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Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA

Heidel, Jeremy D. and Yu, Zhongping and Liu, Joanna Yi-Ching and Rele, Shyam M. and Liang, Yongchao and Zeidan, Ryan K. and Kornburust, Douglas J. and Davis, Mark E. (2007) Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA. Proceedings of the National Academy of Sciences of the United States of America, 104 (14). pp. 5715-5721. ISSN 0027-8424. https://resolver.caltech.edu/CaltechAUTHORS:HEIpnas07

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Abstract

The results of administering escalating, i.v. doses of targeted nanoparticles containing a siRNA targeting the M2 subunit of ribonucleotide reductase to non-human primates are reported. The nanoparticles consist of a synthetic delivery system that uses a linear, cyclodextrin-containing polycation, transferrin (Tf) protein targeting ligand, and siRNA. When administered to cynomolgus monkeys at doses of 3 and 9 mg siRNA/kg, the nanoparticles are well tolerated. At 27 mg siRNA/kg, elevated levels of blood urea nitrogen and creatinine are observed that are indicative of kidney toxicity. Mild elevations in alanine amino transferase and aspartate transaminase at this dose level indicate that the liver is also affected to some extent. Analysis of complement factors does not reveal any changes that are clearly attributable to dosing with the nanoparticle formulation. Detection of increased IL-6 levels in all animals at 27 mg siRNA/kg and increased IFN-{gamma} in one animal indicate that this high dose level produces a mild immune response. Overall, no clinical signs of toxicity clearly attributable to treatment are observed. The multiple administrations spanning a period of 17–18 days enable assessment of antibody formation against the human Tf component of the formulation. Low titers of anti-Tf antibodies are detected, but this response is not associated with any manifestations of a hypersensitivity reaction upon readministration of the targeted nanoparticle. Taken together, the data presented show that multiple, systemic doses of targeted nanoparticles containing nonchemically modified siRNA can safely be administered to non-human primates.


Item Type:Article
Additional Information:Copyright © 2007 by the National Academy of Sciences Contributed by Mark E. Davis, February 20, 2007 (received for review February 6, 2007). This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 25, 2006. Freely available online through the PNAS open access option. We thank Michael Kalos and Shu Mi of the City of Hope National Cancer Center (Duarte, CA) for cytokine measurements; Patricia Giclas and Cindy Marschner of the National Jewish Center (Denver, CO) for complement measurements; Sandra Carriero, Alvira Macanovic, and Helen Legakis of Charles River Laboratories Preclinical Services (Montreal, QC, Canada) for pharmacokinetic measurements; and Jodie Cowan and others at Shin Nippon Biomedical Laboratories USA (Everett, WA) for the in-life experiment and serum and hematology measurements. Author contributions: J.D.H., D.J.K., and M.E.D. designed research; J.D.H., Z.Y., J.Y.-C.L., S.M.R., Y.L., and R.K.Z. performed research; J.D.H., Z.Y., J.Y.-C.L., D.J.K., and M.E.D. analyzed data; and J.D.H., D.J.K., and M.E.D. wrote the paper. Conflict of interest statement: M.E.D. is a consultant to and has stock in Calando Pharmaceuticals. This article contains supporting information online at www.pnas.org/cgi/content/full/0701458104/DC1.
Subject Keywords:systemic administration; RNA interference
Issue or Number:14
Record Number:CaltechAUTHORS:HEIpnas07
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:HEIpnas07
Alternative URL:http://dx.doi.org/10.1073/pnas.0701458104
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8303
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:02 Aug 2007
Last Modified:02 Oct 2019 23:49

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