(732e) Effect of Ionizable Head Group Architecture On the Delivery Efficiency of Lipid-Based siRNA Nanoparticles

Synthetic small interfering RNAs (siRNAs) have emerged as powerful tools for the regulation and silencing of endogenous genes. To achieve efficient gene silencing, siRNAs must be encapsulated or conjugated to delivery vehicles that can ensure cytosolic delivery of intact siRNAs across the cellular membrane.  So far, liposomal delivery vehicles have shown promising results for in vivo systemic delivery to hepatic and immune cellular targets. Using a combinatorial synthetic chemistry approach in conjunction with a lipid nanoparticle (LNP) formulation, our group recently identified a new class lipid-like structures (lipidoids) that facilitate efficient siRNA delivery. In an effort to comprehend the relationship between lipidoid structure and delivery efficiency, both in vitro and in vivo, this body of work focuses on evaluating the effect of the ionizable amine core structure of the lipidoid on the biophysical properties of the LNPs such as particle size, siRNA entrapment, LNP pKa, LNP lytic ability and extracellular LNP stability. These biophysical properties, along with the structure of the amine core are then correlated with uptake and gene silencing efficiency of the LNPs both in vitro and in vivo. The biophysical parameters obtained from this study, along with their correlation to lipidoid structure and gene-silencing efficiency, gives us some insight into possible future design strategies for the synthesis and evaluation of potent lipid structures for siRNA delivery.