A pH-sensitive peptide amphiphilic-based drug delivery system inhibits hepatocellular carcinoma growth by suppressing hepatic stellate cell activation

Chemotherapy is crucial for treating intermediate and advanced hepatocellular carcinoma (HCC). However, anthracycline agents such as doxorubicin (DOX) are often expelled from tumor cells by P-glycoprotein (P-gp), which decreases the intracellular drug levels and leads to treatment failure. Activated hepatic stellate cells (aHSCs) are critical in liver fibrosis and HCC progression and facilitate liver cancer development. Importantly, liver fibrosis progression is closely linked to the expression of cyclooxygenase-2 (COX-2). Here, we developed a pH-responsive peptide drug delivery system, Pep loaded with DOX and CXB (DC/Pep), which targets HCC by transporting the COX-2 inhibitor celecoxib (CXB) alongside the conventional chemotherapeutic drug DOX. DC/Pep transitioned from spherical particles to high aspect ratio aggregates in a mildly acidic environment, delaying chemotherapeutic agent efflux from the tumor. DC/Pep effectively inhibited hepatic stellate cell activation and reduced collagen fiber synthesis, thereby preventing the development of liver fibrosis. Consequently, the proliferation of ectopic and orthotopic HCC tumors was effectively inhibited, leading to an enhanced antitumor effect. This study is important for designing novel drug delivery systems using peptide amphiphiles for the treatment of intermediate and advanced HCC.