Use of pachymic acid B in the preparation of a drug for preventing or reducing peritoneal metastasis of gastric cancer

Abstract

The application discloses application of pachymic acid B in preparation of a medicine for preventing peritoneal metastasis of gastric cancer and a medicine composition thereof. The pachymic acid B is chemically named as 3-O-acetyl-16alpha-hydroxydehydrotrametenolic acid. The in-situ transplantation peritoneal metastasis model of the gastric cancer proves that intraperitoneal injection of the pachymic acid B can significantly reduce the number of peritoneal metastasis nodules and tumor load, the prevention effect is equivalent to that of oxaliplatin, and there is no obvious organ toxicity. Further experiments prove that the pachymic acid B can up-regulate the mRNA and protein expression levels of SPRED2 genes in peritoneal tissues of the gastric cancer, and plays a role in a time-dose dependent manner. The pachymic acid B provided by the application is administered by intraperitoneal injection, can be prepared into a suspension containing sodium carboxymethyl cellulose, and is especially suitable for perioperative administration of gastric cancer primary focus resection. Compared with the prior art, the application has the advantages of clear composition, novel action mechanism, high safety, simple operation, strong accessibility and the like.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the use of pachymic acid B and its compositions in the preparation of drugs for the prevention and / or treatment of peritoneal metastasis of gastric cancer, as well as pharmaceutical compositions with pachymic acid B as the active ingredient, particularly to preparations suitable for intraperitoneal injection and their application in the perioperative period of gastric cancer. Background Technology

[0002] Gastric cancer is a malignant tumor originating from the gastric mucosal epithelium. Peritoneal metastasis is one of the most common modes of metastasis in gastric cancer and a major cause of poor prognosis and significantly shortened survival. Peritoneal metastasis of gastric cancer refers to the pathological process in which gastric cancer cells detach from the primary lesion and implant, proliferate, and form metastatic nodules in the parietal peritoneum, visceral peritoneum, and greater omentum. In the early stages, these are often micrometastases that cannot be detected by imaging. Once they progress to visible metastases, the clinical treatment outcome is extremely poor.

[0003] Currently, the main clinical methods for preventing peritoneal metastasis of gastric cancer include surgical tumor-free techniques and prophylactic intraperitoneal chemotherapy (HIPEC / NIPEC). Surgical tumor-free techniques reduce iatrogenic dissemination by avoiding tumor compression during surgery, isolating tumor tissue, and thoroughly irrigating the peritoneal cavity. However, this technique lacks standardized quantitative operating procedures, is highly dependent on the surgeon's experience, and cannot remove pre-existing peritoneal micrometastases, resulting in limited preventative efficacy. Prophylactic hyperthermic intraperitoneal chemotherapy (HIPEC) kills free tumor cells through intraperitoneal perfusion of chemotherapy drugs at high temperatures, but it faces the following challenges: prolonged surgery and anesthesia time, increased risk of complications such as chemical peritonitis, intestinal adhesions, bone marrow suppression, and liver and kidney damage; high-temperature perfusion can affect anastomotic healing, increasing the probability of anastomotic leakage, bleeding, and peritoneal infection; at the same time, HIPEC requires specialized hyperthermic perfusion equipment and multidisciplinary team cooperation, placing high demands on equipment and technical teams, which limits its widespread clinical application. Furthermore, the drug's tissue penetration ability is weak, and its tumor-killing efficacy is low. The optimal dosing regimen and the target population for benefit are not yet clear.

[0004] Existing technologies include patents disclosing that poricoic acid A can be used to prepare diuretics and drugs for treating chronic kidney disease, but no patents or literature disclose a technical solution for using poricoic acid B to prevent or treat peritoneal metastasis of gastric cancer. This invention addresses the shortcomings of existing technologies by providing a safe, efficient, easy-to-operate, and readily accessible method for preventing peritoneal metastasis of gastric cancer, which has significant clinical value. Summary of the Invention

[0005] We have found that some patients with advanced gastric cancer exhibit primary or secondary immunotherapy resistance during treatment. One of the important mechanisms is the low expression and loss of protein function of the tumor suppressor gene SPRED2 in gastric cancer tissue. Currently, there is no effective method to improve the efficacy of gastric cancer immunotherapy and inhibit peritoneal metastasis by upregulating SPRED2 expression.

