title: Drug solubilization and in vitro toxicity evaluation of lipoamino acid surfactants.
abstract: To improve solubilization of a water insoluble anticancer drug, novel surfactants were synthesized. All surfactants derived from lysine, with a so-called nitrilo triacetic acid (NTA) polar head, and differed from the length and saturation degree of their hydrophobic moieties: C19:0-NTA, C20:4-NTA, C25:0-NTA and C25:4-NTA. Self-assembling properties and critical micellar concentration (CMC) values were determined using pyrene fluorescence and cytotoxicity using MTT and LDH assays on endothelial cells. Surfactant haemolytic activity and drug solubilization capacity were also evaluated. All surfactants self-assemble with low CMC values from 0.012 to 0.430 mg/mL. Cytotoxicity assays showed that C20:4-NTA and C25:0-NTA were less cytotoxic than polysorbate 80. Unsaturations and alkane chain length have a marked influence on toxicity. Saturated surfactants had a similar haemolytic activity, explained by their low CMC values and the linear configuration of their hydrophobic tail. C20:4-NTA and C25:4-NTA were less haemolytic than polysorbate 80. Furthermore, C19:0-NTA, C25:0-NTA and C25:4-NTA increased drug solubility from <0.15 μg/mL up to 7 mg/mL, with 46% (w/w) drug loading, due to their linear and flexible hydrophobic chain configuration, as evidenced by molecular modelling. Although these solubilizers are promising, a compromise between drug solubilization and toxicity remains to be found.
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: 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*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004339:Drug Compounding; D006461:Hemolysis / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000473:pathology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008055:Lipids / Q000737:chemistry* / Q000633:toxicity*; D008239:Lysine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000633:toxicity*; D008823:Micelles; D008958:Models, Molecular; D015394:Molecular Structure; D009571:Nitrilotriacetic Acid / Q000737:chemistry / Q000633:toxicity; D011136:Polysorbates / Q000737:chemistry / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013329:Structure-Activity Relationship; D013501:Surface-Active Agents / Q000737:chemistry* / Q000633:toxicity*; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D008055:Lipids; D008823:Micelles; D011136:Polysorbates; D013501:Surface-Active Agents; D008239:Lysine; D009571:Nitrilotriacetic Acid