Development of Lipidoid-siRNA Formulations for Systemic Delivery to the Liver

RNA interference therapeutics afford the potential to silence target gene expression specifically, thereby blocking production of disease-causing proteins. The development of safe and effective systemic small interfering RNA (siRNA) delivery systems is of central importance to the therapeutic application of siRNA. Lipid and lipid-like materials are currently the most well-studied siRNA delivery systems for liver delivery, having been utilized in several animal models, including nonhuman primates. Here, we describe the development of a multicomponent, systemic siRNA delivery system, based on the novel lipid-like material 98N(12)-5(1). We show that in vivo delivery efficacy is affected by many parameters, including the formulation composition, nature of particle PEGylation, degree of drug loading, and biophysical - parameters such as particle size. In particular, small changes in the anchor chain length of poly(ethylene glycol) (PEG) - lipids can result in significant effects on in vivo efficacy. The lead formulation developed is liver targeted (> 90% injected dose distributes to liver) and can induce fully reversible, long-duration gene silencing without loss of activity - following repeat administration.