Dual-Ligand-Modified Nanoscale Liposomes Loaded with Curcumin and Metformin Inhibit Drug Resistance and Metastasis of Hepatocellular Carcinoma

In the tumor microenvironment (TME), the cross-talk between tumor cells and hepatic stellate cells (HSCs) could facilitate tumor drug resistance and metastasis, leading to poor prognosis in the patients with hepatocellular carcinoma (HCC). Herein, blocking the cross-talk would be an effective antitumor strategy. In this study, nanoscale dual-ligand-modified multifunctional liposomes (CMDLs) were prepared for the codelivery of curcumin and metformin. To mimic a real TME, the "HSC + HCC" cell cocultured model and "m-HSC–HCC" coimplanted model were established to evaluate the antitumor effect in vitro and in vivo, respectively. These models have been proven to be more efficient for antitumor analysis than tumor cells alone. Compared to free drugs, CMDLs well strengthened drug internalization and drug retention in vitro. Notably, the combined drug formulations, especially CMDLs, exhibited a greater proapoptotic effect than single treatment groups. Furthermore, the in vivo antitumor studies showed that CMDLs exhibited low extracellular matrix deposition, less tumor angiogenesis, and superior anti-HCC efficacy than the other groups in both subcutaneous H22 cells and "m-HSC + H22" coimplanted mice models. The antitumor mechanisms revealed that the combination therapy based on the nanoscale CMDLs could not only inhibit the activation of HSCs by blocking the TGF-β/Smad2 pathway but also block tumor metastasis by reversing epithelial mesenchymal transformation of HCC, which provides a promising approach for anti-HCC therapy.