Application of suramin sodium in the prevention and / or treatment of radiation-induced intestinal injury

Abstract

This invention relates to the fields of biology and medicine, and discloses the application of suramin sodium in the prevention and / or treatment of radiation-induced intestinal injury. The inventors of this invention have discovered that suramin sodium treats radiation-induced intestinal injury caused by local ionizing radiation by: improving intestinal tissue damage, promoting intestinal crypt cell regeneration, inhibiting intestinal cell apoptosis, and reducing serum inflammatory factor levels; therefore, it can be considered a potential drug for treating radiation-induced intestinal injury.

Description

Technical Field

[0001] This invention relates to the field of biomedicine, specifically to the use of sodium suramin in the prevention and / or treatment of radiation-induced intestinal injury. Background Technology

[0002] Radiation-induced intestinal injury refers to damage to intestinal tissue caused by radiation, typically resulting from radiation therapy for abdominal tumors (kidneys, adrenal glands, bladder, prostate, uterus, ovaries, etc.). After high-dose radiation, a large number of intestinal stem cells are depleted, thus blocking epithelial renewal and disrupting epithelial integrity. This disruption of the mucosal barrier further leads to fluid loss, electrolyte imbalance, sepsis, and even death. Currently, there are no approved drugs to prevent or mitigate radiation-induced intestinal injury. Despite advancements in medical technology, radiation therapy to the abdomen and pelvis inevitably causes intestinal damage, leading to acute and chronic gastrointestinal complications, thus limiting treatment effectiveness and reducing patients' quality of life. Therefore, there is an urgent need for radiation-protective agents with fewer side effects and better therapeutic efficacy to mitigate radiation-induced intestinal injury.

[0003] Suramin sodium salt is a reversible competitive protein tyrosine phosphatase (PTPases) inhibitor, a sirtuins inhibitor, a competitive reverse transcriptase inhibitor, and a SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) inhibitor. Suramin sodium effectively inhibits IP5K and is an antiparasitic, antitumor, and antiangiogenic agent. However, the role of suramin sodium in radiation-induced intestinal injury remains unclear. Summary of the Invention

[0004] In order to overcome the above-mentioned problems in the prior art, the present invention provides the use of sodium suramin in the prevention and / or treatment of radiation-induced intestinal injury.

[0005] The first aspect of the present invention provides the use of sodium suramin in the preparation of a medicament for the prevention and / or treatment of radiation-induced intestinal injury.

[0006] Sodium suramin, structure shown below:

[0007]

[0008] In this invention, radiation-induced intestinal injury refers to intestinal tissue damage caused by high-dose radiation exposure, typically occurring within a few days after high-dose radiation exposure. The main symptoms include abdominal pain and diarrhea, rectal tenesmus, mucus in stool, and rectal bleeding. Preferably, the radiation-induced intestinal injury is caused by localized ionizing radiation. This radiation-induced intestinal injury is a complication resulting from radiotherapy for malignant tumors in the abdomen and / or pelvis; that is, the target group for prevention and / or treatment is patients with malignant tumors. Generally, malignant tumors requiring radiotherapy include ovarian malignant tumors, endometrial cancer, cervical cancer, and pelvic malignant lymphoma. The absorbed dose of ionizing radiation energy that easily causes radiation-induced damage to ovarian malignant tumors, endometrial cancer, cervical cancer, and pelvic malignant lymphoma is 12-16 Gy / fraction (one fraction).

[0009] A second aspect of the present invention provides the use of sodium suramin in the preparation of a medicament for improving intestinal histopathological damage (intestinal histopathological damage in radiation-induced intestinal injury).

[0010] A third aspect of the present invention provides the use of sodium suramin in the preparation of a medicament for promoting the regeneration of intestinal crypt cells (in radiation-induced intestinal injury).

[0011] The fourth aspect of this invention provides the use of sodium suramin in the preparation of a medicament for inhibiting intestinal cell apoptosis (in radiation-induced intestinal injury).

[0012] The fifth aspect of this invention provides the use of suramin sodium in the preparation of a medicament for reducing the secretion of serum inflammatory factors (especially the secretion of serum inflammatory factors in patients with radiation-induced intestinal injury).

