Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China with high mortality and incidence rates
The transmission electron microscopy (TEM) images (Supplementary Figure 3) illustrated that the nanostructure of CEP-LP@S/D was disrupted in a GSHrich surrounding after 8 h
CEP-LP@S/D-treated 293T cells showed weak red fluorescence (Supplementary Figure 5). These results strongly demonstrate that CEP-LP@S/D could respond to the intracellular redox environment, leading to the disruption of the disulfide bonds in the lipid membranes, which enabled the highly hydrophobic Dox to readily penetrate into the cells and, exhibit greater cellular accumulation
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China with high mortality and incidence rates. CD133 and EpCAM have been widely studied as stem cell markers in liver cancer (Mikhail and He, 2011) These surface markers serve as tools for identifying and isolating liver CSCs and as therapeutic targets for eradicating these cells (Chan et al, 2014; Jiang et al, 2015; Saygin et al, 2019). Targeting these CSC-specific markers by optimized drug combinations would be an ideal method for overcoming the stemness of liver CSCs and ameliorating the disease (Clevers, 2011). Considering the importance of CSCs and the shortcomings of conventional anticancer therapies, dualtargeted CSC-specific delivery systems can possibly overcome this dilemma and leave an impact on the clinical setting (DianatMoghadam et al, 2018; Guo et al, 2019)
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