title: Interaction of self-assembled squalenoyl gemcitabine nanoparticles with phospholipid-cholesterol monolayers mimicking a biomembrane.
abstract: 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 squalenoyl gemcitabine (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 phospholipid-cholesterol 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.
authors.affiliation: Université Paris-Sud, CNRS UMR 8612, Faculté de Pharmacie, Châtenay-Malabry, France.
authors.forename: Anshuman
authors.initials: A
authors.lastname: Ambike
authors.forename: Véronique
authors.initials: V
authors.lastname: Rosilio
authors.forename: Barbara
authors.initials: B
authors.lastname: Stella
authors.forename: Sinda
authors.initials: S
authors.lastname: Lepêtre-Mouelhi
authors.forename: Patrick
authors.initials: P
authors.lastname: Couvreur
mesh_terms: D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D008567:Membranes, Artificial; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry*; D010713:Phosphatidylcholines; D010743:Phospholipids / Q000378:metabolism*; D013185:Squalene / Q000737:chemistry*; D000093542:Gemcitabine
chemical_list: D008567:Membranes, Artificial; D010713:Phosphatidylcholines; D010743:Phospholipids; D003841:Deoxycytidine; D013185:Squalene; D002784:Cholesterol; C010942:1,2-distearoyllecithin; D000093542:Gemcitabine