Abstract
The formation of a novel trichain (TC) lipid was discovered when a cationic lipid possessing a terminal
hydroxyl group and the helper lipid dioleoyl L-α-phosphatidylethanolamine (DOPE) were formulated as
vesicles and stored. Importantly, the transfection efficacies of lipopolyplexes comprised of the TC lipid, a
targeting peptide and DNA (LPDs) were found to be higher than when the corresponding dichain (DC)
lipid was used. To explore this interesting discovery and determine if this concept can be more generally
applied to improve gene delivery efficiencies, the design and synthesis of a series of novel TC cationic
lipids and the corresponding DC lipids was undertaken. Transfection efficacies of the LPDs were found to
be higher when using the TC lipids compared to the DC analogues, so experiments were carried out to
investigate the reasons for this enhancement. Sizing experiments and transmission electron microscopy
indicated that there were no major differences in the size and shape of the LPDs prepared using the TC
and DC lipids, while circular dichroism spectroscopy showed that the presence of the third acyl chain did
not influence the conformation of the DNA within the LPD. In contrast, small angle neutron scattering
studies showed a considerable re-arrangement of lipid conformation upon formulation as LPDs, particularly
of the TC lipids, while gel electrophoresis studies revealed that the use of a TC lipid in the LPD formulation
resulted in enhanced DNA protection properties. Thus, the major enhancement in transfection performance
of these novel TC lipids can be attributed to their ability to protect and subsequently release
DNA. Importantly, the TC lipids described here highlight a valuable structural template for the generation
of gene delivery vectors, based on the use of lipids with three hydrophobic chains.
Original language | English |
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Pages (from-to) | 945-957 |
Journal | Organic & Biomolecular Chemistry |
Volume | 17 |
Issue number | 4 |
Early online date | 19 Dec 2018 |
DOIs | |
Publication status | Published - 28 Jan 2019 |