[0006] The technical problem to be solved by this invention is to overcome the shortcomings of surgical tumor-free techniques, such as inability to remove peritoneal micrometastases, reliance on surgeon experience, and difficulty in standardization, as well as the problems of high toxicity, numerous complications, complex operation, high cost, and poor accessibility of prophylactic intraperitoneal chemotherapy. The invention provides a natural, low-toxicity, and highly targeted active ingredient for the preparation of drugs to prevent peritoneal metastasis of gastric cancer, achieving effective inhibition of peritoneal micrometastases, and is suitable for perioperative application in gastric cancer.

[0007] This invention provides a naturally derived, low-toxicity, and highly targeted active ingredient for the preparation of drugs to prevent peritoneal metastasis of gastric cancer, achieving effective inhibition of peritoneal micrometastases and suitable for perioperative application in gastric cancer.

[0008] The pachymic acid B disclosed in this invention, chemically named 3-O-acetyl-16α-hydroxydehydrotrametenolic acid, is a triterpenoid compound extracted and isolated from Poria cocos. Its molecular formula and purity meet pharmaceutical requirements. It is a clearly defined single active ingredient, rather than a crude extract of Poria cocos or a mixture of multiple components. This invention provides the application of pachymic acid B and its compositions in the preparation of drugs for preventing peritoneal metastasis of gastric cancer.

[0009] Furthermore, pamoate B exerts its preventive and / or therapeutic effects on peritoneal metastasis of gastric cancer by upregulating the SPRED2 gene.

[0010] Furthermore, pachymic acid B upregulates SPRED2 gene expression in a time-dose dependent manner.

[0011] Furthermore, pamoate B is administered via intraperitoneal injection.

[0012] Furthermore, the dosage of pamoate B is 5-20 mg / kg, administered once daily.

[0013] Furthermore, pachymic acid B is prepared as a solution or suspension.

[0014] Furthermore, suspensions contain pharmaceutically acceptable suspending agents.

[0015] Furthermore, the suspending agent is sodium carboxymethyl cellulose.

[0016] Furthermore, pamoate B is used for the prevention and / or treatment of perioperative peritoneal metastases of gastric cancer following surgical resection of the primary gastric cancer lesion.

[0017] In another aspect, the present invention provides a pharmaceutical composition for the prevention and / or treatment of peritoneal metastasis of gastric cancer, wherein the active ingredient is pachymic acid B, the chemical name of which is 3-O-acetyl-16α-hydroxydehydrotrametenolic acid.

[0018] Furthermore, the pharmaceutical composition is a formulation for intraperitoneal injection.

[0019] Furthermore, the intraperitoneal injection formulation comprises pamoate B and a pharmaceutically acceptable suspending agent or solubilizer, wherein the suspending agent is sodium carboxymethyl cellulose.

[0020] Furthermore, the pharmaceutical composition is used for the prevention and / or treatment of perioperative peritoneal metastasis of gastric cancer following surgical resection of the primary gastric cancer lesion.

[0021] Furthermore, the administration method and timing of pamoate B or its pharmaceutical composition: administered via intraperitoneal injection, the drug is directly distributed in the peritoneal cavity, resulting in high local concentration and strong targeting, avoiding the first-pass effect; the preferred timing of administration is the perioperative period after surgical resection of the primary gastric cancer lesion, including preoperative, intraoperative, and early postoperative periods, allowing for multiple administrations to cover the high-risk window for peritoneal metastasis.

[0022] The beneficial effects of this invention are:

[0023] 1) The mechanism of action is clear and novel: For the first time, it has been demonstrated that pachymic acid B can play a role in preventing and / or treating peritoneal metastasis of gastric cancer by upregulating SPRED2 gene expression, filling the gap in the development of drugs with this mechanism of action for the prevention and / or treatment of peritoneal metastasis of gastric cancer;

[0024] 2) Excellent safety: Poria cocos B is a triterpenoid compound of natural origin. It has low local irritation and low systemic toxicity when injected intraperitoneally. It does not have the adverse reactions such as bone marrow suppression, severe liver and kidney damage, and neurotoxicity caused by traditional chemotherapy drugs. Its safety is significantly better than that of HIPEC / NIPEC.

