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Polymorphism of Pyridinium Amphiphiles for Gene Delivery: Influence of Ionic Strength, Helper Lipid Content, and Plasmid DNA Complexation

Marco Scarzello ^*, Vladimir Chupin ^*, Anno Wagenaar ^*, Marc C. A. Stuart ^*, Jan B. F. N. Engberts ^* and Ron Hulst 

^* Physical Organic Chemistry Unit, Stratingh Institute, University of Groningen, The Netherlands; and Kiadis BV, Groningen, The Netherlands

Correspondence: Address reprint requests to Jan Bernard Engberts, Physical Organic Chemistry Unit, Stratingh Institute, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands. E-mail: j.b.f.n.engberts{at}chem.rug.nl.

Two double-tailed pyridinium cationic amphiphiles, differing only in the degree of unsaturation of the alkyl chains, have been selected for a detailed study of their aggregation behavior, under conditions employed for transfection experiments. The transfection efficiencies of the two molecules are remarkably different, especially when combined with 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) as helper lipid. The phase behavior of the cationic amphiphile/DOPE mixtures have been studied using ³¹P- and ²H-NMR (on deuterated cationic amphiphiles) as main techniques, to monitor independently the behavior of the two components. In water, the lamellar organization is dominant for both the surfactants in their mixtures with the helper lipid. In HEPES saline buffer (HBS), the mixtures of the unsaturated surfactant form inverted phases and, in particular, stable H_II phases for DOPE contents 30 mol %. By contrast, the saturated surfactant does not form homogeneously mixed inverted phases in mixtures with DOPE at room temperature. However, mixed inverted phases are observed for this system at higher temperatures and, after mixing has been achieved by heating, the metastable mixed phases remain present for several hours at 5°C. At 35°C the dominant phase is the cubic phase. The lipoplex composed of equimolar mixtures of the unsaturated surfactant with DOPE and plasmid DNA was found to be organized in highly curved bilayers.