Administration in non-human primates of escalating intravenous doses of targeted nanoparticles containing ribonucleotide reductase subunit M2 siRNA.
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.
Heidel
Jeremy D
JD
Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, MC 210-41, Pasadena, CA 91125, USA.
Yu
Zhongping
Z
Liu
Joanna Yi-Ching
JY
Rele
Shyam M
SM
Liang
Yongchao
Y
Zeidan
Ryan K
RK
Kornbrust
Douglas J
DJ
Davis
Mark E
ME
D000818:Animals; D002412:Cations / Q000737:chemistry; D003505:Cyclodextrins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D008024:Ligands; D008252:Macaca fascicularis; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D012262:Ribonucleoside Diphosphate Reductase / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014168:Transferrin / Q000737:chemistry
D002412:Cations; D003505:Cyclodextrins; D008024:Ligands; D034741:RNA, Small Interfering; D014168:Transferrin; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase