Novel Surfactants with Diglutamic Acid Polar Head Group: Drug Solubilization and Toxicity Studies
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Novel surfactants made of diglutamic acid (DG) polar head linked to lithocholic, arachidonic, linoleic or stearic acids were designed for drug solubilization.
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.
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.
Among the surfactants tested, stearoyl-DG is the more efficient for drug solubilization but its use is limited by its possible liver toxicity.
KEY WORDSinsoluble drug micelle self-assembly solubilization surfactant toxicity
ACKNOWLEDGMENTS & DISCLOSUREs
The authors would like to thank X. Quénault for lithocholanoyl-DG synthesis. We would like to thank A. Petit, F. Munari and N. Bongibault-Besnard for 1H RMN experiments for structural determination, P. Vayer for molecular modelling, H. Bertheux and N. Bécourt-Lhote for in vivo toxicity studies from Biologie SERVIER. We also acknowledge M. Lynch for DSC and XRD discussions from Technologie SERVIER. We would like to thank J-P. Lechaire and G. Frébourg (Service de microscopie électronique, IFR de Biologie intégrative-CNRS-Paris VI) and the Région Ile de France for cryo-TEM observations. This work was financially supported by ANRT from the Ministère de l’enseignement supérieur et de la recherche and by Technologie SERVIER. Our laboratory is a member of the Laboratory of Excellence LERMIT supported by a grant from ANR (ANR-10-LABX-33).
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