[0025] 3) Strong targeting: Intraperitoneal injection acts directly on the high-incidence sites of peritoneal metastasis, resulting in high local drug concentrations and direct action on free tumor cells and micrometastases, with definite preventive effects;

[0026] Simple to operate and highly accessible: No special hyperthermic perfusion equipment is required, it can be carried out in hospitals at all levels, and multiple administrations can be given during the perioperative period. It has a wide therapeutic window and high flexibility.

[0027] 4) Simple operation and high accessibility: No special hyperthermic perfusion equipment is required, it can be carried out in hospitals at all levels, and multiple administrations can be given during the perioperative period. It has a wide treatment window and high flexibility.

[0028] 5) Clear composition and controllable quality: With a single compound, pachymic acid B, as the active ingredient, it is different from crude extracts of traditional Chinese medicine. Its quality is controllable and its stability is good, which meets the requirements of modern drug development.

[0029] 6) Overcoming the shortcomings of existing technologies: It can eliminate the risk of intraoperative iatrogenic dissemination and inhibit pre-existing micrometastases, comprehensively covering the needs for prevention of peritoneal metastasis in gastric cancer. Attached Figure Description

[0030] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0031] Figure 1 The figures show in vivo imaging of peritoneal tumor fluorescence signals in mice of each group. Note: The figures, in order, represent the model control group, pamoate B 5 mg / kg group, pamoate B 10 mg / kg group, pamoate B 20 mg / kg group, and oxaliplatin 5 mg / kg group. Compared with the model control group, the peritoneal fluorescence signals in each dose group of pamoate B were significantly reduced, the tumor metastasis burden was significantly decreased, and the preventive effect was comparable to that of the positive control drug oxaliplatin.

[0032] Figure 2 .Statistical graph showing the number of peritoneal metastatic nodules in each group of mice. Note: Ctrl represents the model control group, FB5 / 10 / 20mg / kg represent the different dose groups of pamoate B, and Oxaliplatin represents the oxaliplatin positive control group; compared with the model control group, the number of peritoneal metastatic nodules in the pamoate B group was significantly reduced, and the difference was statistically significant (****P<0.0001).

[0033] Figure 3 Immunohistochemical images of E-cadherin and Vimentin in peritoneal tissues of mice in each group. Note: Ctrl represents the model control group, and FB represents the group treated with pachymic acid B. Compared with the control group, the positive staining intensity of E-cadherin and Vimentin in the peritoneal tissue of the pachymic acid B group was significantly reduced, indicating that pachymic acid B can effectively inhibit the epithelial-mesenchymal transition (EMT) process of gastric cancer cells.

[0034] Figure 4The expression of Spred2 protein in human gastric cancer MKN-45 cells was detected by Western blotting after treatment with different concentrations of pamoate B. NC was the solvent control group (without pamoate B, final DMSO concentration ≤0.1%); 20, 40, and 60 represented pamoate B treatment concentrations of 20 μg / mL, 40 μg / mL, and 60 μg / mL, respectively; GAPDH (molecular weight 36 kDa) was used as the internal reference protein, and the target protein Spred2 had a molecular weight of 46 kDa.

[0035] Figure 5 The images show HE staining and biochemical indicators of major organs in mice of each group. Note: The top image shows HE staining results for the heart, liver, spleen, lungs, and kidneys; Ctrl represents the model control group, and FB represents the group treated with poria cocos B. Both groups showed intact organ and tissue structures without pathological damage. The bottom image shows liver and kidney function indicators such as TBIL, TP, AST, ALT, ALP, CRE, UA, and UREA. There were no significant differences between the poria cocos B group and the control group, confirming the good safety of intraperitoneal administration. Detailed Implementation

[0036] The present invention will be further described in detail below through specific embodiments. These embodiments are only for illustrating the present invention and do not limit the scope of protection of the present invention. Non-essential improvements and adjustments made by those skilled in the art based on the content of the present invention are all within the scope of protection of the present invention.

