title: In vivo siRNA distribution and pharmacokinetics assessed by nuclear imaging are modulated according to radiolabelling site.
abstract: BACKGROUND
  RNA interference is efficient in in vitro studies, and appears as a therapeutic tool of major clinical interest. Nevertheless, the clinical utilisation of siRNAs is restrained by the poor availability of biodistribution data on this new class of pharmaceutics. This study aimed at defining the biodistribution and pharmacokinetics properties of an siRNA directed to the Casein Kinase-2 beta (CK2β) subunit, a potential target in cancer therapy.
  
  
  METHODS
  Four CK2β siRNAs were chemically modified on each extremity of sense or anti-sense strand and radioiodinated. The biodistribution of each entity was analysed in glioblastoma-bearing mice using nuclear imaging and compared to a control GFP siRNA.
  
  
  RESULTS
  The labelling process was associated with preservation of interference activity, except when applied to the 5' antisense terminus. Radioactivity was predominantly observed in organs of the excretory system after intravenous administration: liver, kidneys and bladder. Tumor/Contralateral muscle ratio showed significant differences depending on the labelling site. Activity associated with CK2β5's was quite constant over 2 hours, while CK2β3'as activity decreased by 40% in tumor. Finally, synchrotron X-ray analysis showed that CK2β3's is more abundant in tumor than in liver, brain or muscle, and uniformly distributed between intra- and extracellular compartments.
  
  
  CONCLUSIONS
  In this study, we highlighted the large influence of siRNAs radiolabelling position on their biodistribution and pharmacokinetic profiles, and proposed a systematic approach for the imaging of all siRNAs of clinical interest.
authors.affiliation: Laboratoire des Radiopharmaceutiques Biocliniques, INSERM UMR S1039, Faculté de médecine, F38700, La Tronche, France; Grenoble University, F38041, Saint-Martin-d'Hères, France. Electronic address: dom.garin@gmail.com.
authors.forename: Dominique
authors.initials: D
authors.lastname: Garin
authors.affiliation: Laboratoire des Radiopharmaceutiques Biocliniques, INSERM UMR S1039, Faculté de médecine, F38700, La Tronche, France; Grenoble University, F38041, Saint-Martin-d'Hères, France.
authors.forename: Mitra
authors.initials: M
authors.lastname: Ahmadi
authors.affiliation: Laboratoire des Radiopharmaceutiques Biocliniques, INSERM UMR S1039, Faculté de médecine, F38700, La Tronche, France; CHU de Grenoble, CS 10217, F38043 Grenoble, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Gauchez
authors.affiliation: INSERM U836, Team 6 - Synchrotron Radiation and Medical Research, Rue Fortuné Ferrini, F38706, La Tronche; European Synchrotron Radiation Facility, F38043, Grenoble Cedex 9, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Bohic
authors.affiliation: Grenoble University, F38041, Saint-Martin-d'Hères, France; INSERM U836, Team 7 - Nanomedicine and brain, Rue Fortuné Ferrini, F38706 La Tronche.
authors.forename: Sandra
authors.initials: S
authors.lastname: Boccard
authors.affiliation: European Synchrotron Radiation Facility, F38043, Grenoble Cedex 9, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Cloetens
authors.affiliation: Laboratoire des Radiopharmaceutiques Biocliniques, INSERM UMR S1039, Faculté de médecine, F38700, La Tronche, France; CHU de Grenoble, CS 10217, F38043 Grenoble, France; Grenoble University, F38041, Saint-Martin-d'Hères, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fagret
authors.affiliation: CHU de Grenoble, CS 10217, F38043 Grenoble, France; Grenoble University, F38041, Saint-Martin-d'Hères, France; INSERM U836, Team 7 - Nanomedicine and brain, Rue Fortuné Ferrini, F38706 La Tronche.
authors.forename: François
authors.initials: F
authors.lastname: Berger
authors.affiliation: Laboratoire des Radiopharmaceutiques Biocliniques, INSERM UMR S1039, Faculté de médecine, F38700, La Tronche, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Briat
authors.affiliation: Laboratoire des Radiopharmaceutiques Biocliniques, INSERM UMR S1039, Faculté de médecine, F38700, La Tronche, France; Grenoble University, F38041, Saint-Martin-d'Hères, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ghezzi
authors.affiliation: CHU de Grenoble, CS 10217, F38043 Grenoble, France; Grenoble University, F38041, Saint-Martin-d'Hères, France; INSERM U836, Team 7 - Nanomedicine and brain, Rue Fortuné Ferrini, F38706 La Tronche.
authors.forename: Laurent
authors.initials: L
authors.lastname: Pelletier
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000235:genetics; D049109:Cell Proliferation; D003952:Diagnostic Imaging; D005260:Female; D005910:Glioma / Q000000981:diagnostic imaging* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000235:genetics* / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D017356:Synchrotrons; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; D047390:Casein Kinase II
keywords: Biodistribution; Cancer; Nuclear imaging; Radioiodination; siRNA