Therapeutic Response of Multifunctional Lipid and Micelle Formulation in Hepatocellular Carcinoma.

Hepatic stellate cells (HSCs), as an important part of the tumor microenvironment (TME), could be activated by tumor cells as cancer-associated fibroblasts (CAFs), thereby promoting the production of extracellular matrix (ECM) and favoring the development of tumors. Therefore, blocking the "CAFs-ECM" axis is a promising pathway to improve antitumor efficacy. Based on this, we developed a multifunctional nanosized delivery system composed of hyaluronic acid-modified pH-sensitive liposomes (CTHLs) and glycyrrheic acid-modified nanomicelles (DGNs), which combines the advantages of targeted delivery, pH-sensitivity, and deep drug penetration. To mimic actual TME, a novel HSCs+BEL-7402 cocultured cell model and a m-HSCs+H22 coimplanted mice model were established. As expected, CTHLs and DGNs could target CAFs and tumor cells, respectively, and promote the drug penetration and retention in tumor regions. Notably, CTHLs+DGNs not only exhibited a superior antitumor effect in three-level tumor-bearing mice but also presented excellent antimetastasis efficiency in lung-metastatic mice. The antitumor mechanism revealed that the lipid&micelle mixed formulations effectively inhibited the activation of CAFs, reduced the deposition of ECM, and reversed the epithelial-mesenchymal transition (EMT) of tumor cells. In brief, the nanosized delivery system composed of CTHLs and DGNs could effectively improve the therapeutic effect of liver cancer by blocking the "CAFs-ECM" axis, which has a good clinical application prospect.