV beam; Siemens, Munich, Germany). Tumor volume and body weight were monitored every 2-3 days from tumor implantation to mouse euthanasia. Tumor volume was calculated using the following formula: Tumor volume (mm 3 )=Width 2(mm 2 )×length (mm)×0.5. After 18 days, the mice were euthanized, and the tumors and spleens were weighed. 3 When euthanasia is carried out.

[0097] 2. Experimental results

[0098] The results are as follows Figure 6 All mice showed slight weight loss about one week after radiotherapy and remained within the normal weight range during the treatment period ( Figure 6 In the X-ray + ZIF-8 microneedle group, tumor growth was only slightly delayed. However, in the X-ray + Mn-ZIF-8 microneedle group, tumor growth was significantly delayed ( Figure 6 Mice receiving different treatments were euthanized on day 16 after tumor implantation, and the collected tumors were sliced ​​for immunohistochemistry (IHC) staining or disaggregated into cell suspensions for flow cytometric analysis. It was observed in tumor sections by Ki-67 (proliferation marker) immunohistochemistry staining and H&E staining that the X-ray + Mn-ZIF-8 microneedle treatment group showed the most cell death and the least cell proliferation ( Figure 6 IHC results showed that X-ray + Mn-ZIF-8 microneedle treatment significantly enhanced the radiotherapy enhancement effect of CD4 + T cell infiltration, with the highest levels of CD8 + T cells, but no significant differences in the infiltration of regulatory T cells (Tregs) were found in tumors ( Figure 6 I). Flow cytometry was used to detect the maturation of dendritic cells in the inguinal lymph nodes. Mice treated with X-rays + Mn-ZIF-8 microneedles were able to effectively enhance the maturation of dendritic cells in the lymph nodes, thereby enhancing their antigen presentation ability ( Figure 6 Subsequently, flow cytometry was used to measure the CD4 + T cells ( Figure 6 Medium K), CD8 + T cells ( Figure 6 Middle L) and Tregs cells ( Figure 6 The results were roughly consistent with the IHC results. At the same time, X-ray + Mn-ZIF-8 microneedle treatment increased the proportion of CD8 + T cells and CD4 + Infiltration of T cells ( Figure 6 N, O). In summary, X-ray + Mn-ZIF-8 microneedles can promote the maturation of dendritic cells and CD8 + T cell infiltration, thereby inducing a strong systemic anti-tumor immune response in vivo.

[0099] Example 7 Mn-ZIF-8 microneedles can enhance local and systemic anti-tumor immune activation in combined therapy

[0100] 1. Experimental methods

[0101] The 6-week-old female C57BL / 6 mice used were purchased from Guangdong Zhiyuan Biopharmaceutical Company. The mice were raised under specific pathogen-free conditions in the Laboratory Animal Center of Nanfang Hospital of Southern Medical University. All animal experiments were performed in accordance with the Guide for the Care and Use of Laboratory Animals and approved by the Laboratory Animal Protection, Welfare and Ethics Committee of Nanfang Hospital of Southern Medical University (IACUC-LAC-20231022-001). B16 cells (5×10 5 ) were injected subcutaneously into the right thigh of C57BL / 6 mice. On the third day, B16 cells (3×10 5 On day 7, when the right tumor volume was approximately 100 mm 3 At the time of the experiment, the animals were randomly assigned to: i. irradiation group; ii. irradiation + Mn-ZIF-8 microneedle group; iii. irradiation + Mn-ZIF-8 microneedle group + anti-mouse PD-1 monoclonal antibody. On the 7th day after tumor implantation, the microneedle patch was applied to the tumor site. On the 8th day, all mice were anesthetized by intraperitoneal injection of sodium pentobarbital (20 mg / kg) and subjected to X-ray irradiation (12 Gy) using the small animal radiation research platform of the Department of Radiotherapy of Nanfang Hospital (512 cGy / min, 6-MeV beam; Siemens, Munich, Germany). Anti-mouse PD-1 monoclonal antibody (mAb) (Bio X Cell, Catalog No. BE0146) was injected intraperitoneally on days 8, 10, and 12 (200 mg per mouse). Tumor volume and body weight were monitored every 2-3 days from tumor implantation to mouse euthanasia. Tumor volume was calculated using the following formula: Tumor volume (mm 3 )=Width 2(mm 2)×length (mm)×0.5. After 16 days, the mice were euthanized, and the tumors and spleens were weighed. 3 When euthanasia is carried out.

