title: [In vivo imaging of liposomal small interfering RNA (siRNA) trafficking by positron emission tomography].
abstract: In the development of nucleic acid medicines such as small interfering RNA (siRNA) drugs, one problem is how to study the pharmacokinetics and pharmacodynamics, since the precise in vivo behavior of siRNA is hard to detect. In this research, to establish a highly sensitive detection system of siRNA biodistribution in the whole body, the technology of positron imaging was applied. First, a one-step synthetic method in which double-stranded siRNA was directly labeled by a positron emitter, (18)F, was developed. By using [(18)F]-labeled siRNA ([(18)F]-siRNA), the complex of siRNA and polycation liposomes (PCL) containing dicetylphosphate tetraethylenepentamine (TEPA-PCL) was prepared. Then, the biodistribution of the siRNA after intravenous administration to mice was analyzed by planar positron imaging system (PPIS). As a result, whereas naked [(18)F]-siRNA was immediately excreted in mouse bladder after administration, the complex with cationic liposome (CL) was trapped in the lungs. Furthermore, [(18)F]-siRNA carried with PEGylated CL (PL) was distributed throughout the body, suggesting that it circulated in the bloodstream for an extended period of time. Additionally, PET imaging revealed more detailed biodistribution of the siRNA than in vivo imaging system (IVIS) because PET imaging is not affected by the depth variation of target tissues. On the other hand, to induce high accumulation of siRNAs against c-myc, MDM2, and VEGF in tumor tissue, a tumor-targeting probe, RGD peptide, was grafted at the top of PEG chain in PEGylated TEPA-PCL and the effect of the complex on experimental lung metastasis of B16 melanoma was examined. The complex suppressed the progression of tumor. We believe that the positron imaging data would support the development of siRNA agent for clinical use.
authors.affiliation: Department of Medical Biochemistry, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ando
authors.forename: Norihito
authors.initials: N
authors.lastname: Yonenaga
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Asai
authors.forename: Kentaro
authors.initials: K
authors.lastname: Hatanaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koide
authors.forename: Takuma
authors.initials: T
authors.lastname: Tsuzuku
authors.forename: Norihiro
authors.initials: N
authors.lastname: Harada
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukada
authors.forename: Naoto
authors.initials: N
authors.lastname: Oku
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D055808:Drug Discovery / Q000379:methods*; D005029:Ethylenediamines; D005462:Fluorine Radioisotopes; D006801:Humans; D008081:Liposomes / Q000493:pharmacokinetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D057054:Molecular Imaging / Q000379:methods*; D011092:Polyethylene Glycols; D049268:Positron-Emission Tomography / Q000379:methods*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals; D014018:Tissue Distribution
chemical_list: D005029:Ethylenediamines; D005462:Fluorine Radioisotopes; D008081:Liposomes; D034741:RNA, Small Interfering; D019275:Radiopharmaceuticals; D011092:Polyethylene Glycols; C034269:tetraethylenepentamine