Title:Enhancing Nucleic Acid Delivery, Insights from the Cationic Phospholipid Carriers
Volume: 15
Issue: 9
Author(s): Rumiana Koynova and Boris Tenchov
Affiliation:
Keywords:
Cationic phospholipid, cubic phase, hexagonal phase, lipoplex, nonlamellar, oligonucleotide.
Abstract: The development of nucleic acid-based drugs has attracted considerable interest in the past two decades as a
new category of biologics. A key challenge in successfully achieving the full potential of nucleotide therapeutics is their
efficient delivery. Synthetic cationic lipids are currently the most extensively used non-viral nucleotide carriers because of
their ability to form complexes with the nucleic acids. Here we examine the properties of oligonucleotide lipoplexes with
a particularly noteworthy cationic lipid class, the cationic phosphatidylcholines (PCs) which exhibit low toxicity and good
nucleotide delivery efficacy. Studies on a set of cationic PCs reveal the existence of a strong, systematic dependence of
their carrier efficiency on the lipid hydrocarbon chain structure. Their activity rises with the increase in chain unsaturation
and declines with the increase in chain length. Maximum transfection is detected for ethyl-PC (ePC) with monounsaturated
14:1 chains. The same lipid exhibits maximum activity also in intracellular delivery of siRNA. As the lipid phase
behavior is known to depend substantially on the hydrocarbon chain structure, the above relationships validate a view that
cationic PC phase properties are an important factor for their activity. Indeed, time-resolved X-ray diffraction studies
showed that the rate of the nucleotide release from the lipoplexes, as well as their transfection activity, correlate with the
non-lamellar phase progressions detected in mixtures of cationic PCs with biomembrane lipids. These findings emphasize
the role of the non-lamellar lipid mesophases in the nucleic acid transport across the cellular membranes and their intracellular
release.
