Vitamin E-based redox-sensitive salinomycin prodrug-nanosystem with paclitaxel loaded for cancer targeted and combined chemotherapy

Cancer stem cells (CSCs) can resist conventional chemotherapy to lead to cancer recurrence. For complete eradication of cancers, an effective CSCs therapeutic strategy should be developed to combine with conventional chemotherapy. In this work, a novel vitamin E-based redox-sensitive salinomycin (SAL, an inhibitor for CSCs) prodrug nanoparticles (TS NPs) and hyaluronic acid (HA)-coated TS NPs (HTS NPs) were fabricated to deliver paclitaxel (PTX) for cancer-targeted and combined chemotherapy. Both TS and HTS prodrug NPs had mean diameter of about 200 nm with uniform size distribution, excellent drug loading capacity for PTX, and glutathione-triggered SAL and PTX release profiles. The HTS prodrug NPs had enhanced cellular uptake efficiency over TS NPs due to CD44 receptor-mediated endocytosis, hence exerting stronger potency of SAL upon CSCs-enriched mammospheres formation and G(0)/G(1) cell phase arresting. Cytotoxicity and 3D tumor spheroids assays demonstrated that both TS and HTS prodrug NPs themself can synergize with loaded PTX to maximize the chemotherapeutic effect. Obviously, the latter demonstrated a more potent anticancer efficacy due to improved intracellular drug delivery efficiency. These results suggested that the designed TS prodrug NPs, especially the coated HTS NPs can serve as an effective anti-CSCs strategy for cancer targeted and combination treatments.