Interaction of self-assembled squalenoyl-gemcitabine nanoparticles with phospholipid-cholesterol monolayers mimicking a biomembrane.

Gemcitabine (dFdC or Gem) is a water-soluble cytotoxic drug, with poor cellular uptake in the absence of a nucleoside transporter. To improve its diffusion through membranes, it was modified by grafting of a squalenoyl moiety. In water, this derivative is able to form stable and monodispersed nanoparticles made of inverse hexagonal phases. The formation and interfacial properties of the squalenoylgemcitabine (SQ-Gem) nanoparticles, and their ability to interact with phospholipid and cholesterol monolayers modeling a biomembrane, was assessed from surface tension measurements and Brewster angle microscopy. To get a better insight into the mechanisms of SQ-Gem interaction with the various lipids, the interfacial behavior of SQ-Gem and squalene was also studied by surface pressure and surface potential measurements, in the absence and in the presence of phospholipids and cholesterol. The results showed that SQ-Gem nanoparticles adsorbed at the free air/water interface and disrupted to form a monolayer. SQ-Gem molecules released from the adsorbed nanoparticles were also able to penetrate into condensed phospholipidcholesterol mixed monolayers. The kinetics of this penetration was apparently controlled by intermolecular interactions between the drug and the adsorbed lipids. Whereas distearoylphosphatidylcholine (DSPC) hindered SQ-Gem penetration, cholesterol favored it, which could have important implications in the therapeutic field since cholesterol targeting could alter lipid raft composition and cancer cell survival.