Cancer stem cells (CSCs) are a small subset of cells that sit atop the hierarchical ladder in many
cancer types. Liver CSCs have been associated with high chemoresistance and recurrence rates in
hepatocellular carcinoma (HCC). However, as of yet, no satisfactorily effective liver CSC-targeted treatment is available, which drove us to design and investigate the efficacy of a
liposome-based delivery system. Here, we introduce a redox-triggered dual-targeted
liposome, CEP-LP@S/D, capable of co-delivering
doxorubicin (Dox) and
salinomycin (Sal) for the synergistic treatment of
liver cancer. This system is based on the association of CD133- and
EpCAM-targeted
peptides to form Y-shaped CEP
ligands that were anchored to the surface of the
liposome and allowed the selective targeting of CD133+ EpCAM+ liver CSCs. After arriving to the CSCs, the CEP-LP@S/D
liposome undergoes endocytosis to the cytoplasm, where a high concentration of
glutathione (GSH) breaks its
disulfide bonds, thereby degrading the
liposome. This then induces a rapid release of Dox and Sal to synergistically inhibit
tumor growth. Notably, this effect occurs through Dox-induced apoptosis and concurrent lysosomal
iron sequestration by Sal. Interestingly, both in vitro and in vivo studies indicated that our GSH-responsive co-delivery system not only effectively enhanced CSC targeting but also eliminated the non-CSC faction, thereby exhibiting high antitumor efficacy. We believe that the smart
liposome nanocarrier-based co-delivery system is a promising strategy to combat
liver cancer, which may also lay the groundwork for more enhanced approaches to target other
cancer types as well.