Manganese-doped zeolitic imidazolate framework and its use in tumor radiotherapy

Abstract

The application belongs to the technical field of biological medicine, and particularly relates to a manganese-doped zeolitic imidazolate framework and application thereof in tumor radiotherapy. The application discloses a new use of the manganese-doped zeolitic imidazolate framework as a tumor radiosensitizer, and Mn-ZIF-8 has ray responsiveness and continuously releases Mn 2+ ions under X-ray irradiation, enhances the activation of the cGAS-STING signal pathway, promotes the maturation and antigen presentation of DCs, enhances the T cell-mediated immune response, and thus enhances the tumor treatment effect. Further, the application provides a Mn-ZIF-8 microneedle, which has the characteristics of rapid dissolution and controlled release, ensures the accurate delivery and sustained effect of the drug at the tumor site, reduces systemic toxicity, and when used in combination with an immune checkpoint inhibitor, can significantly amplify the local and systemic immune effects caused by radiotherapy and improve the treatment effect.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically relating to a manganese-doped zeolite imidazole framework and its application in tumor radiotherapy. Background Technology

[0002] Melanoma is a highly malignant skin tumor, accounting for 72% of skin cancer-related deaths, and its incidence is increasing at a rate of 3-5% annually. Although surgical treatment is effective for early-stage melanoma, its aggressiveness and high risk of early metastasis lead to poor patient prognosis. Therefore, exploring new treatment methods and developing effective combination therapies are crucial for improving patient outcomes. In the field of oncology, radiotherapy (RT) is a primary treatment method, and its effectiveness is significantly influenced by the tumor microenvironment (TME). Physiological barriers within the tumor microenvironment, such as hypoxia, dense extracellular matrix, and immunosuppressive environment, often limit the efficacy of radiotherapy. Studies have found that radiotherapy (RT) has effective local control of melanoma, and many radiotherapy-immunotherapy combinations aim to activate a systemic anti-tumor immune response through radiation-induced in situ tumor vaccines. However, in practice, the synergistic effect of combination therapies is not significant. Therefore, how to improve the efficacy of combination therapies has become an urgent problem to be solved in clinical practice.

[0003] Current technologies for radiotherapy have the following problems:

[0004] (1) Limitations of radiotherapy: Although traditional radiotherapy can directly kill tumor cells, it often cannot effectively eliminate distant micrometastases, 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 novel radiosensitizers to enhance the sensitivity of tumor cells to radiation while activating the body's immune response. Summary of the Invention

[0007] The first objective of this invention is to provide the application of manganese-doped zeolite imidazole frameworks in the preparation of tumor radiosensitizer products.

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

[0009] The third objective of this invention is to provide a method for preparing a manganese-doped zeolite imidazole framework.

[0010] The fourth aspect of this invention is to provide a manganese-doped zeolite imidazole framework microneedle.

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

[0012] To achieve the above-mentioned objectives of this invention, the technical solution adopted by this invention is as follows:

[0013] In a first aspect, the invention provides the use of manganese-doped zeolite imidazole frameworks in the preparation of tumor radiosensitizer products.

[0014] The radiosensitizer refers to an agent used when radiation is used to treat tumors. Some tumors are not very sensitive to radiation, or they are resistant to radiation. In this case, 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 1-30%;

[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 may also include other substances that enhance the efficacy of tumor radiotherapy; or other tumor-treating 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 includes pharmaceutically acceptable excipients.

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

[0020] The pharmaceutically acceptable excipients mentioned above are generally recognized for use in this purpose and as inactive ingredients in the pharmaceutical preparation. Compilations of pharmaceutically acceptable excipients can be found in reference books such as the *Handbook of Pharmaceutical Excipients* (2nd edition, edited by A. Wade and P.J. Weller; published by the American Pharmaceutical Association, Washington and The Pharmaceutical 6Gess, London, 1994) and the *Pharmacopoeia - List 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, drop pills, honey pills, pills, granules, honey-infused pastes, sustained-release preparations, oral liquids, preparations, chewable tablets, oral 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 includes at least one of solid tumors and hematomas.