[0013] In a preferred embodiment of the present invention, the inflammatory factor is selected from at least one of TNF-α, IL-6, MCP-1, IL-10 and IL-12p70.

[0014] The “prevention and / or treatment” in this invention includes: relief of intestinal injury-related symptoms, including: relief of symptoms of inflammation and edema.

[0015] In this invention, there are no particular requirements for the method of administration of suramin sodium, but at least one of intravenous injection, intramuscular injection, and subcutaneous injection is preferred. Those skilled in the art can formulate suramin sodium into specific dosage forms, such as injections, according to the method of administration.

[0016] In this invention, the patient may include a mammal, such as a mouse or a human.

[0017] In this invention, the dosage of suramin sodium can be determined according to the patient's condition. For example, in mice, the dosage of suramin sodium can be 10-50 mg / kg body weight / day.

[0018] Suramin sodium can improve histopathological damage, promote the regeneration of intestinal crypt cells, inhibit intestinal cell apoptosis, and reduce serum inflammatory factor levels. Therefore, suramin sodium can be used as a potential drug for the prevention and / or treatment of radiation-induced intestinal injury. Attached Figure Description

[0019] Figure 1 The image shows the results of sodium suramin improving intestinal tissue damage in radiation-induced intestinal injury.

[0020] Figure 2 The image shows the results of sodium suramin promoting the regeneration of intestinal crypt cells in radiation-induced intestinal injury.

[0021] Figure 3 The image shows the results of sodium suramin inhibiting intestinal cell apoptosis in radiation-induced intestinal injury.

[0022] Figure 4 The graph shows the results of sodium suramin reducing serum inflammatory factor secretion in radiation-induced intestinal injury. Detailed Implementation

[0023] The present invention will be described in detail below through examples. In the following examples, the number of mice in each treatment group is 6.

[0024] Example 1

[0025] Male C57BL / 6J mice, approximately 8-10 weeks old, were subjected to abdominal examination. 60 A radiation-induced intestinal injury model was established by irradiation with 14 Gy of Co. Specifically, suramin sodium solution was administered intraperitoneally to mice in the suramin group (injected with suramin) and the irradiated suramin group (injected with suramin after irradiation) at a dose of 20 mg / kg 16 hours before and 6 hours after irradiation. The same dose of the solvent was injected into the control group (NC) and the irradiated group (IR+NC). Subsequent intraperitoneal injections were administered every other day at the same time. The model was established over a period of 4 days. The mice were then treated as follows:

[0026] (1) Sodium suramin improves radiation-induced intestinal injury and midgut tissue damage.

[0027] Radiation significantly reduces intestinal villus length and crypt depth, leading to loss of intestinal absorption and barrier function. After the intestinal barrier function is disrupted, a large number of intestinal bacteria invade the body, subsequently causing multi-organ failure. Therefore, intestinal villus length and crypt depth are among the most direct indicators for assessing radiation-induced intestinal injury. To evaluate the protective effect of sodium suramin against radiation-induced intestinal injury, intestinal tissue was collected 4 days after radiation exposure and stained with hematoxylin and eosin (HE) using the Solarbauer hematoxylin and eosin (HE) staining kit, G1120). Images were observed and acquired under an optical microscope. Results showed that the intestinal structure of mice in the NC and Suramin groups was intact, with neatly arranged and morphologically complete villus, and clearly distinguishable crypt size and outline without significant loss. Four days after irradiation, the intestinal mucosal structure of mice in the IR group was significantly damaged, with villus loss and irregular crypt arrangement. Compared with the IR group, the intestinal villus structure of mice in the IR+Suramin group was relatively intact, and the difference in villus length was statistically significant. Figure 1 (* indicates p < 0.05). These results indicate that sodium suramin can improve intestinal tissue structure damage in radiation-induced intestinal injury.

[0028] (2) Sodium suramin promotes the regeneration of midgut crypt cells in radiation-induced intestinal injury.

