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.E ffective delivery of therapeutics to the brain has remained elusive owing to many factors, including inadequate transport across the blood-brain barrier (BBB). Numerous multidisciplinary-based strategies for transporting therapeutic agents from the blood into the brain have been proposed (1), including the use of receptor-mediated transcytosis. Recently, Yu et al. (2) reported increased accumulation of antibodies to transferrin (Tf) receptor (TfR) in the brain parenchyma when the antibody affinity was reduced. In that work, antibodies with high TfR affinity bound strongly to and remained associated with TfRs in the BBB, whereas antibodies with lower TfR affinity allowed for their detachment from TfRs and subsequent release into the brain parenchyma. These results are consistent with a previous report of a low-affinity (nearly identical to Tf-TfR interaction strength) antibody that significantly accumulated in the brain parenchyma (3).Targeted nanoparticles are finding applications for the delivery of a wide variety of therapeutic agents, and several have already reached the clinical testing stage in humans (4, 5). For example, in a Phase I clinical trial, a Tf-containing nanoparticle was used to deliver siRNA to cancer patients and shown to deliver functional siRNA to melanoma tumors in a dose-dependent manner (6). The results demonstrate that Tf-containing nanoparticles can be administered safely to humans.It is well known that the avidity and receptor selectivity of targeted nanoparticles can be tuned by the choice of targeting ligand and its number density; multivalent nanoparticles can engage multiple cell surface receptors simultaneously (7,8). When an individual targeting ligand is conjugated to a nanoparticle, the affinity of the ligand to the receptor is reduced. However, if the receptor density is such that multiple targeting ligands on...

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 tissuespecific 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.

Pancreatic Ductal Adenocarcinoma (PDA) is a deadly disease, with no effective available treatment. Primary chemoresistance is common and has been attributed to the hypovascularity characteristic of the disease and the dense desmoplastic response that accompanies virtually every case of PDA. Effectively delivering therapeutic anticancer agents to PDA cells is therefore a specific, difficult and understudied problem in PDA that must be resolved for successful treatments to emerge. With the goal of eventually delivering drug payloads via nanoparticles (NP), we used well-defined mouse models of the disease to iteratively test NP distribution to both the cancerous and normal pancreas. Minimal deposition was observed in normal pancreas after intravenous or intraperitoneal administration of a variously sized (25nm or 40nm) NP. Surprisingly, abundant NP deposition was seen in both syngenic xenografted and autochthonous KPC models of PDA. NP deposition tended to be greater with IP administration and was enriched in stoma rich tumor regions. These findings have encouraging ramifications for delivery of depot or novel (e.g. siRNA, radiopharmaceutical, etc.) agents in this deadly disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2906. doi:1538-7445.AM2012-2906