[0024] In some embodiments of the present invention, the solid tumors include liver cancer, colorectal cancer, bladder cancer, breast cancer, cervical cancer, prostate cancer, glioma, melanoma, pancreatic cancer, nasopharyngeal carcinoma, lung cancer, gastric cancer, adrenocortical carcinoma, adrenocortical carcinoma, anal cancer, appendiceal cancer, astrocytoma, atypical teratoma, rhabdomyosarcoma, basal cell carcinoma, bile duct carcinoma, bladder cancer, bone cancer, brain tumor, bronchial tumor, Burkitt lymphoma, carcinoid tumor, cardiac tumor, bile duct epithelial carcinoma, chordoma, colorectal cancer, craniopharyngioma, ductal carcinoma in situ, germinal tumor, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, intracranial blastic tumor, gonadal germ cell tumor, eye cancer, fallopian tube cancer, gallbladder cancer, head and neck cancer, hypopharyngeal cancer, Kaposi's sarcoma, kidney cancer, Langerhans cell carcinoma. Histiocytosis, laryngeal cancer, lip cancer, oral cancer, Merkel cell carcinoma, malignant mesothelioma, multiple endocrine neoplasia syndrome, mycosis fungoides, nasal cavity and sinus cancer, neuroblastoma, non-small cell lung cancer, ovarian cancer, pancreatic neuroendocrine tumor, islet cell tumor, papilloma, paraganglioma, sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pituitary adenoma, pleural pulmonary blastoma, primary peritoneal cancer, retinoblastoma, salivary gland tumor, sarcoma, Cézare syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, testicular cancer, thymoma and thymic carcinoma, 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 hematologic malignancy is selected from at least one of B-cell acute lymphoblastic leukemia (BALL), T-cell acute lymphoblastic leukemia (TALL), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), B-cell prolymphoblastic leukemia, blastic plasmacytoid dendritic cell tumor, 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 tumor, Waldenstrom's macroglobulinemia, and preleukemia.

[0026] A 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] A third aspect of the present invention provides a method for preparing a manganese-doped zeolite imidazole framework.

[0031] Zinc salt and manganese salt are mixed in a solvent, and the mixed solution is added dropwise to a 2-methylimidazole solution. The mixture is stirred and reacted at 40-60°C for 20-120 min. The mixture is then centrifuged to obtain the final product.

[0032] In some embodiments of the present invention, the zinc salt is Zn(NO3)2·6H2O.

[0033] In some embodiments of the present invention, the manganese salt is Mn(NO3)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 includes 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 polyvinylpyrrolidone, hyaluronic acid or its salt, polyvinyl alcohol, chitosan, and sodium alginate.

[0038] In some embodiments of the present invention, the mass-to-volume ratio of the polymerizing 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 manganese-doped zeolite imidazole framework microneedles, comprising the following steps:

[0040] 1) Manganese-doped zeolite imidazole framework, polymerizing agent, and solvent are mixed to obtain needle solution;

[0041] 2) Place the needle solution into a microneedle mold, centrifuge and dry to obtain the solution.

[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 polyvinylpyrrolidone, 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 material 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 this invention are:

[0046] This invention discovers a novel application of manganese-doped zeolite imidazole frameworks as tumor radiosensitizers. Mn-ZIF-8 exhibits radiation responsiveness and continuously releases Mn upon X-ray irradiation. 2+ Ions enhance the activation of the cGAS-STING signaling pathway, thereby promoting DC maturation and antigen presentation, enhancing T cell-mediated immune responses, and thus improving the therapeutic effect of tumor treatment. Furthermore, this invention provides a Mn-ZIF-8 microneedle with rapid dissolution and controlled release properties, ensuring precise delivery and sustained action of drugs at the tumor site, reducing systemic toxicity. When used in combination with immune checkpoint inhibitors, it can significantly amplify the local and systemic immune effects induced by radiotherapy, improving the therapeutic effect. Attached Figure Description

[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 are shown below, including: (A) Transmission electron microscopy (TEM) images of Mn-ZIF-8, scale bars = 10, 20, 50, 100 nm; (B) High-angle annular dark field (HAADF) and corresponding elemental mapping images (TEM) of Mn-ZIF-8, scale bar = 200 nm; (C) Microparticle size distribution 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 (XRD) patterns of ZIF-8 and Mn-ZIF-8; (F) X-ray photoelectron spectroscopy (XPS) curves of Mn-ZIF-8; (G) XPS spectrum of Mn 2p.

[0049] Figure 2The structure and characterization results of Mn-ZIF-8 microneedles are shown, including: (A) a photograph of Mn(20%)-ZIF-8 microneedles, scale bar = 1 nm; (B) scanning electron microscope (SEM) images of Mn(20%)-ZIF-8 (left) and ZIF-8 (right) microneedles, scale bar = 500 μm; (C) high-angle annular dark-field (HAADF) and elemental mapping (TEM) images of Mn(20%)-ZIF-8 microneedles, front and top views. View, scale bar = 100 μm; (D) Dissolution of Mn(20%)-ZIF-8 microneedles at different times after insertion into the skin, scale bar = 200 μm; (E) Force-displacement curves of Mn(20%)-ZIF-8 and ZIF-8 microneedles; (F) Mechanical compressive strength of Mn(20%)-ZIF-8 and ZIF-8 microneedles; (G) H&E stained sections of Mn(20%)-ZIF-8 microneedles inserted into the abdominal skin of rats, scale bar = 100 μm.