[0037] Example 1: Preparation of Poria cocos B intraperitoneal injection suspension

[0038] Weigh out the raw material of pamoate B (purity ≥98%), add 0.5% (w / v) sodium carboxymethyl cellulose (CMC-Na) aqueous solution, grind and mix well to prepare a pamoate B suspension with a concentration of 2 mg / mL, store it at 4℃, and shake well before administration to obtain the preparation for intraperitoneal injection.

[0039] Example 2: In vivo pharmacodynamic experiment of pamoate B in preventing peritoneal metastasis of gastric cancer.

[0040] 2.1 Experimental Materials

[0041] Laboratory animals: SPF-grade BALB / c nude mice, male, 4-6 weeks old, weighing 18-22 g, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0042] Cell line: Human gastric cancer MKN-45-luc fluorescently labeled cell line (provided by the Cell Bank of the Chinese Academy of Sciences Type Culture Collection Committee).

[0043] Drugs: Poria cocos B (purity ≥98%, Shanghai Yuanye Biotechnology Co., Ltd.); Oxaliplatin (Sigma-Aldrich).

[0044] 2.2 Model Establishment and Group Dosing

[0045] MKN-45-luc cells were subcutaneously inoculated on the back of nude mice. When the subcutaneous tumor volume reached 0.8-1.0 cm³, the tumor tissue was aseptically dissected, cut into 1 mm³ pieces, and transplanted in situ into the subserosal layer of the nude mouse stomach. The incision was then sutured to establish a peritoneal metastasis model of gastric cancer in situ transplantation.

[0046] Twenty-four hours after successful modeling, the mice were randomly divided into 5 groups of 10 mice each, and the administration methods were as follows:

[0047] (1) Low-dose group of pamoate B: The suspension prepared in Example 1 was injected intraperitoneally at a dose of 5 mg / kg once a day for 21 consecutive days;

[0048] (2) Medium dose group of pamoate B: Intraperitoneal injection of the suspension prepared in Example 1, the dosage was 10 mg / kg, once a day for 21 consecutive days;

[0049] (3) High-dose group of pamoate B: Intraperitoneal injection of the suspension prepared in Example 1, dose of 20 mg / kg, once a day for 21 consecutive days;

[0050] (4) Model control group: Intraperitoneal injection of 0.5% CMC-Na solvent, 20 mL / kg, once a day for 21 consecutive days;

[0051] (5) Positive control group: intraperitoneal injection of oxaliplatin solution (dissolved in 5% glucose aqueous solution), dose 5 mg / kg, once every 2 days, for a total of 11 times (equivalent to 21 days).

[0052] 2.3 Detection Indicators

[0053] (1) Peritoneal fluorescence signals were detected weekly using a small animal in vivo imaging system (IVIS Spectrum, PerkinElmer) to quantitatively analyze tumor metastasis burden. The results are shown in […]. Figure 1 .

[0054] (2) After administration, the mice were sacrificed, the peritoneum was dissected, the number of metastatic nodules on the peritoneal surface was counted, and the diameter of the largest nodule was measured. The results are shown in […]. Figure 2 .

[0055] 2.4 Experimental Results

[0056] like Figure 1As shown, compared with the model control group, the peritoneal metastasis burden in mice in the low, medium, and high dose groups of pamoate B was reduced by 72.3%, 78.6%, and 81.5%, respectively (P<0.01), and the tumor fluorescence signal was significantly reduced. The preventive effect was not statistically different from that in the oxaliplatin group (reduction of 79.2%, P<0.01). Mice in each dose group of pamoate B maintained stable body weight, and no adverse events such as organ damage, reduced activity, prickly hair, or death were observed, indicating good safety.

[0057] like Figure 2 As shown, the number of peritoneal metastatic nodules in the medium and high dose groups of poria cocos B (24.5% and 18.2% of the control group, respectively) and the largest nodule diameter (29.1% and 22.4% of the control group, respectively) were significantly smaller than those in the model control group (P<0.01).

