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CN-121987561-A - Ginsenoside liposome gel and application thereof in tumor treatment

CN121987561ACN 121987561 ACN121987561 ACN 121987561ACN-121987561-A

Abstract

The invention discloses application of ginsenoside liposome gel in tumor treatment. The medicine system uses ginsenoside Rg3 to replace cholesterol as a liposome membrane material, prepares liposome by a thin film hydration method in combination with lecithin, carries chemotherapeutic medicine cisplatin to form Rg3& cis@lipomes, and further encapsulates the liposome into chitosan-beta-sodium glycerophosphate-gelatin temperature sensitive hydrogel to construct injectable Rg3& cis@lipogel. The system realizes stable and synchronous drug delivery through tumor periphery/local injection, targets and inhibits IDO1-KYN-AhR metabolism-immune checkpoint axis, activates cGAS-STING-IFN-I immune signal path, and enhances Cell immunity has remarkable inhibiting effect on bladder cancer, triple negative breast cancer and melanoma.

Inventors

  • LI CHENCHEN
  • Shi Zhuangbiao
  • Kong Jinrong
  • WU YANHONG
  • LIANG YIHAO
  • TAN XIYANG
  • YUAN KAI

Assignees

  • 深圳大学附属华南医院

Dates

Publication Date
20260508
Application Date
20260305

Claims (10)

  1. 1. A pharmaceutical composition of ginsenoside liposome gel, comprising: Liposome structure formed by ginsenoside Rg3 and lecithin; cisplatin, a chemotherapeutic agent entrapped in said liposomes; the temperature-sensitive hydrogel matrix is used for encapsulating the liposome, and the temperature-sensitive hydrogel consists of chitosan, beta-sodium glycerophosphate and gelatin; Wherein, the ginsenoside Rg3 is used as a liposome membrane material and has the dual functions of structure and active pharmaceutical ingredients.
  2. 2. The pharmaceutical composition according to claim 1, wherein the mass ratio of ginsenoside Rg3 to lecithin is 2-5:10, and the mass ratio of cisplatin to ginsenoside Rg3 is 1-4:6.
  3. 3. The pharmaceutical composition according to claim 1, wherein the mass ratio of chitosan, gelatin and beta-sodium glycerophosphate in the temperature sensitive hydrogel is 0.25:0.1:1.11.
  4. 4. The pharmaceutical composition according to claim 1, wherein the liposome has an average particle size of 90-95nm and a spherical structure.
  5. 5. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 4, comprising the steps of: (1) Dissolving ginsenoside Rg3 and lecithin in a mixed solvent of absolute ethyl alcohol and chloroform, removing an organic solvent by rotary evaporation to form a film, and adding a glucose solution with the mass fraction of 3-8% for hydration to obtain a ginsenoside Rg 3-lecithin liposome film material; (2) Dissolving cisplatin in DMSO, adding into PBS solution, mixing with ultrasound, adding into the hydration solution obtained in step (1), performing ice water bath ultrasound treatment, and repeatedly squeezing film by using a liposome film squeezing device to obtain Rg3& cis@lipomes liposome solution; (3) Dissolving chitosan and gelatin in acetic acid solution, stirring to uniformity, filtering beta-sodium glycerophosphate solution, adding dropwise, and mixing uniformly to obtain a temperature-sensitive hydrogel matrix; (4) And (3) adding the liposome solution obtained in the step (2) into the hydrogel matrix obtained in the step (3) after freeze-drying, and uniformly mixing to obtain the ginsenoside Rg3 and cisplatin liposome gel drug system.
  6. 6. The preparation method according to claim 5, wherein the volume ratio of the absolute ethyl alcohol to the chloroform in the step (1) is 1:1, the rotary evaporation temperature is 40-80 ℃, the hydration time is 10-60 minutes, the ice water bath ultrasonic time in the step (2) is 1-10 minutes, the film extrusion times are 20-100 times, the concentration of the acetic acid solution in the step (3) is 0.05M-0.2M, and the beta-sodium glycerophosphate solution is filtered by a 0.22 μm filter membrane.
  7. 7. Use of a pharmaceutical composition according to any one of claims 1-4 for the preparation of a medicament for the treatment of tumors, wherein the medicament is administered by intratumoral or topical injection, achieving in situ, stable, sustained release of the medicament from the tumor.
  8. 8. The use of claim 7, wherein the neoplasm comprises bladder cancer, triple negative breast cancer and melanoma.
  9. 9. The use according to claim 7, wherein the administration mode of the ginsenoside liposome gel is tumor peri-tumor or tumor in-situ local injection, stable slow release of the medicament in tumor foci is realized, and the administration frequency is once every 3-4 days.
  10. 10. The use according to claim 7, wherein the ginsenoside liposome gel is used for tumor neoadjuvant chemotherapy, alone or in combination with tumor surgery, radiotherapy, other immunotherapeutic drugs.