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

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

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

[0053] Figure 6 The results show the antitumor effect of Mn-ZIF-8 microneedles in a mouse model of B16 melanoma xenograft, including: (A) timeline of treatment experiments in C57BL / 6J mice bearing B16 melanoma; (B) curve of mouse body weight change during treatment; (C) photograph of B16 tumors isolated from the subcutaneous tissue of mice on day 18; (D) tumor growth curves of mice under different treatments; (E), (F), and (G) tumor growth curves of each mouse after different treatments; (H) tumor weight isolated from the subcutaneous tissue of mice on day 18; (I) Ki67 and CD44 levels shown in H&E staining (scale bar = 100 nm) and immunohistochemical images (scale bar = 50 nm) of tumor tissue. + T and CD8 + T cell infiltration and Foxp3 expression; (J) Mature DCs (CD11c) in the paratumoral inguinal lymph nodes after treatment + CD80 in cells + CD86 + Quantitative analysis of (K), (L) and (M) tumor-infiltrating CD4 + T, CD8 + Percentage of T and Treg cells; percentage of (N) and (O) infiltrating CD4+ T and CD8+ T cells in the spleen; *P<0.05,**P<0.01,***P<0.001,****P<0.0001.

[0054] Figure 7The results of Mn-ZIF-8 microneedles combined with RT+ICB inducing systemic antitumor immunity include: (A) a treatment timeline for C57BL / 6J mice bearing bilateral B16 melanoma; (B) photographs of bilateral B16 tumors isolated subcutaneously from mice on day 16; (C) and (D) weights of primary and metastatic tumors isolated subcutaneously from mice on day 16; (E) and (F) tumor growth curves of primary and metastatic tumors in mice after different treatments; and (G) mature DCs (CD11c) in the inguinal lymph nodes adjacent to the primary tumor after treatment. + CD80 in cells + CD86 + Quantitative analysis of CD4 infiltration in primary tumors (H), (I), and (J); + T, CD8 + Percentage of T and Treg cells; (K), (L), and (M) metastatic tumor infiltration CD4 + T, CD8 + Percentage of T and Treg cells; (N) Bilateral tumor tissue H&E staining (bar = 100 nm) and immunohistochemical images (bar = 50 nm) showing Ki67 and 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 study presents complete blood cell and blood biochemical data of mice 18 days after treatment with Mn-ZIF-8 microneedles combined with radiotherapy.

[0056] Figure 9 H&E staining of major organs in mice 18 days after treatment with Mn-ZIF-8 microneedles combined with radiotherapy; scale bar = 100 μm. Detailed Implementation

[0057] The following will describe the concept and technical effects of the present invention clearly and completely with reference to embodiments, so as to fully understand the purpose, features and effects of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are all within the scope of protection of the present invention.

[0058] This invention aims to develop a microneedle (MN) system loaded with manganese-based nanoparticles (Mn-ZIF-8NPs). By altering the tumor microenvironment (TME), this system can overcome radioresistance and reduce immunosuppression. Furthermore, the transdermal drug delivery route using microneedles as a carrier is expected to improve transdermal drug delivery efficiency and increase drug accumulation 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 radioimmunotherapy combination therapy, 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(NO3)2·4H2O and 2 mmol Zn(NO3)2·6H2O, and dissolve them together in 20 mL of methanol to obtain mixed solution 1. Weigh 40 mM 2-methylimidazole and dissolve it in 80 mL of methanol. Under magnetic stirring at room temperature, use a pipette to add mixed solution 1 dropwise to the methanol solution of 2-methylimidazole. After the addition is complete, stir at room temperature for 4 h, and then maintain at 50 °C for 1 h. Centrifuge at 10000 rpm at room temperature for 10 min, wash twice with methanol solution, and enrich to obtain 20 mL of Mn(20%)-ZIF-8 (mass percentage) methanol solution.

[0062] Based on the same preparation method, by adjusting the amount of Mn(NO3)2·4H2O, methanol solutions of Mn(5%)-ZIF-8 and Mn(10%)-ZIF-8 were obtained.

[0063] Comparison of combinations:

[0064] ZIF-8 nanoparticles: Weigh 2.5 mmol of Zn(NO3)2·6H2O and dissolve it 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 add mixed solution 1 dropwise to the 2-methylimidazole methanol solution. After the addition is complete, stir at room temperature for 4 h, and then maintain at 50 °C for 1 h. Centrifuge at 10000 rpm at room temperature for 10 min, wash twice with methanol solution, and concentrate to obtain 20 mL of ZIF-8 methanol solution.

[0065] 2. Structural characterization

[0066] Transmission electron microscopy (TEM) images were used to display the morphology and particle size; elemental mapping was used to detect characteristic elements 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) patterns were used to display the crystal structure of NAs; X-ray photoelectron spectroscopy (XPS) was used to display the chemical composition, valence state, and electronic structure of NAs.

