- Yusuke Sato (Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University / email@example.com)
- Hideyoshi Harashima (Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University / firstname.lastname@example.org)
1) Laboratory for Molecular Design of Pharmaceutics, Faculty of Pharmaceutical Sciences, Hokkaido University , 2) Vascular Biology and Molecular Pathology, Graduate School of Dental Medicine, Hokkaido University
Melanomas are one of the most aggressive form of skin cancer and are resistant to many cancer therapies. Lipid nanoparticles (LNPs) containing a pH-sensitive cationic lipid, YSK05 (YSK05-LNPs), for delivering short interfering RNA (siRNA) were found to strongly triggers in vitro toxicity in human A375 and A375-SM melanoma cell lines regardless of gene silencing. Assessing the localization of the toxicity was done by controlling the cellular uptake of the YSK05-LNPs that contained different polyethyleneglycol (PEG)-lipid. The YSK05-LNPs exhibited consistent dose- and time-dependent toxicity, independent of their cellular uptake, indicating that the toxicity is triggered by an interaction between the YSK05-LNPs and the cell surface. Treatment with free YSK05 resulted in only time-dependent toxicity. These results suggest that the YSK05-LNPs trigger two modes of action; a fast-acting component that is related to the LNP formulation and a slow-acting mode, which is related to the YSK05 lipid itself. Necrosis was determined to be the cause of cell death, as evidenced by the results of Annexin V assays, which are specific for confirming lipid-based toxicity. These findings indicate that these YSK05-LNPs have substantial potential for use as an antimelanoma agent as both an RNA interference-based drug and as a chemotherapeutic drug.