[0058] Example 3: Effect of pachymic acid B on epithelial-mesenchymal transition (EMT) related markers

[0059] Experimental methods:

[0060] 1. Experimental Methods: Peritoneal tissue specimens from mice in each group after the orthotopic peritoneal tumor model experiment in Example 2 were collected, fixed with 4% paraformaldehyde, embedded in paraffin, and serially sectioned (4 μm thick). Immunohistochemistry (IHC) was used to detect the expression levels of epithelial marker E-cadherin (E-cad) and stromal marker Vimentin (Vim) in the peritoneal tissue. The specific steps are as follows: After dewaxing and hydration of paraffin sections, antigen heat retrieval was performed using citrate buffer, and endogenous peroxidase activity was blocked with 3% hydrogen peroxide solution. Non-specific binding sites were blocked with 5% bovine serum albumin (BSA); E-cadherin and Vimentin primary antibody working solutions were added and incubated overnight at 4°C; the next day, horseradish peroxidase (HRP)-labeled secondary antibody was added and incubated at room temperature for 1 hour; DAB chromogenic solution was used for staining, hematoxylin was used to counterstain cell nuclei, and after dehydration, clearing, and mounting, the slides were observed and images were acquired under an optical microscope; brown-yellow / brown staining was used as a positive expression signal, and the expression differences of E-cadherin and Vimentin in peritoneal tissue between the control group and the poria cocos B-treated group were compared and analyzed.

[0061] Experimental results:

[0062] like Figure 3The results show the immunohistochemical staining of peritoneal tissues from mice in the control group (Ctrl) and the pachymic acid B treatment group (scale bar consistent): E-cadherin (E-cad) expression: Abundant brown-yellow positive staining was observed in the peritoneal tissue of the control group, indicating high E-cadherin expression; in the pachymic acid B treatment group, brown-yellow positive staining was significantly reduced, and E-cadherin expression was significantly downregulated. Vimentin (Vim) expression: Scattered brown-yellow positive staining was observed in the peritoneal tissue of the control group, indicating basal Vimentin expression; in the pachymic acid B treatment group, brown-yellow positive staining was further reduced, and Vimentin expression was further decreased compared to the control group. Overall staining characteristics: After intervention with pachymic acid B, the expression of epithelial-mesenchymal transition (EMT) related markers in the peritoneal tissue changed significantly. The positive staining intensity of E-cadherin and Vimentin was significantly weaker than that of the control group, indicating that pachymic acid B can significantly inhibit epithelial-mesenchymal transition during gastric cancer peritoneal metastasis.

[0063] Example 4: Regulatory effect of pachymic acid B on Spred2 protein expression in human gastric cancer MKN-45 cells.

[0064] I. Experimental Materials and Equipment

[0065] 1. Cell line: Human gastric cancer MKN-45 cells (source can be noted, such as the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences), cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U / mL penicillin and 100 μg / mL streptomycin, and routinely cultured in a 37℃, 5% CO2 saturated humidity incubator.

[0066] 2. Test drug: Poria cocos B (purity ≥98%, verified by HPLC), prepared into a 10 mg / mL stock solution with DMSO, stored at -20℃ protected from light, diluted with culture medium to the required working concentration before use, with a final DMSO concentration ≤0.1% (v / v), and a solvent control group (NC, i.e., 0 μg / mL group) without poria cocos B was set up.

[0067] 3. Main reagents and consumables: RIPA lysis buffer, BCA protein quantification kit, SDS-PAGE gel preparation kit, PVDF membrane, Spred2 primary antibody (rabbit, 1:1000 dilution), GAPDH primary antibody (mouse, 1:5000 dilution), HRP-labeled goat anti-rabbit / anti-mouse secondary antibody (1:5000 dilution), ECL chemiluminescence detection kit, etc.

[0068] 4. Main equipment: CO2 incubator, high-speed refrigerated centrifuge, vertical electrophoresis system, semi-dry transfer apparatus, chemiluminescence imaging system.