[0067] The results are as follows Figure 1 As shown. Transmission electron microscopy (TEM) images show that, when using Mn...2+ and Mn 4+ After modification, ZIF-8 retained its original rhombic dodecahedral structure. Figure 1 (A). Manganese and zinc elements are distributed throughout all nanoparticles. Figure 1 (B). The area of ​​manganese corresponds to a 20% doping rate, which is consistent with the theoretical value. Hydrodynamic diameters of ZIF-8 and Mn-ZIF-8 ( Figure 1 (C) and zeta potential ( Figure 1 The mean diameters (D) of the ZIF-8 nanoparticles are almost identical, with average particle sizes of 124.5, 136.9, 113.7, and 123.3 nm, and average potentials of 22.7, 24.8, 22.3, and 23.2 mV, respectively. This indicates that manganese ion doping does not alter the fundamental properties of the ZIF-8 nanoparticles. X-ray diffraction (XRD) patterns of ZIF-8 and Mn-ZIF-8 show characteristic diffraction peaks (…). Figure 1 (Mn-ZIF-8). Furthermore, with increasing Mn doping rate, the main peak (011) of Mn-ZIF-8 gradually shifts to the right, possibly because zinc ions in the ZIF-8 framework are replaced by manganese ions. The chemical composition and valence state of manganese were analyzed using X-ray photoelectron spectroscopy (XPS). Figure 1 The middle F shows the main corresponding peaks of Zn, Mn and O. Figure 1 The image 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 correspond to Mn 2p3 / 2 peaks. 2+ and Mn 4+ This is consistent with reported data. This indicates the presence of Mn in the Mn-ZIF-8 structure. 2+ and Mn 4+ Mn 2+ The proportion was 50.05%, Mn 4+ The proportion was 49.95%.

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

[0069] 1. Preparation method

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

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

[0072] Comparison of combinations:

[0073] ZIF-8 Microneedles: 1 mL of ZIF-8 methanol solution was used as the tip solution. A precise amount of polyvinylpyrrolidone (PVP K90) was accurately weighed and dissolved in anhydrous ethanol at a ratio of 1:3.2 (w / v). The solution was stirred until homogeneous and allowed to swell overnight to obtain the microneedle base solution. An appropriate amount of tip solution was placed on a negative mold, and ZIF-8 microneedles were prepared using a three-step centrifugation method. 200 μL / well of tip solution was added to the negative mold, and the mold was placed in a centrifuge basket and centrifuged at 4000 rpm at 4-10°C for 5 minutes to fill the microchannels of the negative mold with the tip solution. The negative mold was then removed, and any remaining tip solution on its surface was thoroughly scraped off using an aluminum scraper. The negative mold was then returned to the centrifuge and centrifuged at 4000 rpm at 4-10°C for 30 minutes to fully compress the tip solution and allow it to dry to a certain extent. Finally, apply 300 μL / well of the microneedle base solution to the negative mold and centrifuge at 4000 rpm at 4-10℃ for 5 minutes to ensure the base solution uniformly covers the microchannels. Place the negative mold in a desiccator to dry at room temperature for 48 hours. After the microneedles are completely dry, gently remove the ZIF-8 microneedles with tweezers and store them in a desiccator. 2. Structural Characterization

