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Lipid Lateral Segregation Driven by Diacyl Cyclodextrin Interactions at the Membrane Surface

Michel Roux ^*, Stéphane Moutard , Bruno Perly  and Florence Djedaini-Pilard 

^* Commissariat à l'Energie Atomique/Direction des Sciences du Vivant/Institut de Biologie et Technologies de Saclay, URA Centre National de la Recherche Scientifique 2096, Service de Bioénergétique, Biologie Structurale et Mécanismes, F-91191 Gif sur Yvette Cedex, France; OZ-Biosciences, Parc Scientifique de Luminy, BP13, F-13273 Marseille Cedex 9, France; Commissariat à l'Energie Atomique/Service de Chimie Moléculaire/Département de Recherche sur l'État Condensé, les Atomes et les Molécules, F-91191 Gif sur Yvette Cedex, France; and Laboratoire des Glucides, UMR6219, Université de Picardie Jules Verne, F-80039 Amiens, France

Correspondence: Address reprint request to Dr. Michel Roux, CEA/DSV/iBiTec-S, URA CNRS 2096, SB²SM, F-91191 Gif sur Yvette Cedex, France. Tel.: 33-69-08-9678; Fax: 33-69-08-8139; E-mail: michel.roux{at}cea.fr.

Cyclodextrins are hydrophilic molecular cages with a hydrophobic interior allowing the inclusion of water-insoluble drugs. Amphiphilic cyclodextrins obtained by appending a hydrophobic anchor were designed to improve the cell targeting of the drug-containing cavities through their liposome transportation in the organism. After insertion in model membranes, they were found to induce a lateral phase separation into a pure lipid phase and a fluid cyclodextrin-rich phase (L_CD) with reduced acyl chain order parameters, as observed with a derivative containing a cholesterol anchor (M. Roux, R. Auzely-Velty, F. Djedaïni-Pilard, and B. Perly. 2002. Biophysical Journal, 8:813–822). We present another class of amphiphilic cyclodextrins obtained by grafting aspartic acid esterified by two lauryl chains on the oligosaccharide core via a succinyl spacer. The obtained dilauryl-ß-cyclodextrin (ßDLC) was inserted in chain perdeuterated dimyristoylphosphatidylcholine (DMPC-d54) membranes and studied by deuterium NMR (²H-NMR). A laterally segregated mixed phase was found to sequester three times more lipids than the cholesteryl derivative (4–5 lipids per monomer of ßDLC), and a quasipure L_CD phase could be obtained with a 20% molar concentration of ßDLC. When cooled below the main fluid-to-gel transition of DMPC-d54 the ßDLC-rich phase stays fluid, coexisting with pure lipid in the gel state, and exhibits a sharp transition to a gel phase with frozen DMPC acyl chains at 12.5°C. No lateral phase separation was observed with partially or fully methylated ßDLC, confirming that the stability of the segregated L_CD phase was governed through hydrogen-bond-mediated intermolecular interactions between cyclodextrin headgroups at the membrane surface. As opposed to native ßDLC, the methylated derivatives were found to strongly increase the orientational order of DMPC acyl chains as the temperature reaches the membrane fluid-to-gel transition. The results are discussed in relation to the "anomalous swelling" of saturated phosphatidylcholine multilamellar membranes known to occur in the vicinity of the main fluid-to-gel transition.