[0029] Under normal circumstances, intestinal stem cells at the base of the intestinal crypts continuously proliferate and differentiate to ensure normal turnover of intestinal tissue. After intestinal damage, intestinal stem cells proliferate rapidly, promoting the regeneration and repair of the intestinal mucosa. 5-Bromodeoxyuridine (BrdU) is a nucleoside analog that can compete with thymidine for DNA incorporation and is commonly used to detect proliferating cells. Colorimetric staining with a BrdU-specific antibody can accurately reflect cell proliferation and assess cell proliferative capacity. Four days after irradiation, intestinal tissue was collected 1 hour after intraperitoneal injection of BrdU (100 mg / kg) and subjected to BrdU immunohistochemical staining (MedChemExpress, #HY-15910). Images were observed and acquired under a light microscope. Results showed that on day 4 post-irradiation, the number of BrdU-positive crypt cells in the IR group was significantly reduced, while the number of BrdU-positive crypt cells in the IR+Suramin group was significantly increased; both differences were statistically significant. Figure 2 "**" indicates p < 0.01.

[0030] (3) Sodium suramin inhibits intestinal cell apoptosis in radiation-induced intestinal injury.

[0031] Radiation leads to the production of large amounts of reactive oxygen species in the body, which in turn rapidly induces apoptosis of intestinal cells. Therefore, the apoptosis of crypt cells was observed 6 hours after irradiation. Terminal deoxynucleotidyl transferase (dUTP) nick-terminal (TUNEL) labeling of apoptotic cell nuclei has been widely used in the study of apoptosis. After 6 hours of irradiation, intestinal tissue was collected, and TUNEL immunohistochemical staining (Boster Biologics TUNEL Apoptosis Two-Step Detection Kit (POD)) was performed. Images were then observed and acquired under a light microscope. The results showed that after 6 hours of irradiation, the apoptosis rate of intestinal cells in the IR group was significantly increased, while the apoptosis rate in the IR+Suramin group was significantly decreased, and the difference was statistically significant. Figure 3 "**" indicates p < 0.01.

[0032] (4) Sodium suramin reduces the secretion of serum inflammatory factors in radiation-induced intestinal injury.

[0033] Radiation causes the body to produce large amounts of PAMPs and DAMPs, activating the immune system and generating an inflammatory response, thereby causing a significant increase in the level of inflammatory factors in the serum. Before collecting mouse intestinal tissue in step (1), mouse serum samples were collected, and the effect of suramin sodium on the secretion of inflammatory factors in mouse systemic serum was detected by micro-sample multi-index flow cytometry (Cytometric Bead Array, CBA). The results showed that the serum levels of TNF-α, IL-6, MCP-1, IL-10, and IL-12p70 in the IR group were significantly higher than those in the NC group (P<0.0001), while the serum levels of TNF-α, IL-6, MCP-1, IL-10, and IL-12p70 in the IR+Suramin group were significantly lower than those in the IR group, and the differences were statistically significant. Figure 4 "*" indicates P < 0.05, "**" indicates P < 0.01, and "****" indicates P < 0.0001.

[0034] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. The use of sodium suramin in the preparation of a medicament for the prevention and / or treatment of radiation-induced intestinal injury, wherein the radiation-induced intestinal injury is intestinal injury caused by local irradiation with ionizing radiation, wherein the energy absorbed dose of the ionizing radiation is 12-16 Gy / exposure.

2. The application according to claim 1, wherein, The radiation-induced intestinal injury is a complication caused by radiotherapy for malignant tumors in the abdomen.

3. The application according to claim 1, wherein, The radiation-induced intestinal injury is a complication caused by radiotherapy for malignant tumors in the pelvis.

4. The application according to claim 2 or 3, wherein, The malignant tumor is at least one of the following: ovarian malignant tumor, endometrial cancer, cervical cancer, and pelvic malignant lymphoma.

5. The application according to any one of claims 1-3, wherein, The sodium suramin is used to improve pathological damage to intestinal tissue.

6. The application according to any one of claims 1-3, wherein, The sodium suramin is used to promote the regeneration of intestinal crypt cells.

7. The application according to any one of claims 1-3, wherein, The sodium suramin is used to inhibit intestinal cell apoptosis.

8. The application according to any one of claims 1-3, wherein, The sodium suramin is used to reduce the secretion of serum inflammatory factors.

9. The application according to claim 8, wherein, The inflammatory factors are selected from at least one of TNF-α, IL-6, MCP-1, IL-10 and IL-12p70.

Images