Evaluation of the selective toxic effect of the charge switchable diethyldithiocarbamate-loaded nanoparticles between hepatic normal and cancerous cells

Liver cancer is mainly originated by cancer stem cells (CSCs). Due to difference in pH between normal and tumor cell microenvironments, targeting hepatic CSCs exploiting pH-dependent charge switchable nanoparticles (NPs) is extremely required to limit nonselective toxicity to normal hepatocytes (NHCs) and to completely eliminate the root of cancer origin. In this study, NPs were prepared from cationic chitosan and then coated with anionic albumin namely uncoated and coated NPs, respectively. Both NPs were loaded with diethyldithiocarbamate (DDC) which is an inhibitor of the critical enzyme, aldehyde dehydrogenase (ALDH) 1A1, for CSCs survival. The charge switchable of coated DDC-loaded NPs in neutral and acidic pH (-19 and +28.5 mv, respectively) was illustrated. This special privilege of coated NPs mediated DDC releasing in a slightly acidic pH (tumor microenvironment) rather than a neutral pH (microenvironment of normal cells). Thence, these coated NPs showed the highest selective apoptosis-mediated toxicity only in murine hepatoma cells (Hepa) that may attribute to suppression of NF-kappa B expression and ALDH1A1 activity, subsequently collapsing 89.7% CD133(+)CSCs. These new findings declare that coated NPs could be promising safe selective anticancer drug for targeting hepatic CSCs and that requires additional future investigations using animal models of liver cancer.