[0102] 2. Experimental results

[0103] The results are as follows Figure 7 Compared with other groups, the X-ray + αPD-1 + Mn-ZIF-8 microneedle treatment group showed the most significant control of primary and metastatic tumor growth ( Figure 7 First, the maturation of dendritic cells (DCs) in the inguinal lymph nodes on the primary tumor side was detected by flow cytometry. In mice treated with X-ray + αPD-1 + Mn-ZIF-8 microneedles, the maturation of DCs in the lymph nodes was significantly enhanced, thereby enhancing their antigen presentation ability ( Figure 7 Middle G). Flow cytometry results showed that X-ray + αPD-1 + Mn-ZIF-8 microneedle treatment significantly promoted CD4 + T cells and CD8 + T cell infiltration in primary tumors; however, there was no significant difference in the infiltration of Tregs cells in primary tumors among the three groups ( Figure 7 HJ). CD4 + T cells and CD8 + Changes in the proportion of T cells were similar to those observed in primary tumors ( Figure 7 However, the X-ray + αPD-1 + Mn-ZIF-8 microneedle treatment group significantly reduced the percentage of Tregs in metastatic tumors ( Figure 7 Subsequently, CD4 + T cells, CD8 + The ratio of T cells and Tregs cells is roughly consistent with the results of flow cytometry ( Figure 7 N). H&E and immunohistochemical Ki67 staining of primary and metastatic tumor sections showed that in the X-ray + αPD-1 + Mn-ZIF-8 microneedle treatment group, cell death was the most and cell proliferation was the least ( Figure 7 These results indicate that Mn-ZIF-8 microneedle combined with X-ray therapy induced a strong systemic immune response and effectively synergized with ICB to control primary and metastatic tumors.

[0104] Example 8 Biosafety Evaluation of Mn-ZIF-8 Microneedles

[0105] The in vivo toxicity of ZIF-8 or Mn-ZIF-8 microneedles under irradiation was evaluated in healthy C57BL / 6 mice (6 weeks old). The grouping and other parameters were consistent with the in vivo antitumor efficacy test. The body weight of mice was recorded until day 18. Blood samples were collected on day 18 for blood cell counts. Blood biochemical values, including serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), blood urea nitrogen (BUN), uric acid (UA), and creatinine (CREA) levels, were subsequently analyzed to evaluate possible liver and kidney toxicity. On day 18, major organs (heart, liver, spleen, lungs, and kidneys) were removed and analyzed using H&E staining.

[0106] 2. Experimental results

[0107] The results are as follows Figure 8 , 9 The main organs (heart, liver, spleen, lung and kidney) of mice were analyzed by H&E staining ( Fig. 9 No obvious tissue damage or side effects were found in mouse organs, indicating that it has excellent biosafety. In addition, complete hematological analysis and serum biochemical tests were performed ( Figure 8 ). It is noteworthy that almost all the test parameters were within the normal range, indicating that the treatment had no obvious systemic toxic side effects.

Claims

1. Application of manganese-doped zeolite imidazole framework in the preparation of tumor radiosensitizer products.

2. The use according to claim 1, characterized in that: The mass percentage of Mn in the manganese-doped zeolite imidazole framework is 1 to 30%; Preferably, the mass percentage of Mn in the manganese-doped zeolite imidazole framework is 5-20%.

3. The use according to claim 1, characterized in that: The radiosensitizer also includes other substances that improve the effect of tumor radiotherapy.

4. The use according to claim 1, characterized in that: The product also includes pharmaceutically acceptable excipients.

5. The use according to claim 1, characterized in that: The dosage form of the product includes at least one of capsules, tablets, microcapsule preparations, injections, suppositories, sprays, powders, soft capsules, pellets, honey pills, pills, granules, honey pastes, sustained-release preparations, oral liquids, preparations, chewable tablets, buccal tablets, and transdermal microneedles.

6. The use according to claim 1, characterized in that: The tumor includes at least one of a solid tumor and a blood tumor.

7. A manganese-doped zeolite imidazole framework microneedle, characterized in that: The microneedle includes a manganese-doped zeolite imidazole framework and a polymerizing agent.

8. The manganese-doped zeolite imidazole framework microneedle according to claim 7, characterized in that: The polymerizing agent is selected from at least one of polyvinyl pyrrolidone, hyaluronic acid or its salt, polyvinyl alcohol, chitosan and sodium alginate.

9. The method for preparing the manganese-doped zeolite imidazole framework microneedle according to any one of claims 7 or 8, comprising the following steps: 1) mixing a manganese-doped zeolite imidazole framework, a polymerization agent, and a solvent to obtain a needle solution; 2) The needle body solution is placed in a microneedle mold and centrifuged to dry to obtain.

10. The preparation method according to claim 9, characterized in that: The solvent comprises an alcohol; The mass volume ratio of the polymerization agent to the manganese-doped zeolite imidazole framework is 1:(1-5).

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