Injectable multi-component hydrogels for the treatment of ascites caused by hepatocellular carcinoma via anti-tumor and reduction of ascites generation

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide, and malignant ascites (MA) caused by HCC is almost incurable. However, the efficacy of chemotherapy is limited by poor tumor drug targeting and the presence of an immunosuppressive microenvironment. Therefore, it is urgent to find drugs for dual-therapy that have both anti-tumor effect and reduction of MA production. Inspired by self-assembly of two molecules, we enriched the effective parts of Genkwa Flos (GK), which was decocted with glycyrrhizic acid (GA) from licorice, one pot of green synthesis of an injectable multi-component hydrogel of TCM (GK-GA). The GK-GA hydrogel demonstrated excellent injectability and sustained retention properties in the peritoneal cavity following intraperitoneal administration. In vivo pharmacodynamic experiments demonstrated potent therapeutic efficacy, achieving a 47.62% reduction in ascites formation at 6.25 mg/kg. By integrating network pharmacology, transcriptomics, and metabolomics, mechanistic studies revealed its dual therapeutic pathways against MA: (1) as a pro-apoptotic agent that significantly induces tumor cell apoptosis by elevating intracellular reactive oxygen species (ROS) levels via mitochondrial membrane potential depolarization, and modulat related proteins in the PI3K-AKT signaling pathway, and (2) as a metabolic regulator that effectively suppresses ascites formation by normalizing the aldosterone metabolic pathway. The method of self-assembly of supramolecular hydrogel by enriching the effective parts is more in line with the characteristics of multi-component, multi-pathway and multi-target comprehensive prevention and treatment of diseases in TCM, and offers a promising approach for novel drug development.