Novel Dual CAFs and Cancer Cell Targeting Nano-Drug Delivery System for Anti-Fibrosis Mechanism of Liver Cancer

Abstract

This study proposed the construction of a delivery system based on dual targeting cancer-associated fibroblasts (CAFs) and tumor cell for the treatment of liver cancer. (Z-Glycine-Proline)-Hyaluronic Acid-Sulcanidone-Ginger Anone, named as GHSO, was an amphiphilic carrier material with dual pH/ROS sensitive and dual targeting properties that could be used to load hydrophobic drug to improve their solubility and enhance biocompatibility. Consequently, we combined paclitaxel (PTX) with GHSO to design a novel nano-micelles, called GHSO@PTX micelles. Also, we prepared a single targeted nano-micelles (Hyaluronic Acid-Sulcanidone-Ginger Anone) named HSO@PTX. The GHSO@PTX micelles was 159.40±14.30 nm-sized in neutral water. The electron microscopy results showed that the two micelles were relatively uniform in size and spherical in shape. The results of in vitro release experiments shown that GHSO@PTX micelles had better pH sensitivity and ROS responsiveness. Under the conditions of low pH/high H2O2 concentration, the cumulative release of micelles was the largest, which could achieve better therapeutic effects. Cell uptake, cytotoxicity of GHSO@PTX micelles were examined at different concentrations by using SMMC-7721 cells and CAFs. The 3D tumor ball experiment showed that GHSO@Cur micelles were more permeable than HSO@Cur, and proved the superiority of GHSO carrier. It first targeted CAFs cells, opened the physical barrier of tumor cells, and achieved deep penetration of tumor sites. We conducted pathological studies and immunohistochemical studies on isolated tissues and tumor tissue sections of nude mice, and investigated the safety and effectiveness of the preparations H&E staining confirmed its safety, Ki 67 was down-regulated, proving that tumor cell proliferation was inhibited, and the down-regulation of α-SMA and Masson proved that CAFs were inhibited and the preparation GHSO@PTX has the effect of killing CAFs and reducing the fibrosis of the tumor. A promising hyaluronic acid-based nanomedicine platform acts as a new drug delivery system to enhance the deep penetration effect of the tumor, and reduce the degree of fibrosis.