Synthesis and Characterization of Long Chain Alkyl Acyl Carnitine Esters. Potentially Biodegradable Cationic Lipids for Use in Gene Delivery

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Abstract
A series of alkyl acyl carnitine esters (alkyl 3-acyloxy-4-trimethylammonium butyrate chloride) were synthesized as potential biocompatible cationic lipids for use in gene transfer. The physicochemical properties of the lipids, liposomes prepared from them, and their complexes with DNA were characterized by differential scanning calorimetry (DSC), particle size, ζ potential, and surface monolayer measurements. The transition temperatures and behavior at an air−water interface for this series are similar to phosphatidylcholines with the same hydrocarbon chain length. The physical properties of the l derivatives were not significantly different from the dl derivatives. At 70 °C, the acyl chains were readily hydrolyzed at pH 7. The influence of the aliphatic chain length (n = 12−18) on transfection efficiency in vitro was determined using cationic liposomes prepared from these lipids or their mixtures with the helper lipids, dioleoylphosphatidylethanolamine (DOPE), dioleoylphosphatidylcholine, monooleoylglycerol, and cholesterol (Chol). The mixture of myristyl 3-myristoyloxy-4-trimethylammonium butyrate chloride (MMCE, 4d) with DOPE at a 1:1 molar ratio mediated the highest transfection efficiency in cell culture. The mixture of oleyl 3-oleoyloxy-4-trimethylammonium butyrate chloride (OOCE, 4f) with Chol at a 1:1 molar ratio gave the highest transfection efficiency after intravenous administration in mice. In vivo gene expression using 4f was comparable to values obtained with the best cationic lipids reported to date.