title: Molecular imaging study on in vivo distribution and pharmacokinetics of modified small interfering RNAs (siRNAs).
abstract: Molecular imaging was used to study the biodistribution, pharmacokinetics, and activity of naked small interfering RNAs (siRNAs). siRNAs with riboses chemically modified in the 2' position were compared with unmodified siRNA. In vitro, replacement of the 2'-hydroxyl (2'OH) group of certain nucleotides in an siRNA sequence by a fluorine atom (2'F) on both antisense (AS) and sense (S) strands [2'F(AS/S)], or by a methoxy group (2'OMe) on the S strand [2'OH(AS)/2'OMe(S)], was compatible with RNA interference. Different siRNAs [2'F(AS/S), 2'OH(AS)/2'OMe(S), and 2'OH(AS/S)] were labeled with fluorine-18 (conjugation with [(18)F]FPyBrA), and comparative dynamic and quantitative imaging was performed with positron emission tomography. After intravenous injections of [(18)F]siRNAs in rodents, total radioactivity was rapidly eliminated by the kidneys and the liver. Tissue distribution of the different siRNAs were similar, and their bioavailability (as judged from blood persistence and stability) increased in the order 2'OH(AS/S) = 2'OH(AS)/2'OMe(S) < 2'F(AS/S). However, in our in vivo model, the 2'F(AS/S) siRNA, despite its higher bioavailability, was not able to induce a higher interference effect with respect to the 2'OH(AS/S) siRNA. Molecular imaging approaches, applied in the present work to both natural and chemically modified siRNAs, can contribute to the development of these macromolecules as therapeutic agents.
authors: Laboratoire d'imagerie de l'Expression des gènes, CEA, DSV, I2BM, SHFJ, LIME, INSERM, Orsay, France.
authors: Thomas
authors: T
authors: Viel
authors: Raphael
authors: R
authors: Boisgard
authors: Bertrand
authors: B
authors: Kuhnast
authors: Benoit
authors: B
authors: Jego
authors: Karine
authors: K
authors: Siquier-Pernet
authors: Françoise
authors: F
authors: Hinnen
authors: Frédéric
authors: F
authors: Dollé
authors: Bertrand
authors: B
authors: Tavitian
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D051381:Rats; D014162:Transfection; D051598:Whole Body Imaging / Q000379:methods*
chemical_list: D005462:Fluorine Radioisotopes; D034741:RNA, Small Interfering