Nanoparticle-mediated Delivery of Ascorbyl Palmitate Targets Patient-derived Sarcoma Stem Cells

Background/Aim: Renewed interest in the application of ascorbic acid for anti-tumor therapy led to the discovery of its effect on cancer stem cells (CSC), a small group of cells in tumor bulk with specific properties that enable them to resist conventional therapy and metastasize. The application of ascorbate in high concentrations has a prooxidative effect on cancer cells, causing extensive oxidative stress that can induce cell death. Therefore, the aim of the study was to explore the effect of ascorbate delivered by nanoparticles on patient-derived CSC. Materials and Methods: We previously synthesized and characterized solid lipid nanoparticles containing ascorbyl palmitate (SLN-AP), a more stable lipid derivative of ascorbate. SLN-coumarin-6 were applied for visualization of the cellular uptake of the SLN. SLN-AP were applied to sarcoma stem cells isolated from samples of six patients to test their cytotoxicity and effect on oxidative stress in CSC. Results: SLNs with incorporated coumarin-6 enter the cells gradually, however, CSC react with abrupt generation of vesicles of a wide range of sizes (up to 20 μm). SLN-AP have higher IC₅₀ values in osteosarcoma CSC than in soft tissue sarcomas. Nanoparticles without incorporated AP show strong cytotoxic effect. The treatment with nanoparticles shows antioxidative effect in CSC. Conclusion: Soft-tissue sarcoma stem cells were more sensitive to the treatment than osteosarcoma stem cells and cytotoxicity is not due to oxidative stress. SLN-AP formulation should be further optimized to reduce the cytotoxicity of SLNs and to reduce their efflux from the CSC population.