[0074] The morphology of the microneedles was determined using stereomicroscopy and scanning electron microscopy (SEM); elemental mapping (TEM) images showed the presence of Zn and Mn characteristic elements in the microneedles; Mn-ZIF-8 microneedles were applied to pigskin to dissolve encapsulated Mn-ZIF-8 nanoparticles, and micropore insertion and dissolution capabilities were examined using confocal microscopy (CLSM); the mechanical properties of Mn-ZIF-8 microneedles and ZIF-8 microneedles were evaluated using a force measurement system; Mn-ZIF-8 microneedles were inserted into the abdominal skin of rats, skin samples were taken, fixed with 4% paraformaldehyde, and stained with H&E to evaluate the insertion capability of Mn-ZIF-8 microneedles; 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 using a three-step centrifugal casting method. The resulting Mn-ZIF-8 microneedles were pyramidal in shape and regularly arranged in a 12×12 array. Figure 2 (Middle A). The needle height of MNs is 1200 micrometers, the base width is 300 micrometers, the tip-to-tip gap is 800 micrometers, and it is located on a 1×1 cm patch. Figure 2 (B) Furthermore, elemental maps of the front and top views of the microneedles were scanned to investigate the distribution of Mn and Zn ions within the microneedles. It was observed that most 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 centrifugal force. Figure 2 (C). The solubility of microneedles facilitates drug release and diffusion from MNs, thereby improving drug delivery efficiency. Morphological changes of ZIF-8 and Mn-ZIF-8 microneedles were recorded using optical microscopy, showing that the microneedles completely dissolved 8 minutes after application. Figure 2 (D). The mechanical properties of microneedles are a key factor determining their skin insertion capability. The average breaking forces of Mn-ZIF-8MNs and ZIF-8MNs are 0.3305 N / needle and 0.3285 N / needle, respectively. The breaking forces of both types of microneedles are greater than the minimum force required to penetrate the stratum corneum (0.1 N / needle). Figure 2 (E, F). Hematoxylin and eosin (H&E) staining was performed on rat skin subjected to 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 and can successfully deliver drugs to the dermis (…). Figure 2 (G). In this embodiment, fluorescence images of IR780-labeled Mn-ZIF-8 were captured at different time points after the Mn-ZIF-8 microneedles were inserted into the subcutaneous tumor. Figure 3 (A) and constructed fluorescence intensity curves ( Figure 3 (Mn-ZIF-8 was released slowly, reaching its peak value in 1–6 hours, and remained in vivo 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 (1×10⁻⁶) 3 Cells were seeded in 96-well plates, and 100 μL of 1640 / DMEM containing 10% fetal bovine serum was added per well to support cell growth. Cells were incubated at 37°C for 6-8 hours. ZIF-8 / Mn(5%)-ZIF-8 / Mn(10%)-ZIF-8 / Mn(20%)-ZIF-8 nanoparticle stock solution (corresponding mass concentrations of 99.5, 78.74, 80.88, and 124.98 mg / ml) was added to each well to prepare the nanoparticle concentration in each well to 10 or 20 μg / ml. An equal volume of PBS was added to the control group. Incubation continued for 16 hours, followed by X-ray irradiation (0 / 2 / 4 / 6 Gy). After another 24 hours of culture, 10 μL of CCK (5 mg / mL) stock solution was added to each well, and the plates were incubated at 37°C for 2 hours. The absorbance was then measured at 450 nm using a multifunctional enzyme labeling device (TECAN). Adjust the relative percentage of untreated cells to represent 100% cell viability, and calculate and plot cell viability curves using GraphPad Prism.

[0079] Cell proliferation activity assay: B16 and A375 cells (2×10⁻⁶) were used to detect cell proliferation. 3 Cells were seeded in six-well plates, and 2 mL of 1640 / DMEM containing 10% fetal bovine serum was added to support cell growth. Cells were incubated at 37°C for 6-8 hours. ZIF-8 / Mn-ZIF-8 (specifically Mn(20%)-ZIF-8 in subsequent experiments) nanoparticle stock solution (corresponding mass concentrations of 99.5 and 124.98 mg / mL, respectively) was added to each well, adjusting the nanoparticle concentration in each well to 10 or 20 μg / mL. An equal volume of PBS was added to the control group. Incubation continued for 16 hours, followed by X-ray irradiation (0 / 2 / 4 / 6 Gy), and then further cultured for 10 days. Subsequently, cells were gently soaked three times in PBS, fixed with 4% paraformaldehyde for 15 minutes at room temperature, stained with 0.1% crystal violet for 30 minutes, and the colonies were imaged under a stereomicroscope and analyzed using ImageJ software. A histogram of cell colony formation rate was then plotted using GraphPad Prism.

[0080] 2. Experimental Results

[0081] The results are as follows Figure 4As shown. First, the changes in cell viability of B16 cells (epithelial-like cells isolated from the skin of mice with melanoma) treated with 10 or 20 μg / ml ZIF-8 / Mn(5%)-ZIF-8 / Mn(10%)-ZIF-8 / Mn(20%)-ZIF-8 nanoparticles, or an equal volume of PBS, after irradiation with 6 Gy X-rays were evaluated. The analysis in this embodiment revealed a negative correlation between cell viability and drug concentration. The addition of Mn(20%)-ZIF-8, particularly at a concentration of 20 μg / mL, showed the most significant inhibitory effect on cell viability, with cell viability only reaching 60% of the PBS group. This was also significantly lower than the cell viability of the 20 μg / mL ZIF-8 / Mn(5%)-ZIF-8 / Mn(10%)-ZIF-8 groups (81.8%, 79.8%, and 64.7%, respectively). This indicates that Mn(20%)-ZIF-8 significantly enhanced the cytotoxic effect of radiotherapy. Figure 4 Therefore, ZIF-8 at a concentration of 20 μg / ml and Mn-ZIF-8 (hereinafter specifically referring to Mn(20%)-ZIF-8) were selected for subsequent studies. Cell counting kit 8 (CCK8) assays showed that treatment with Mn-ZIF-8 combined with 6 Gy radiotherapy exhibited significant cytotoxicity against B16 and A375 melanoma cells, with cell counts only 26.3% and 35.6% of the blank control group, respectively. Figure 4 (Mn-ZIF-8 combined with 6Gy radiotherapy) Furthermore, the colony counts 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, respectively. Mn-ZIF-8 combined with 6Gy radiotherapy showed the most significant inhibitory effect on the colony formation of B16 and A375 melanoma cells, with colony counts only 2.75% and 2.3% of those in the blank control group, respectively. Figure 4 (C). In summary, these results indicate 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) 4Cells were seeded in 24-well plates and incubated 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. Cells 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 (2 Gy), and cultured for another hour. Subsequently, cells were gently soaked three times with PBS and fixed with 4% paraformaldehyde for 15 minutes at room temperature. Then, cells were washed three times with PBS, incubated with 0.5% Triton X-100 at room temperature for 15 minutes, washed twice with PBS, blocked with 5% BSA sealing solution for 1 hour, incubated overnight at 4°C with anti-γ-H2AX antibody, washed three times with PBST, incubated with Alexa fluorescently conjugated secondary antibody at room temperature for 1 hour, washed three times with PBST, stained with DAPI for 10 minutes, washed three times with PBST, mounted with mounting medium, and observed and photographed under a confocal microscope (Zeiss). Then, ImageJ was used for analysis, and GraphPadPrism was used to plot the mean fluorescence intensity histogram of cells.

