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siRNA Delivery to the Glomerular Mesangium Using Polycationic Cyclodextrin Nanoparticles Containing siRNA

Zuckerman, Jonathan E. and Gale, Aaron and Wu, Peiwen and Ma, Rong and Davis, Mark E. (2015) siRNA Delivery to the Glomerular Mesangium Using Polycationic Cyclodextrin Nanoparticles Containing siRNA. Nucleic Acid Therapeutics, 25 (2). pp. 53-64. ISSN 2159-3337. doi:10.1089/nat.2014.0505.

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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.

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Davis, Mark E.0000-0001-8294-1477
Additional Information:© 2012 Mary Ann Liebert, Inc. Received for publication August 12, 2014; accepted September 19, 2014. We would like to thank Carol M. Garland (Caltech) for help obtaining electron microscopy images. This work benefited from the use of the Caltech Materials Science Transmission Electron Microscope facility, which is partially supported by the Materials Research Science and Engineering Centers Program of the National Science Foundation under award number DMR-0520565. We thank Han Han for preparing the AF350-CDP and AD-PEG-Mannose, and Chung Hang J. Choi for processing kidney san1ples for transmission electron microscope imaging. This work was supported by National Cancer Institute grant CAI 19347, Sanofi-Aventis, and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases, DK079968 (to R.M.). Jonathan E. Zuckerman is also supported by the Caltech-University of California Los Angeles (UCLA) Joint Center for Translational Medicine, National Institutes of Health National Institute of General Medical Sciences training grant, GM08042, and the UCLA Medical Scientist Training Program.
Funding AgencyGrant Number
National Cancer InstituteCAI 19347
NIH/National Institute of Diabetes and Digestive and Kidney DiseasesDK079968
Caltech-UCLA Joint Center for Translational MedicineUNSPECIFIED
NIH National Institute of General Medical SciencesGM08042
UCLA Medical Scientist Training ProgramUNSPECIFIED
Issue or Number:2
Record Number:CaltechAUTHORS:20150311-084546625
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Official Citation:Zuckerman Jonathan E., Gale Aaron, Wu Peiwen, Ma Rong, and Davis Mark E.. Nucleic Acid Therapeutics. April 2015, 25(2): 53-64. doi:10.1089/nat.2014.0505.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:55698
Deposited By: Jason Perez
Deposited On:16 Mar 2015 17:19
Last Modified:10 Nov 2021 20:49

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