A Novel Cationic Lipophosphoramide with Diunsaturated Lipid Chains: Synthesis, Physicochemical Properties, and Transfection Activities

Abstract

Cationic lipophosphoramidates constitute a class of cationic lipids we have previously reported to be efficient for gene transfection. Here, we synthesized and studied a novel lipophosphoramidate derivative characterized by an arsonium headgroup linked, via a phosphoramidate linker, to an unconventional lipidic moiety consisting of two diunsaturated linoleic chains. Physicochemical studies allowed us to comparatively evaluate the specific fluidity and fusogenicity properties of the liposomes formed. Although corresponding lipoplexes exhibited significant but relatively modest in vitro transfection efficiencies, they showed a remarkably efficient and reproducible ability to transfect mouse lung, with in vivo transfection levels higher than those observed with a monounsaturated analogue previously described. Thus, these results demonstrate that this diunsaturated cationic lipophosphoramidate constitutes an efficient and versatile nonviral vector for gene transfection. They also invite further evaluations of the transfection activity, especially in vivo, of gene delivery systems incorporating the lipid reported herein and/or other lipids bearing polyunsaturated chains.

Synthetic vectors for gene delivery: An overview of their evolution depending on routes of administration.

“…Modifications effecting the nature of the fatty chains were also performed. Among these compounds, BSV4, an arsonolipophosphoramidate characterized by two linoleic chains (double unsaturations), was more effective for the transfection of murine lung tissues after intravenous administration than the homologous compound bearing a single unsaturation (KLN47) [24]. Indeed, in harvested lungs, luciferase expression achieved (1.43 ± 0.59) × 10 5 and only (4.60 ± 2.58) × 10 3 RLU/mg total protein, after treatment with BSV4 and KLN47, respectively [24].…”

“…Among these compounds, BSV4, an arsonolipophosphoramidate characterized by two linoleic chains (double unsaturations), was more effective for the transfection of murine lung tissues after intravenous administration than the homologous compound bearing a single unsaturation (KLN47) [24]. Indeed, in harvested lungs, luciferase expression achieved (1.43 ± 0.59) × 10 5 and only (4.60 ± 2.58) × 10 3 RLU/mg total protein, after treatment with BSV4 and KLN47, respectively [24]. Replacement of oleic or linoleic aliphatic chains (KLN47 and BSV4, respectively) by phytanyl chains permitted the formation of more fusogenic type structures identified as inversed hexagonal phases without the addition of DOPE, significantly improving in vivo transfection efficiency [25].…”

Smart DNA Vectors Based on Cyclodextrin Polymers: Compaction and Endosomal Release

“…In vitro transfection experiments reported in the literature are often realized in serum-free culture medium for a few hours before changing the medium for fresh medium supplemented with serum (25)(26)(27). In the presence of serum, cationic complexes adsorb onto negatively charged proteins and this in turn usually results in a reduction of the transfection efficiency.…”

Polyamine – Lipid Conjugates as Effective Gene Carriers: Chemical Structure, Morphology, and Gene Transfer Activity

“…These compounds could hence provide new category of polycationic lipids. Gall et al have developed cationic lipid derivatives bearing P-N linkage, which possess gene transfer activity (Gall et al, 2010).…”