Regorafenib enhances the efficacy of photodynamic therapy in hepatocellular carcinoma through MAPK signaling pathway suppression

Photodynamic therapy (PDT) is a promising and innovative approach for treating tumors. The synergistic effect of PDT and chemotherapy can enhance the anti-tumor efficacy by leveraging their complementing benefits. In this study, we created lipid vesicles to deliver a photosensitizer (chlorin e6, Ce6) and Regorafenib into tumors for the purpose of examining the effectiveness and mechanism of Lipo-Ce6@Rego-PDT (LCR-P) on Hepatocellular carcinoma (HCC) both in vitro and in vivo. We found that the cytotoxicity on HCC caused by LCR-P was significantly stronger than that caused by Lipo-Ce6-PDT (LC-P). Cellular ROS production in the LCR-P group was approximately higher than that in the LC-P group, and Regorafenib significantly inhibited the phosphorylation of JNK, ERK, and P38 of Lipo-Ce6-PDT group in vitro and in vivo. Furthermore, Regorafenib significantly downregulated the expression of Bcl-2 and upregulated the expression of Bax and cleaved caspase-3 of LC-P group in vitro and in vivo. Compared with LC-P, LCR-P significantly increased cell apoptosis rate. The body weight and HE staining of normal organs primarily indicated the safety of this combined strategy. These results indicate that the combination of Regorafenib and Lipo-Ce6 can significantly enhance the anti-tumor efficiency of PDT for HCC and exhibits good biosafety.