title: Novel surfactants with diglutamic acid polar head group: drug solubilization and toxicity studies.
abstract: OBJECTIVE
  Novel surfactants made of diglutamic acid (DG) polar head linked to lithocholic, arachidonic, linoleic or stearic acids were designed for drug solubilization.
  
  
  METHODS
  Surfactants 3-D conformer and packing parameter were determined by molecular modelling and self-assembling properties by pyrene fluorescence measurements. Cytotoxicity was assessed on Human Umbilical Vein Endothelial Cells (HUVEC) and haemolyitic activity on rat red blood cells. Drug solubilization was quantified and its interaction with hydrophobic moieties was characterized using differential scanning calorimetry and X-ray diffraction. Self organisation of stearoyl-DG was observed by cryogenic transmission electron microscopy. Toxicity after repeated injections of stearoyl-DG was investigated in Wistar rats.
  
  
  RESULTS
  DG-based surfactants self-assemble into water and their critical micellar concentrations are comprised between 200 and 920 μg/mL. Cytotoxicity and haemolysis were lower than for polysorbate 80. At best, stearoyl-DG solubilized the drug up to 22% (w/w). Solid-state characterization evidenced drug/lipid interactions leading to the formation of a new complex. Stearoyl-DG formed spherical micelles of 20 nm, as predicted by packing parameter calculation. However, it induced a possible liver toxicity after intravenous administration in rats.
  
  
  CONCLUSIONS
  Among the surfactants tested, stearoyl-DG is the more efficient for drug solubilization but its use is limited by its possible liver toxicity.
authors.affiliation: Technologie Servier, 25-27 Rue Eugène Vignat, 45000 Orléans, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ménard
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tsapis
authors.forename: Cécile
authors.initials: C
authors.lastname: Poirier
authors.forename: Thomas
authors.initials: T
authors.lastname: Arnauld
authors.forename: Laurence
authors.initials: L
authors.lastname: Moine
authors.forename: Claire
authors.initials: C
authors.lastname: Gignoux
authors.forename: François
authors.initials: F
authors.lastname: Lefoulon
authors.forename: Jean-Manuel
authors.initials: JM
authors.lastname: Péan
authors.forename: Elias
authors.initials: E
authors.lastname: Fattal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D016718:Arachidonic Acid / Q000737:chemistry / Q000633:toxicity; D004912:Erythrocytes / Q000187:drug effects; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000633:toxicity*; D006461:Hemolysis / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D019787:Linoleic Acid / Q000737:chemistry / Q000633:toxicity; D008095:Lithocholic Acid / Q000737:chemistry / Q000633:toxicity; D008823:Micelles; D008958:Models, Molecular; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013229:Stearic Acids / Q000737:chemistry / Q000633:toxicity; D013501:Surface-Active Agents / Q000737:chemistry* / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D013229:Stearic Acids; D013501:Surface-Active Agents; D016718:Arachidonic Acid; D018698:Glutamic Acid; C031183:stearic acid; D008095:Lithocholic Acid; D019787:Linoleic Acid