It remains a challenge to increase
drug tumor-specific accumulation as well as to achieve intracellular-controlled drug release for
hepatocellular carcinoma (HCC)
chemotherapy. Herein, we developed a dual-functional biodegradable micellar system constituted by
glycyrrhetinic acid coupling poly(
ethylene glycol)-
disulfide linkage-
poly(lactic-co-glycolic acid) (GA-
PEG-SS-PLGA) to achieve both
hepatoma-targeting and redox-responsive intracellular drug release.
Tanshinone IIA (TAN IIA), an effective anti-HCC
drug, was encapsulated. Notably, it exhibited rapid aggregation and faster drug release in 10 mM
dithiothreitol compared with the redox-insensitive control. Furthermore, GA-decorated
micelles revealed HCC-specific cellular uptake in human
liver cancer HepG2 cells with an energy-dependent manner, in which micropinocytosis and caveolae-mediated endocytosis were demonstrated as the major cellular pathways. The enhanced cytotoxicity and pro-apoptotic effects against HepG2 cells in vitro were observed, mediated by up-regulation of the intracellular ROS level, the increased cell cycle arrest at S phase, enhanced necrocytosis and up-regulation of
caspase 3/7, P38
protein expression. In addition, TAN IIA-loaded
micelles had a significantly prolonged circulation time, improved bioavailability, and resulted in an increased accumulation of TAN IIA in the liver. With the synergistic effects of HCC-targeting and controlled drug release, TAN IIA-loaded GA-
PEG-SS-PLGA
micelles significantly inhibited
tumor growth and increased survival time in a mouse HCC-xenograft model. Collectively, the GA-
PEG-SS-PLGA
micelles with HCC-targeting and redox-sensitive characters would provide a novel strategy to deliver TAN IIA effectively for HCC
therapy.