Triggering bilayer to inverted-hexagonal nanostructure formation by thiol–ene click chemistry on cationic lipids: consequences on gene transfection

Abstract

The ramification of cationic amphiphiles on their unsaturated lipid chains is readily achieved by using the thiol-ene click reaction triggering the formation of an inverted hexagonal phase (HII). The new ramified cationic lipids exhibit different bio-activities (transfection, toxicity) including higher transfection efficacies on 16HBE 14o-cell lines.

Substitution of unsaturated lipid chains by thioether-containing lipid chains in cationic amphiphiles: physicochemical consequences and application for gene delivery

“…22 It must be noted that the reference compound BSV36 produced in similar hydration state a layered packing. 12 The 31 P NMR spectrum of compound 4d (hydrated at a concentration of 100 mg/mL) indicates that this compound adopts also a layered supramolecular packing as attested by both the symmetry of the signal (the most intense peak   is on the right hand side of the pattern) and the chemical shift anisotropy ( > 40 ppm) (ESI 6). 12 Then, the capacity of compounds 4a-d to transfect two humanderived cell lines (i.e.…”

“…12 The 31 P NMR spectrum of compound 4d (hydrated at a concentration of 100 mg/mL) indicates that this compound adopts also a layered supramolecular packing as attested by both the symmetry of the signal (the most intense peak   is on the right hand side of the pattern) and the chemical shift anisotropy ( > 40 ppm) (ESI 6). 12 Then, the capacity of compounds 4a-d to transfect two humanderived cell lines (i.e. A549 and 16HBE) was assessed at different charge ratios (CR); the latter corresponds to the number of positive charges belonging to the cationic amphiphiles divided by the number of negatives charges coming from the nucleic acids.…”

“…18h), especially when compared with branched lipid chains-containing amphiphiles (which synthesis was previously reported by using thiol-ene click reaction and that required 3 days of hydration before their formulation as liposomal solution). 12 Dynamic Light Scattering (DLS) measurements indicated that liposomal solutions of 4a-d exhibited average sizes from 75 to 94 nm with close polydispersity indexes (0.24 to 0.34). Of note, the smaller liposomes were observed for the compounds for which the thioether function was closer to the polar head group.…”

“…However, if DNA compaction is usually required for gene delivery, too much stable lipoplexes typically yield low transfection efficacies as observed for instance with amphiphiles incorporating stearyl (C18:0) lipid chains. 10 The incorporation of unsaturation or ramification (phytanyl chains 11 or synthetically branched lipid chains 12 ) within the hydrophobic moiety disturbs the packing of the lipid chains which in turn is correlated with low temperature fused lipid phase and higher transfection efficacies. It was suggested that a subtle balance between stability (needed before cell internalization) and instability (required after internalization by endocytosis) 13 of the lipoplexes has to be reached.…”

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

“…through thiol-ene click chemistry) lipid chains can be used. [33] The presence of lateral moieties decreases the strength of the packing [34][35][36] but can also affect the supramolecular organization (e.g. production of inverted hexagonal phase).…”