siRNA delivery to the glomerular mesangium using polycationic cyclodextrin nanoparticles containing siRNA.

There is an urgent need for new therapies that can halt or reverse the course of chronic kidney disease with minimal side-effect burden on the patient. Small interfering RNA (siRNA) nanoparticles are new therapeutic entities in clinical development that could be useful for chronic kidney disease treatment because they combine the tissue-specific targeting properties of nanoparticles with the gene-specific silencing effects of siRNA. Recent reports have emerged demonstrating that the kidney, specifically the glomerulus, is a readily accessible site for nanoparticle targeting. Here, we explore the hypothesis that intravenously administered polycationic cyclodextrin nanoparticles containing siRNA (siRNA/CDP-NPs) can be used for delivery of siRNA to the glomerular mesangium. We demonstrate that siRNA/CDP-NPs localize to the glomerular mesangium with limited deposition in other areas of the kidney after intravenous injection. Additionally, we report that both mouse and human mesangial cells rapidly internalize siRNA/CDP-NPs in vitro and that nanoparticle uptake can be enhanced by attaching the targeting ligands mannose or transferrin to the nanoparticle surface. Lastly, we show knockdown of mesangial enhanced green fluorescent protein expression in a reporter mouse strain following iv treatment with siRNA/CDP-NPs. Altogether, these data demonstrate the feasibility of mesangial targeting using intravenously administered siRNA/CDP-NPs.

Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor.

Receptor-mediated transcytosis across the blood-brain barrier (BBB) may be a useful way to transport therapeutics into the brain. Here we report that transferrin (Tf)-containing gold nanoparticles can reach the brain parenchyma from systemic administration in mice through a receptor-mediated transcytosis pathway. This transport is aided by tuning the nanoparticle avidity to Tf receptor (TfR), which is correlated with nanoparticle size and total amount of Tf decorating the nanoparticle surface. Nanoparticles of both 45 nm and 80 nm diameter reach the brain parenchyma, and their accumulation there (visualized by silver enhancement light microscopy in combination with transmission electron microscopy imaging) is observed to be dependent on Tf content (avidity); nanoparticles with large amounts of Tf remain strongly attached to brain endothelial cells, whereas those with less Tf are capable of both interacting with TfR on the luminal side of the BBB and detaching from TfR on the brain side of the BBB. The requirement of proper avidity for nanoparticles to reach the brain parenchyma is consistent with recent behavior observed with transcytosing antibodies that bind to TfR.