Abstract
Five novel cationic lipids, the polar head group of which was attached to the cholesterol backbone via a tertiary carbamate linker, were synthesized and their physicochemical properties were compared to their transfection efficiencies. Transfection activity of the primary amine analog was highest among the series, while the quaternary ammonium iodide salt was essentially transfection incompetent. Contrary to DC-Chol, methyl and ethyl carbamoyl derivatives of DC-Chol mediated high levels of transfection in the absence of DOPE. Ionization of the cationic assemblies in 40 mM Tris buffer pH 7.2 exactly correlated with the competitive nature of the inductive and steric effects of the methyl groups on the aliphatic nitrogen of the lipids’ polar moiety. Interestingly, the pH interaction zone of all lipid dispersions at 25°C was extended by ± 2 pH units from the pKa, while the pKa of the cationic lipids determined in mixed vesicles composed of 90 % DOPC and cholesterol was approximately 1.3 to 1.5 times higher than that of pure cationic assemblies. The interaction of cationic lipids with plasmid DNA was correlated with pKa, but not the transfection activity.
Highlights
Cholesterol-based cationic lipids are one of the most promising series of reagents for in vitro and in vivo gene delivery [1,2,3,4]
The polar head group of these lipids is composed of a primary, secondary, tertiary or quaternary amine and almost always these lipids require the presence of the helper lipid DOPE in order to mediate transfection
The physicochemical properties of cholesterol-based cationic lipids carrying a secondary carbamate linker were correlated with their transfection activity in the absence of helper lipids
Summary
Cholesterol-based cationic lipids are one of the most promising series of reagents for in vitro and in vivo gene delivery [1,2,3,4]. The study found that the tertiary and quaternary amine derivatives, DCChol and TC-Chol ( termed DC and TC), failed to mediate transfection and further concluded that the high transfection activity mediated by the primary and secondary analogs AC and MC in the absence of DOPE, was due to their increased association with plasma membrane and endosomal escape [14]. The aim of this investigation was to examine how methylation on the carbamoyl nitrogen affects the lipids’ ionization, interaction with plasmid DNA and transfection activity
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