[0085] 2. Experimental Results

[0086] The results are as follows Figure 4 As shown. Immunofluorescence was used to detect γ-H2AX focal points to assess DNA damage in melanoma cells. The mean number of γ-H2AX focal points in B16 cell lines induced by PBS, ZIF-8, and Mn-ZIF-8 combined with 2Gy radiotherapy were 38, 42, and 98, respectively, while the mean number of γ-H2AX focal points in A375 cell lines were 37, 39, and 79, respectively. Figure 4 D). These results indicate 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 antitumor immunity.

[0088] 1. Experimental Methods

[0089] CRT exposure, HMGB1 release, and ATP secretion assays: B16 and A375 cells (5 × 10⁶ cells per well) were used to measure these assays. 4Cells were seeded into 24-well plates and incubated 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. Cells 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 cultured for another 24 or 8 hours. Subsequently, cells were gently soaked three times with PBS and fixed with 4% paraformaldehyde at room temperature for 15 minutes. Then, cells were washed three times with PBS, incubated overnight at 4°C with anti-HMGB1 / anti-CRT antibody, washed three times with PBST, incubated with fluorescently labeled secondary antibody at room temperature for 1 hour, washed three times with PBST, stained with DAPI for 10 minutes, washed three times with PBST, mounted, and observed and photographed under a confocal microscope (Zeiss). The images were then analyzed using ImageJ, and a histogram of the average fluorescence intensity of the cells was plotted using GraphPadPrism. After irradiation, the cells were cultured for another 18 hours, and the culture medium was collected. Dead cells were removed by centrifugation. The supernatant was used to quantitatively analyze ATP content using an ATP assay kit (Beyotime), and an ATP content histogram was plotted using GraphPad Prism.

[0090] GAS-STING pathway protein expression level detection: B16 and A375 cells (1×10⁶ cells per well) were used. 5 Cells were seeded into 6-well plates and incubated 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. Cells were then co-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 cultured for another 24 hours. Total protein extracts from the cells were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and transferred to a polyvinylidene fluoride membrane. After blocking with 5% BSA, the membrane was incubated overnight at 4°C with a primary antibody. The membrane was then incubated with a secondary antibody for 60 minutes. The bands were incubated using an ECL kit and analyzed using a luminescence imaging system.

[0091] Cytokine detection: B16 cells (1×10⁻⁶) were used to detect cytokines 5 Cells were seeded per well into 6-well plates containing complete culture medium and incubated 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. Cells 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 cultured for another 48 hours. The supernatant was collected, and IFN-β levels were detected using an ELISA kit (catalog number: 4107). A histogram of IFN-β levels was plotted using GraphPad Prism.

[0092] 2. Experimental Results

[0093] The results are as follows Figure 5 As shown. This example investigated the effect of Mn-ZIF-8 on RT-induced ICD by detecting CRT exposure, HMGB1 release, and ATP secretion. Significant CRT expression was observed after treatment with Mn-ZIF-8 combined with IR (6 Gy), in stark contrast to other groups. Figure 5 (A, B). Furthermore, 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 (CE). These results indicate that treatment with Mn-ZIF-8 combined with RT significantly promotes ICD in tumor cells, a prerequisite for subsequent anti-tumor immune responses. Next, Western blotting was used to detect STING pathway-related proteins. Figure 5 As shown in Figure F, increased levels of pSTING and pIRF3 were observed after treatment with Mn-ZIF-8 combined with IR (6 Gy), indicating that Mn-ZIF-8 contributes to the activation of the STING pathway in RT-induced melanoma cells. Furthermore, Mn-ZIF-8 significantly promoted IFN-β secretion after IR treatment, further demonstrating that Mn-ZIF-8 effectively activates the STING pathway. Figure 5 (G).

