CN-122005592-A - Pharmaceutical composition for inhibiting tumor drug resistance and application thereof

Abstract

The invention discloses a pharmaceutical composition for inhibiting tumor resistance and application thereof, wherein the pharmaceutical composition comprises an exosome inhibitor, nidamib and gemcitabine, the exosome inhibitor, the Nidamib and the gemcitabine are used together, so that the cell viability of CTS can be obviously reduced, the proportion of apoptotic cells in CTS can be obviously improved, the pharmaceutical composition interferes with the process of interconversion between normal fibroblasts and CAFs, the CAFs existing in TME is restored into normal fibroblasts, meanwhile, the secretion and release of EVs are inhibited, and the formation of new CAFs is reduced, thereby successfully reversing the drug resistance of tumors.

Inventors

• SUN ZHIXUE
• LU WEI

Assignees

• 浙江迈镝生物科技有限公司

Dates

Publication Date

20260512

Application Date

20260402

Claims (8)

1. 1. A pharmaceutical composition for inhibiting tumor resistance, comprising an exosome inhibitor, nidanib, and gemcitabine.
2. 2. The pharmaceutical composition for inhibiting tumor resistance according to claim 1, wherein the concentration ratio of the exosome inhibitor to the nintedanib to the gemcitabine in the pharmaceutical composition is 1-2 to 1-2.
3. 3. The pharmaceutical composition for inhibiting tumor resistance according to claim 1, wherein the exosome inhibitor is GW4869.
4. 4. A pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 1-3 and a pharmaceutically acceptable adjuvant.
5. 5. A pharmaceutical formulation according to claim 4, wherein the pharmaceutical formulation is in the form of an injection, tablet, capsule, granule, suspension, emulsion, solution, sol, lyophilized powder for injection, cement, aerosol, microcapsule, microsphere, liposome, micelle, sustained release formulation or controlled release formulation.
6. 6. Use of a pharmaceutical composition according to any one of claims 1-3 for the preparation of a medicament for inhibiting tumor resistance.
7. 7. Use of a pharmaceutical composition according to any one of claims 1-3 for the preparation of a medicament for reversing tumor resistance.
8. 8. The method of claim 7, wherein the agent is used to normalize CAFs activated tumor cells while decreasing their viability.

Description

Pharmaceutical composition for inhibiting tumor drug resistance and application thereof Technical Field The invention belongs to the field of medicines, and in particular relates to a pharmaceutical composition for inhibiting tumor drug resistance and application thereof. Background Tumor resistance is one of the major causes of failure of clinical chemotherapy and poor prognosis for patients. Traditional views have focused on genetic mutations in tumor cells themselves, but recent studies have shown that Tumor Microenvironment (TME) plays a key role in mediating acquired drug resistance. The tumor microenvironment is composed of various stromal cells, extracellular matrix and signal molecules, wherein abnormal communication between non-tumor cells and tumor cells can significantly influence the effect of tumor treatment. Cancer-associated fibroblasts (CAFs) are the most abundant stromal cell fraction in the tumor microenvironment. Under the continuous stimulation of factors such as extracellular vesicles secreted by tumor cells, normally quiescent fibroblasts are activated and transformed into cancer-associated fibroblasts with myofibroblast phenotype. The activated cancer-related fibroblasts induce tumor to generate drug resistance through multiple mechanisms, namely, on one hand, the cancer-related fibroblasts transmit specific microRNAs and cytokines to tumor cells through a paracrine mode to directly activate anti-apoptosis signal channels in the tumor cells, and on the other hand, the cancer-related fibroblasts form a compact physical barrier on the periphery of the tumor through depositing extracellular matrix proteins, which not only prevents effective infiltration of immune cells, but also limits infiltration of chemotherapeutic drugs to the deep part of the tumor. In addition, cancer-associated fibroblasts themselves can also inhibit the activity of immune cells, resulting in tumors that are resistant to immunotherapy. Thus, disrupting the communication between fibroblasts and tumor cells, reversing the pro-neoplastic phenotype of cancer-associated fibroblasts, has become an important strategy to overcome tumor resistance. At present, the intervention strategy aiming at the tumor microenvironment mainly faces two major challenges, namely that a large number of inherent cancer-related fibroblasts exist in the tumor microenvironment when the tumor is diagnosed, and that the tumor cells continuously release the secretion factors such as Extracellular Vesicles (EVs) and the like in the treatment process, so that new fibroblasts are continuously activated into the cancer-related fibroblasts to form malignant circulation. Although a single anti-fibrotic drug can act on a partially activated phenotype, it is difficult to prevent the sustained production of new-born cancer-associated fibroblasts, while simply inhibiting extracellular vesicle release does not reverse existing cancer-associated fibroblasts. Thus, there is a need to develop a combination regimen that can simultaneously interfere with the cancer-associated fibroblast maintenance and neogenesis process. Disclosure of Invention In order to solve at least one of the problems, the invention provides a pharmaceutical composition for inhibiting tumor resistance and application thereof. In order to achieve the above purpose, the invention adopts the following technical means: The invention provides a pharmaceutical composition for inhibiting tumor resistance, which comprises an exosome inhibitor, nidanib and gemcitabine. In some embodiments of the invention, the concentration ratio of exosome inhibitor, nidanib, gemcitabine in the pharmaceutical composition (1-2): 1 (1-2). In some embodiments of the invention, the concentration of the exosome inhibitor is 10. Mu. Mol/L, the concentration of the nilamide is 5. Mu. Mol/L, and the concentration of the gemcitabine is 10. Mu. Mol/L. In some embodiments of the invention, preferably, the exosome inhibitor in the pharmaceutical composition is GW4869. In a second aspect of the present invention there is provided a pharmaceutical formulation comprising a pharmaceutical composition according to the first aspect and a pharmaceutically acceptable adjuvant. According to different prepared pharmaceutical formulations, common auxiliary materials comprise starch, dextrin, powdered sugar, lactose, microcrystalline cellulose, medicinal calcium sulfate, medicinal calcium carbonate, glycerol, gelatin, ethyl oleate, myristyl alcohol, polysorbate and the like. In some embodiments of the invention, the pharmaceutical formulation is in the form of an injection, tablet, capsule, granule, suspension, emulsion, solution, sol, lyophilized powder for injection, mucilage, aerosol, microcapsule, microsphere, liposome, micelle, sustained release formulation or controlled release formulation. Use of the pharmaceutical composition according to the first aspect for the preparation of a medicament for inhibiting tumor resistance. Use o