Squalene versus cholesterol: Which is the best nanocarrier for the delivery to cells of the anticancer drug gemcitabine?

It has been previously shown that the linkage of the anticancer drug gemcitabine (Gem) to the squalene (SQ), a natural lipid precursor of the cholesterol biosynthesis, allowed the resulting bioconjugates to spontaneously self-assemble as nanoparticles (NPs) with improved pharmacological activity. We show here that when the squalene moiety was replaced by the cholesterol and the conjugation performed through a carbamate linker, although rather stable nanoparticles were obtained, the in vitro anticancer activity in the human breast cancer cell line MDA-MB-231 was completely abolished. This was attributed to reduced enzymatic accessibility toward the carbamate linker, which may hamper the gemcitabine release. A lower propensity of incorporation into the plasma cell membrane, which was revealed by molecular simulations, may also play a role in lower activity of cholesterol derivative. (C) 2018 Academie des sciences. Published by Elsevier Masson SAS.