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

[0095] 1. Experimental Methods

[0096] Six-week-old female C57BL / 6 mice were purchased from Guangdong Zhiyuan Biopharmaceutical Co., Ltd. The mice were housed under specific pathogen-free conditions at the Laboratory Animal Center of Nanfang Hospital, Southern Medical University. All animal experiments were conducted in accordance with the "Guidelines for the Care and Use of Laboratory Animals" and were approved by the Laboratory Animal Protection, Welfare and Ethics Committee of Nanfang Hospital, Southern Medical University (IACUC-LAC-20231022-001). B16 cells (5 × 10⁻⁶) were used. 5 (Number of mice) were subcutaneously injected into the right thigh of C57BL / 6 mice. On day 7, when the tumor volume on the right side was approximately 100 mm... 3Animals were randomly assigned to: i. X-ray group; ii. X-ray + ZIF-8 microneedle group; iii. X-ray + Mn-ZIF-8 microneedle group. On day 7 post-tumor implantation, each mouse in groups ii and iii received one microneedle patch applied to the tumor site. On day 8, all mice were anesthetized by intraperitoneal injection of sodium pentobarbital (20 mg / kg) and irradiated with X-rays (12 Gy) (512 cGy / min, 6-MeV beam; Siemens, Munich, Germany) using the small animal radiation research platform of the Department of Radiation Oncology, Southern Hospital. Tumor volume and body weight were monitored every 2-3 days from tumor implantation to euthanasia. Tumor volume was calculated using the following formula: Tumor volume (mm²) 3 ) = Width 2 (mm) 2 () × length (mm) × 0.5. After 18 days, the mice were euthanized, and the tumor and spleen were weighed. Mice were euthanized when they showed poor health or the tumor volume exceeded 2000 mm². 3 At that time, euthanasia was performed.

[0097] 2. Experimental Results

[0098] The results are as follows Figure 6 As shown. All mice experienced a slight decrease in weight approximately one week after radiotherapy and maintained a normal weight range throughout the treatment period. Figure 6 (Mn-ZIF-8 microneedle group). 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 (CH). Mice receiving different treatments were euthanized on day 16 after tumor implantation, and the collected tumors were sectioned for immunohistochemical (IHC) staining or decomposed into cell suspensions for flow cytometry analysis. Immunohistochemical staining with Ki-67 (a proliferation marker) and H&E staining were used to observe in the tumor sections that the X-ray + Mn-ZIF-8 microneedle treatment group showed the highest cell death and the lowest cell proliferation. Figure 6 Further investigation revealed the radiotherapy enhancement effect induced by Mn-ZIF-8 microneedles. IHC results showed that X-ray combined with Mn-ZIF-8 microneedle treatment significantly enhanced CD4+. + T cell infiltration, showing the highest levels of CD8 + T cells, but no significant difference in regulatory T cell (Treg) infiltration was found in tumors. Figure 6 (I). Flow cytometry was used to detect the maturation of dendritic cells in inguinal lymph nodes. Mice treated with X-rays and Mn-ZIF-8 microneedles showed significantly enhanced maturation of dendritic cells in the lymph nodes, thereby increasing their antigen-presenting capacity. Figure 6 (J). Subsequently, CD4 levels in the tumor were measured by flow cytometry. + T cells ( Figure 6 (Middle K), CD8 + T cells ( Figure 6 (L) and Tregs cells ( Figure 6 The proportion of CD8+ in the spleen was roughly consistent with the results of IHC. Simultaneously, X-ray combined with Mn-ZIF-8 microneedling treatment increased CD8+ levels in the spleen. + T cells and CD4 + T cell infiltration ( Figure 6 (N, O). In summary, X-ray combined with Mn-ZIF-8 microneedles can promote the maturation of dendritic cells and CD8+. + T cell infiltration induces a powerful 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] Six-week-old female C57BL / 6 mice were purchased from Guangdong Zhiyuan Biopharmaceutical Co., Ltd. The mice were housed under specific pathogen-free conditions at the Laboratory Animal Center of Nanfang Hospital, Southern Medical University. All animal experiments were conducted in accordance with the "Guidelines for the Care and Use of Laboratory Animals" and were approved by the Laboratory Animal Protection, Welfare and Ethics Committee of Nanfang Hospital, Southern Medical University (IACUC-LAC-20231022-001). B16 cells (5 × 10⁻⁶) were used. 5 On the third day, B16 cells (3 × 10⁶) were subcutaneously injected into the right thigh of C57BL / 6 mice. 5 (number). On day 7, when the right-side tumor volume was approximately 100mm. 3 Animals were randomly assigned to: i. X-ray group; ii. X-ray + Mn-ZIF-8 microneedle group; iii. X-ray + Mn-ZIF-8 microneedle group + anti-mouse PD-1 monoclonal antibody. On day 7 post-tumor implantation, microneedle patches were applied to the tumor site. On day 8, all mice were anesthetized by intraperitoneal injection of sodium pentobarbital (20 mg / kg) and irradiated with X-rays (12 Gy) (512 cGy / min, 6-MeV beam; Siemens, Munich, Germany) using the small animal radiation research platform of the Department of Radiation Oncology, Southern Hospital. Anti-mouse PD-1 monoclonal antibody (mAb) (Bio X Cell, catalog number BE0146) was administered 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 (mm²) 3 ) = Width 2 (mm) 2() × length (mm) × 0.5. Sixteen days later, the mice were euthanized, and the tumor and spleen were weighed. Mice showing poor health or tumors exceeding 2000 mm² were considered euthanized. 3 At that time, euthanasia was performed.

