In vivo disposition and stability of DNA frayed wires in mice.
DNA frayed wires (DNA(FW)) are an alternate form of DNA organization formed by the self-association of several strands of guanine-rich oligonucleotides. The purpose of this study was to define for the first time the blood clearance kinetics, tissue distribution, and stability of DNA(FW) in vivo in mice. Single bolus doses (1200 pmol/mouse) of (32)P-DNA(FW) and (32)P-random DNA were administered intravenously (IV) and intraperitoneally (IP) followed by scheduled blood, urine, fecal and tissue samplings. Blood clearance kinetics was described well by a first order two-compartment open model. The overall half-lives of elimination from the central compartment (T(1/2))(K10) were 3.57+/-0.1h for IV and 2.38+/-0.11 h for IP. In contrast, random DNA was completely degraded after 15 min regardless of the route of administration. Tissue distribution results demonstrated that DNA(FW) were primarily distributed and retained in the liver, intestines, kidneys, and heart. Low levels could also be detected in brain. Autoradiographs of blood, tissues, feces and urine extracts established that DNA(FW) remained intact after administration as no measurable levels of metabolites or degradation products were found after 24h. (32)P-DNA(FW) was primarily eliminated via hepato-biliary excretion into feces after either IV or IP administration (51.8+/-4.53% and 36.2+/-3.4%, respectively). The improved stability and longer half-life of DNA(FW), previously shown in vitro, is also seen in vivo, indicating that DNA(FW) may provide a stable delivery system for DNA gene therapies. In conclusion, this is the first study demonstrating the in vivo stability, pharmacokinetics, and disposition of DNA superstructures.
Yanze
Maximum F
MF
Department of Pharmaceutical Sciences, University of Toronto, 19 Russell Street, Toronto, Ont, Canada.
Ho
Emmanuel A
EA
Macgregor
Robert B
RB
Piquette-Miller
Micheline
M
D000818:Animals; D004247:DNA / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics*; D004355:Drug Stability; D005260:Female; D006147:Guanine / Q000737:chemistry; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution
D046911:Macromolecular Substances; D009838:Oligodeoxyribonucleotides; D006147:Guanine; D004247:DNA