Manganese-based radiotherapy sensitizer as well as preparation method and application thereof

A sensitizer, manganese-based technology, applied in the field of biomedicine, to achieve the effect of preventing tumor re-inoculation, optimizing process parameters, and high toxicity and side effects

Pending Publication Date: 2022-07-26
SHANGHAI TENTH PEOPLES HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] A hollow MnO that can effectively load related drugs has been preliminarily designed. 2 Composite nanomaterials, but its loading of different drugs needs to be further studied, and its structure still needs to be further improved, and the prior art does not involve the direct loading of small molecule PI3K kinase inhibitors to hollow MnO 2 Reports on the Application of Composite Nanomaterials

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  • Manganese-based radiotherapy sensitizer as well as preparation method and application thereof
  • Manganese-based radiotherapy sensitizer as well as preparation method and application thereof
  • Manganese-based radiotherapy sensitizer as well as preparation method and application thereof

Examples

Experimental program
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Embodiment 1

[0054] Example 1 - Preparation of Manganese-Based Radiosensitizers

[0055] This embodiment provides a preparation method of a manganese-based radiosensitizer (IPI549@HMP) with dual functions of radiotherapy sensitization and immune regulation for inhibiting postoperative tumor recurrence, such as figure 1 As shown, the monodisperse hard-templated solid silica spheres (sSio 2 ), after reacting with potassium permanganate solution, a uniform layer of manganese dioxide is coated on the surface of the silica sphere; then, the obtained sSiO is treated with sodium carbonate solution 2 @MnO 2 Etched to obtain hollow manganese dioxide (HMnO 2 ); then, the obtained hollow manganese dioxide nanoparticles were modified with polyethylene glycol (PEG) to obtain PEGylated hollow manganese oxide nanoparticles (HMP) to improve their physiological stability; finally, IPI549 loaded into the hollow structure of HMP, resulting in the IPI549@HMP nanosystem for further experiments.

[0056] Th...

Embodiment 2

[0068] Example 2 - Validation of the efficacy of manganese-based radiosensitizers

[0069] In this example, the efficacy and performance of the manganese-based radiosensitizer IPI549@HMP prepared in Example 1 is verified by in vitro and in vivo experiments, which specifically include:

[0070] 1. Magnetic resonance effects of manganese-based radiosensitizers in vitro and in vivo

[0071] The T1 imaging performance of IPI549@HMP was monitored using a 3.0T magnetic resonance clinical scanner (United Imaging, uMR770) equipped with a mouse coil. The parameters of the instrument are set as: Freq.FOV=8.0mm 2 , phase FOV: 1.00mm 2 , Slice thickness: 2.0mm, Slices: 8, spacing=0.3mm, TR: 500ms, TE: 21ms. Different IPI549@HMP concentrations (0.64, 0.32, 0.16, 0.08, 0.04 mM) were measured by MR system (uExeed, R002) in PBS (pH=7.4), PBS (pH=6.5) and PBS (pH=6.5) containing H 2 O 2 (100 μM) T1-mapping and T1W1 images. For tumor imaging, intravenous injection of IPI549@HMP (mangane...

Embodiment 3

[0104] Example 3 - Radioimmunotherapy method of manganese-based radiosensitizers applied to animals

[0105] The manganese-based radiosensitizer IPI549@HMP prepared in step (7) in Example 1 of the present invention can be used for radioimmunotherapy, and the specific implementation steps are as follows: Balb / c mice are injected with IPI549@HMP (MnO 2 =7.5mg·kg -1 , IPI549=1.5mg·kg -1 ); received two doses of 3Gy of radiation therapy at 8 hours and 24 hours after drug injection.

[0106] The specific method of the above radioimmunotherapy is as follows: anesthetize the mice with 1% sodium pentobarbital according to the amount of 15g / 100μL; then place the anesthetized mice in an independent lead box, so that the tumor area is exposed and the body is exposed. The other parts of IPI549@HMP were completely shielded; X-ray irradiation was performed using an X-ray irradiator (RadSourceRS2000) with parameters set to 225KV and 8mA; IPI549@HMP was injected twice during the whole treat...

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Abstract

The invention discloses a manganese-based radiotherapy sensitizer. The manganese-based radiotherapy sensitizer is a pegylation hollow manganese oxide nanoparticle material loaded with a small molecule PI3K gamma kinase inhibitor; wherein the small molecule PI3K gamma kinase inhibitor is IPI549 (Institute of Phosphorus Institute 549). The invention also provides a preparation method of the manganese-based radiotherapy sensitizer and application of the manganese-based radiotherapy sensitizer in preparation of tumor therapeutic agents. The manganese-based radiotherapy sensitizer disclosed by the invention has dual functions of radiotherapy sensitization and immunoregulation, and can be applied to inhibition of remnant tumor recurrence; the manganese dioxide nanoparticles are degraded in an acidic tumor microenvironment, so that responsive drug release at a tumor site is realized, and radiotherapy of postoperative hypoxia relief can be realized; pI3K gamma inhibition radiotherapy-mediated immunogenic cell death effects are synergistic, so that after excision, the immunosuppressive TME is reprogrammed into an immunogenic phenotype, and meanwhile, the susceptibility of blocking treatment on an immune checkpoint is improved. Radiotherapy based on the manganese-based radiotherapy sensitizer is combined with PD-L1 blocking, so that local residual tumors and distant metastatic tumors can be remarkably inhibited, and tumor re-inoculation can be prevented.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a manganese-based radiotherapy sensitizer and a preparation method and application thereof. Manganese oxide nanoparticulate material. Background technique [0002] With the rapid development of nanotechnology, functionalized nanomaterials can be effectively used as adjunctive "drugs" against oxygen-dependent standard therapy against solid tumors. Among them, manganese oxide-based nanosystems (manganese dioxide NS) have been extensively studied as a unique tumor microenvironment responsive agent. Studies have shown that manganese dioxide nanoparticles can catalyze the production of oxygen from hydrogen peroxide overexpressed in the tumor microenvironment, thereby significantly alleviating tumor hypoxia. At the same time, manganese dioxide nanoparticles can be further decomposed into water-soluble Mn 2+ ions, achieve enhanced T1 magnetic resonance imaging, and are rapidly ex...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K41/00A61K31/519A61K47/69A61K47/60A61K49/12A61K49/18A61P35/00A61P35/04A61K33/32
CPCA61K47/6923A61K47/60A61K31/519A61K41/0038A61K33/32A61P35/00A61P35/04A61K49/1824A61K49/126
Inventor 徐辉雄官昕岳雯雯沈玉婷
Owner SHANGHAI TENTH PEOPLES HOSPITAL
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