[0102] 2. Experimental Results

[0103] The results are as follows Figure 7 As shown. 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 (as shown). Figure 7 (Middle BF). First, the maturation of dendritic cells (DCs) in the inguinal lymph nodes on the side of the primary tumor was detected by flow cytometry. Mice treated with X-ray + αPD-1 + Mn-ZIF-8 microneedles showed significantly enhanced DC maturation in the lymph nodes, thereby enhancing their antigen-presenting capacity. Figure 7 (G). Flow cytometry results showed that X-ray combined with αPD-1 and Mn-ZIF-8 microneedling significantly promoted CD4. + T cells and CD8 + T cell infiltration in the primary tumor; however, there was no significant difference in Treg cell infiltration in the primary tumor among the three groups. Figure 7 (HJ). CD4 in metastatic tumors + T cells and CD8 + The changes in the proportion of T cells were similar to those observed in the primary tumor. Figure 7 (K, L). However, the X-ray + αPD-1 + Mn-ZIF-8 microneedle treatment group significantly reduced the percentage of Tregs in metastatic tumors ( Figure 7 (M). Subsequently, IHC was used to detect CD4 in primary and metastatic tumors. + T cells, CD8 + The ratio of T cells to Treg cells was largely consistent with the results of flow cytometry. Figure 7 H&E and immunohistochemical Ki67 staining of primary and metastatic tumor sections showed that the X-ray + αPD-1 + Mn-ZIF-8 microneedle treatment group had the highest cell death and the lowest cell proliferation. Figure 7 (N). The above results indicate that Mn-ZIF-8 microneedles 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] In vivo toxicity of ZIF-8 or Mn-ZIF-8 microneedles under irradiation was evaluated in healthy C57BL / 6 mice (6 weeks old). Grouping and other parameters were consistent with in vivo antitumor efficacy assays. Mouse body weight 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 then analyzed to assess potential hepatotoxicity and renal 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 As shown. Analysis of major organs (heart, liver, spleen, lungs, and kidneys) in mice using H&E staining (…). Figure 9 No significant tissue damage or side effects were observed in mouse organs, indicating excellent biocompatibility. Furthermore, complete hematological analysis and serum biochemical tests were performed. Figure 8 It is worth noting that almost all test indicators were within the normal range, indicating that the treatment did not have significant systemic toxic side effects.

Claims

1. A method for preparing manganese-doped zeolite imidazole framework microneedles, comprising the following steps: 1) Manganese-doped zeolite imidazole framework, polymerizing agent and solvent are mixed to obtain needle solution; 2) Place the needle solution in a microneedle mold, centrifuge and dry to obtain; The preparation method of the manganese-doped zeolite imidazole framework is as follows: Mix zinc and manganese salts in a solvent, and add the mixture dropwise to 2 In a methylimidazole solution, stir and react at 40–60°C for 20–120 min, then centrifuge to obtain; The mass-to-volume ratio of the polymerizing agent to the manganese-doped zeolite imidazole framework is 1:1 to 5; The polymerizing agent is selected from at least one of polyvinylpyrrolidone, hyaluronic acid or its salt, polyvinyl alcohol, chitosan, and sodium alginate.

2. The preparation method according to claim 1, characterized in that: The zinc salt is Zn(NO3)2·6H2O; The manganese salt is Mn(NO3)2.

3. The preparation method according to claim 2, characterized in that: The solvent includes alcohols.

4. A manganese-doped zeolite imidazole framework microneedle, characterized in that: The manganese-doped zeolite imidazole framework microneedles are prepared by the preparation method described in any one of claims 1 to 3.

5. The application of the manganese-doped zeolite imidazole framework microneedles according to claim 4 in the preparation of tumor radiosensitizer products.

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