This study utilized siRNA designed to target the gene CCR2, a chemokine receptor that mediates trafficking of monocytes to injured tissues. When formulated in a novel and proprietary lipid nanoparticle (LNP) formulation and administered systemically in an animal model, this siRNA showed rapid blood clearance, accumulated in spleen, bone marrow and liver, and was found to localize to monocytes. Administration of the LNP-formulated CCR2-specific siRNA resulted in target gene silencing in monocytes; this was shown to be mediated by RNAi, as evidenced by a molecular biology technique known as 5’-RACE. As a result of CCR2 silencing in monocytes, a number of therapeutic effects were observed in a broad range of distinct pre-clinical animal models. Specifically, siRNA treatment attenuated the recruitment of inflammatory monocytes in atherosclerotic plaques, reduced the infarct size after coronary artery occlusion, prolonged normal glycemic levels in diabetic mice after pancreatic islet transplantation, and, resulted in reduced tumor volumes in two independent cancer models.
The study desribes the discovery of “core-shell” nanoparticles for systemic delivery of RNAi therapeutics. The core-shell nanoparticles were generated using a high-throughput polymer synthesis strategy and screened for intracellular delivery applications including siRNA delivery. These findings, published with our collaborators at MIT, allow for the development of novel nanoparticles that have optimal chemical and physical properties for effective intracellular delivery of RNAi therapeutics. Specifically, this study evaluated a library of over 1,500 chemically diverse nanoparticles as drug delivery vehicles, with precise control over particle size, chemical composition and architecture. Initial in vivo studies on one of these novel nanoparticles showed silencing of hepatocyte-specific Factor VII in a pre-clinical model. The ability to control and modify the chemical nature of the core and shell of the nanoparticle may afford utility of these materials in a wide range of drug delivery applications.