Glycyrrhetinic Acid-Modified Sulfated Hyaluronic Acid Nanoparticles Coencapsulating Doxorubicin and Magnolol for the Synergistic Treatment of Hepatocellular Carcinoma

Cancer-associated fibroblasts (CAFs) play a crucial role in the progress of tumor growth, metastasis, and multidrug resistance. In this study, glycyrrhetinic acid-modified sulfated hyaluronic acid nanoparticles (MDHG) were prepared for the codelivery of doxorubicin (DOX) and magnolol (MAG). To mimic the tumor microenvironment (TME), we successfully established tumor cells/CAFs mixed research models in vivo and in vitro. The results showed that MDHG could be taken up by both CAFs and tumor cells and exhibited strong antiproliferation and antimigration effects in the mixed cell model in vitro. Moreover, the in vivo studies showed that MDHG effectively decreased the side effect of DOX and inhibited CAFs activation, tumor angiogenesis, antiprolifera-tion, and lung metastasis on tumor cells, leading to enhanced antitumor effects. In summary, the study verified that there is a synergistic antitumor effect between DOX and MAG, and the combination therapy of DOX and MAG based on sulfated hyaluronic acid nanoparticles has potential in clinical application.