[0069] II. Experimental Methods

[0070] 1. Cell treatment: MKN-45 cells in logarithmic growth phase were treated with 1×10⁻⁶ cells / cells. 6 Cells were seeded per well in 6-well plates. When the cells adhered and grew to 70%-80% confluence, complete culture medium containing 0 μg / mL (solvent control group, NC), 20 μg / mL, 40 μg / mL, and 60 μg / mL pamoate B was added respectively, and the cells were cultured for another 24 h.

[0071] 2. Total Protein Extraction and Quantification: After treatment, discard the culture medium, wash cells twice with pre-cooled PBS, add 100 μL of RIPA lysis buffer containing protease inhibitors to each well, and lyse on ice for 30 min; scrape cells and transfer them to 1.5 mL EP tubes, centrifuge at 12000 rpm for 15 min at 4 °C, and collect the supernatant as total protein. Protein concentration was determined using the BCA method. After adjusting the protein concentration of each group to be consistent, add 5× loading buffer, denature in boiling water for 10 min, and store at -80 °C for later use.

[0072] 3. SDS-PAGE electrophoresis and transfer: Prepare a 10% separating gel and a 5% stacking gel. Load equal amounts of protein (30 μg / well) onto each well. Electrophore at a constant voltage of 80V until the bromophenol blue indicator enters the separating gel. Adjust the voltage to 120V and continue electrophoresis until the bromophenol blue indicator migrates to the bottom of the gel. Use a semi-dry transfer method to transfer the protein from the gel to a PVDF membrane. Transfer conditions are 25V for 15 min.

[0073] 4. Blocking and antibody incubation: After the transfer was completed, the PVDF membrane was placed in 5% skim milk (prepared with TBST) and blocked at room temperature for 1 hour. The blocking solution was discarded, and the membrane was washed 3 times with TBST (5 min each time). Diluted Spred2 primary antibody (1:1000) and GAPDH primary antibody (1:5000) were added respectively, and the membrane was incubated overnight at 4°C. The next day, the membrane was washed 3 times with TBST (5 min each time), and the corresponding HRP-labeled secondary antibody (1:5000) was added and incubated at room temperature for 1 hour. The membrane was washed 3 times with TBST (5 min each time).

[0074] 5. Development and Imaging Analysis: ECL luminescent solutions A and B were mixed in a 1:1 ratio and uniformly dropped onto the PVDF film. The film was then exposed and images were acquired using a chemiluminescence imaging system (see results). Figure 4 ImageJ software was used to perform quantitative analysis of the band gray values, and GAPDH was used as an internal reference to calculate the relative expression level of Spred2 protein in each group.

[0075] III. Experimental Results and Conclusions

[0076] like Figure 4(Western Blot results, where the upper band represents Spred2 protein with a molecular weight of approximately 46 kDa; the lower band represents the internal control GAPDH protein with a molecular weight of approximately 36 kDa) As shown, compared with the solvent control group (NC), the gray values ​​of the Spred2 protein band in the 20, 40, and 60 μg / mL pachymic acid B treatment groups significantly increased with increasing drug concentration; the gray value quantitative analysis results showed that the relative expression level of Spred2 protein showed a significant concentration-dependent upregulation trend with increasing pachymic acid B concentration.

[0077] The above results indicate that pachymic acid B can upregulate the expression level of Spred2 protein in human gastric cancer MKN-45 cells in vitro in a concentration-dependent manner, suggesting that pachymic acid B can exert its anti-gastric cancer biological activity by regulating the expression of Spred2 protein, providing direct experimental evidence for the application of pachymic acid B in the preparation of gastric cancer therapeutic drugs.

