1 research outputs found
Stabilization of Ostwald Ripening in Low Molecular Weight Amino Lipid Nanoparticles for Systemic Delivery of siRNA Therapeutics
Lipid
nanoparticles (LNPs) represent the most clinically advanced
technology for the systemic delivery of therapeutic siRNA in vivo.
Toward this end, a novel class of LNPs comprising low molecular weight
(MW) ionizable amino lipids having asymmetric architecture was recently
reported. LNPs of these amino lipids,
termed asymmetric LNPs, were shown to be highly efficacious and well
tolerated in vivo; advances were enabled by improved endosomal escape,
coupled with enhanced amino lipid metabolism and clearance. In this
work, we show that, in contrast to their desirable pharmacological
performance, asymmetric LNPs present a significant pharmaceutical
developability challenge, namely physical instability limiting extended
shelf life. Using orthogonal characterization methods, we identify
the mechanism of LNP instability as Ostwald ripening and establish
it to be driven predominantly by the asymmetric amino lipid component.
Through rational optimization of LNP physical and macromolecular properties,
we are able to significantly attenuate or entirely eliminate the Ostwald
ripening instability. Modulation of LNP size, for example, effectively
halts particle growth. Similarly, optimization of LNP macromolecular
packing through deliberate selection of structurally matched colipids
significantly diminishes the rate of ripening. This later experimental
observation is substantiated by molecular dynamics simulations of
LNP self-assembly, which establish a quantitative dependence of LNP
macromolecular order on colipid structure. In totality, the experimental
and molecular dynamics outcomes of this work support the rational
design of LNP physical and chemical properties leading to effective
Ostwald ripening stabilization and enable the advance of asymmetric
LNPs as a clinic-ready platform for siRNA therapeutics