Cationic dialkylarylphosphates: a new family of bio-inspired cationic lipids for gene delivery

Abstract

In this work that aims to synthesize and evaluate new cationic lipids as vectors for gene delivery, we report the synthesis of a series of cationic lipids in which a phosphate functional group acts as a linker to assemble on a molecular scale, two lipid chains and one cationic polar head. The mono or dicationic moiety is connected to the phosphate group by an aryl spacer. In this work, two synthesis strategies were evaluated. The first used the Atherton-Todd coupling reaction to introduce a phenolic derivative to dioleylphosphite. The second strategy used a sequential addition of lipid alcohol and a phenolic derivative on POCl3. The two methods are efficient, but the latter allows larger yields. Different polar head groups were introduced, thus producing amphiphilic compounds possessing either one permanent (N-methyl-imidazolium, pyridinium, trimethylammonium) or two permanent cationic charges. All these cationic lipids were formulated as liposomal solutions and characterized (size and zeta potential). They formed stable liposomal solutions both in water (at pH 7.0) and in a weakly acidic medium (at pH 5.5). Finally, this new generation of cationic lipids was used to deliver DNA into various human-derived epithelial cells cultured in vitro. Compared with Lipofectamine used as a reference commercial lipofection reagent, some cationic dialkylarylphosphates were able to demonstrate potent gene transfer abilities, and noteworthily, monocationic derivatives were much more efficient than dicationic analogues.

Establishment of Lipofection Protocol for Efficient miR-21 Transfection into Cortical Neurons In Vitro

“…Some transfection reagents are currently used to introduce miRNAs into cells, but poor transfection efficiency and low expression level of miRNAs are a common problem in neurons. The cationic lipofection has been shown to perform well in many passage cells, such as osteoclasts , endothelial cells (Rohde et al, 2015), and human-derived epithelial cells (Le Corre et al, 2015), but the mature primary cells, like neurons, are still described as difficult-totransfect (Morris and Labhasetwar, 2015). In some studies, the cationic lipofection reagents, like Lipofectamine 2000, were efficient in terms of delivery in primary cells (Chen et al, 2014), but there are no special protocols to maintain the functionality of the internalized RNA oligos.…”

Synthesis of lipid-based unsymmetrical O,O-dialkylphosphites

“…Supplementary data (experimental procedures, characterization data, 1 H, 31 P, 13 C spectra for all compounds and mass spectrometry analysis) associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.03.093.…”

Bis‐Thioether‐Containing Lipid Chains in Cationic Amphiphiles: Physicochemical Properties and Applications in Gene Delivery

“…To improve the efficacies of cationic amphiphiles for nucleic acids delivery, both the modification of the structure of the polar head group (e.g. nature of the cationic charge [22] polycationic moieties [23,24] ) and the structure of the hydrophobic domain were explored. [25] In the last case, it was shown that cationic amphiphiles containing saturated lipid chains produced ineffective pDNA carriers.…”