Description

Ginsenoside liposome gel and application thereof in tumor treatment Technical Field The invention belongs to the technical field of medicines, and particularly relates to a ginsenoside liposome gel pharmaceutical composition, a preparation method thereof and application thereof in tumor chemistry-metabolism-immunity combined treatment. Background Cancer is a disease that is ubiquitous worldwide and constitutes a major threat to human health. Clinically, cisplatin (CISPLATIN, cis) is widely used as a basic drug in the new adjuvant chemotherapy of most cancers, but its efficacy is limited by intrinsic or acquired drug resistance and toxicity issues. In view of these challenges, increasing cisplatin-based neoadjuvant chemotherapy efficacy through biomarker-directed intervention, combination therapy strategies, or resistance modulation is critical to improving prognosis in cancer patients. Previous studies have shown that the efficacy of chemotherapy is largely mediated by T cell-associated immunity, with the type I interferon (IFN-I) signaling pathway playing a key role. As a representative chemotherapeutic agent, cisplatin stimulates IFN-I production by activating the cyclic guanylate-adenylate synthetase (cGAS) -interferon gene stimulatory protein (STING) signaling pathway, which is the core of the mechanism of action of cisplatin, which recognizes free double-stranded DNA (dsDNA) in the cytoplasm and triggers an immune response. However, this signaling pathway is often inhibited in a variety of cancer types, suggesting that cancer cells have a potential mechanism to evade cGAS-STING signaling monitoring during tumor formation and progression. Furthermore, a metabolic imbalance of tumor cells contributes to the formation of an immunosuppressive tumor microenvironment. Amino acid metabolites, especially those derived from essential amino acids, play an important role in signal transduction and have direct biological activity compared to carbohydrate and lipid metabolites. Notably, cisplatin treatment promotes the accumulation of Kynurenine (KYN) in the Tryptophan (TRP) metabolic pathway, which is the most variable metabolic pathway. Ginsenoside Rg3 is an anticancer agent used in combination with chemotherapy in clinic, and can promote anti-tumor immunity by regulating signal transduction and transcription activator 3 (STAT 3) signaling pathway and NF- κB signaling pathway. However, it is not clear whether Rg3 can affect the metabolic process of tumors. The research shows that Rg3 can cooperate with cisplatin to specifically inhibit KYN accumulation driven by indoleamine 2, 3-dioxygenase 1 (IDO 1) after cisplatin treatment. Theoretically IDO 1-driven KYN accumulation can further activate the aromatic hydrocarbon receptor (AhR) in a ligand-dependent manner, which is critical for the expression of a range of genes. This suggests that Rg3 has a synergistic potential with cisplatin in targeting the IDO1-KYN-AhR axis. However, the problems of poor solubility and low bioavailability of ginsenoside Rg3 limit its wide application, and liposome-based drug delivery strategies are ideal solutions to the above problems. Liposomes composed of lipids are readily enriched in tumor tissue by enhancing the permeation and retention (EPR) effect. In view of the similarity of chemical structures of ginsenoside Rg3 and cholesterol, it can replace cholesterol to construct liposome membranes. It has been found that ginsenoside-based liposomes have powerful and active tumor cell targeting ability for glucose transporter 1 (GLUT 1) which is commonly and highly expressed in a variety of tumors. In the prior art, ginsenoside is usually selected as a liposome membrane material, liposome is formed by a thin-film hydration method, and the administration mode is usually tail vein system administration. However, the disadvantage of systemic administration is that although liposomes have a certain tumor targeting effect, the complex intrahumoral environment of the body can destroy the stability of the liposome administration system, and it is difficult to ensure that the liposome drug stably and fully reaches the tumor site and exerts the drug effect. Disclosure of Invention The invention aims to solve the technical problem of providing a ginsenoside liposome gel pharmaceutical composition which can realize local treatment of tumor in situ, stably and permanently release medicines and has the function of chemical-metabolic-immune triple regulation. In order to achieve the above object, the present invention provides a ginsenoside liposome gel pharmaceutical composition, comprising: Liposome structure formed by ginsenoside Rg3 and lecithin; cisplatin, a chemotherapeutic agent entrapped in said liposomes; the temperature-sensitive hydrogel matrix is used for encapsulating the liposome, and the temperature-sensitive hydrogel consists of chitosan, beta-sodium glycerophosphate and gelatin; Wherein, the ginsenoside Rg3 is used as a liposome membran