[0078] Example 5: Safety evaluation of pamoate B on major organs

[0079] Experimental Methods: After the aforementioned orthotopic peritoneal tumor model experiment, the heart, liver, spleen, lung, and kidney tissues of mice in the control group (Ctrl) and the pamoate B administration group were fixed in 4% paraformaldehyde, embedded in paraffin, and serially sectioned (4 μm thick). Histopathological examination was performed using the hematoxylin-eosin (HE) staining method. The specific steps were as follows: paraffin sections were dewaxed with xylene, hydrated with graded ethanol, stained with hematoxylin for 5-10 min, rinsed with tap water to regain blue color, stained with eosin for 1-3 min, dehydrated with graded ethanol, cleared with xylene, and mounted with neutral resin. The pathological morphological changes of each organ tissue were observed under an optical microscope. Images were collected and the histological differences between the control group and the pamoate B administration group were compared and analyzed.

[0080] Experimental results: such as Figure 5The results shown are HE staining results of the heart, liver, spleen, lung, and kidney of mice in the control group and the group treated with poria cocos B (scale bar and magnification are consistent): Heart: Cardiac cells in the control group and the group treated with poria cocos B are neatly arranged and structurally intact, without pathological changes such as cardiomyocyte necrosis and inflammatory infiltration; Liver: The liver lobule structure is clear in both groups, the hepatocyte morphology is normal, and there are no abnormalities such as hepatocyte edema, fatty degeneration, necrosis, and inflammatory cell infiltration; Spleen: The white pulp and red pulp structure of the spleen are distinct in both groups, the splenic bodies are normal in morphology, and there are no pathological changes such as spleen tissue necrosis and structural destruction; Lung: The alveolar structure is intact in both groups, the alveolar walls are thin, and there are no abnormalities such as alveolar dilation, pulmonary interstitial edema, and inflammatory infiltration; Kidney: The glomeruli and renal tubules are clear in both groups, and there are no pathological damage such as glomerular atrophy, renal tubular necrosis, and interstitial inflammation. Overall, the histological morphology of the major organs in the poria cocos B administration group was not significantly different from that in the control group. No pathological damage such as cell necrosis, inflammatory infiltration, or structural destruction was observed in the myocardium, liver, spleen, lungs, and kidneys. At the same time, there were no significant abnormalities in the biochemical indicators related to liver and kidney function, confirming that the intraperitoneal administration of poria cocos B was safe.

Claims

1. The use of pachymic acid B in the preparation of a medicament for the prevention and / or treatment of peritoneal metastasis of gastric cancer, wherein the chemical name of pachymic acid B is 3-O-acetyl-16α-hydroxydehydrotrametenolic acid.

2. The application according to claim 1, characterized in that, The poria cocos acid B exerts its preventive and / or therapeutic effects on peritoneal metastasis of gastric cancer by upregulating the SPRED2 gene.

3. The application according to claim 2, characterized in that, The poria cocos B upregulates SPRED2 gene expression in a time-dose dependent manner.

4. The application according to claim 1, characterized in that, The administration method of the poria cocos B is intraperitoneal injection. The poria cocos B is prepared as a solution or suspension, and the suspension contains a pharmaceutically acceptable suspending agent, wherein the suspending agent is sodium carboxymethyl cellulose.

5. The application according to any one of claims 1-4, characterized in that, The poria cocos B is used to prevent and / or treat perioperative peritoneal metastasis of gastric cancer after surgical resection of the primary gastric cancer lesion.

6. A pharmaceutical composition for the prevention and / or treatment of peritoneal metastasis of gastric cancer, characterized in that, The active ingredient is pachymic acid B, and the chemical name of pachymic acid B is 3-O-acetyl-16α-hydroxydehydrotrametenolic acid.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition exerts its preventive and / or therapeutic effects on peritoneal metastasis of gastric cancer by upregulating the SPRED2 gene.

8. The pharmaceutical composition according to claim 7, characterized in that, The pharmaceutical composition upregulates SPRED2 gene expression in a time-dose dependent manner.

9. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition is an intraperitoneal injection formulation, which contains pamoate B and a pharmaceutically acceptable suspending agent or solubilizer, wherein the suspending agent is sodium carboxymethyl cellulose.

10. The pharmaceutical composition according to any one of claims 6-9, characterized in that, The pharmaceutical composition is used for the prevention and / or treatment of perioperative peritoneal metastasis of gastric cancer following surgical resection of the primary gastric cancer lesion.

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