PMID- 24566256
OWN - NLM
STAT- MEDLINE
DCOM- 20141223
LR  - 20140331
IS  - 1873-4995 (Electronic)
IS  - 0168-3659 (Linking)
VI  - 180
DP  - 2014 Apr 28
TI  - Quantitative evaluation of the improvement in the pharmacokinetics of a nucleic 
      acid drug delivery system by dynamic PET imaging with (18)F-incorporated 
      oligodeoxynucleotides.
PG  - 92-9
LID - S0168-3659(14)00102-3 [pii]
LID - 10.1016/j.jconrel.2014.02.014 [doi]
AB  - Recently, we demonstrated the utility of positron emission tomography (PET) 
      imaging-based pharmacokinetic evaluation studies for preclinical experiments and 
      microdose clinical trials, mainly focused on low molecular weight compounds. In 
      order to investigate the pharmacokinetics of nucleic acid drugs and their drug 
      delivery systems (DDSs) in vivo by using PET imaging, we developed a novel and 
      efficient method for radiolabeling oligodeoxynucleotides with the 
      positron-emitting radionuclide (18)F (stoichiometry-focused Huisgen-type (18)F 
      labeling). By using this method, we succeeded in synthesizing a variety of 
      (18)F-labeled oligodeoxynucleotides with not only phosphodiesters (PO) in natural 
      forms, but also phosphorothioate (PS) and bridged nucleic acid (BNA) in 
      artificial forms, and then performed PET studies and radioactive metabolite 
      analyses of these (18)F-labeled oligodeoxynucleotides. The tissue-distribution 
      and dynamic changes in radioactivity showed significantly different profiles 
      between these antisense oligodeoxynucleotides. The radioactivity of (18)F-labeled 
      PO-DNA and PO-BNA rapidly accumulated in the kidneys and liver and then moved to 
      the renal medulla, ureter, bladder, and intestine. However, the radioactivity of 
      (18)F-labeled PS-DNA and PS-BNA, possessing PS backbone structures, was retained 
      in the blood for relatively long periods and then gradually accumulated in the 
      liver and kidneys. The metabolite analysis showed that (18)F-labeled PO-DNA 
      rapidly degraded by 5min and (18)F-labeled PO-BNA gradually degraded over time by 
      60min. Conversely, (18)F-labeled PS-DNA and PS-BNA were shown to be much more 
      stable. To demonstrate the usefulness of the PET imaging technique for evaluating 
      the improved targeting potential of the DDS, we designed and synthesized a 
      cholesterol-modified oligodeoxynucleotide, that we developed as an antisense 
      nucleic acid drug against proprotein convertase subtilisin/kexin type 9 (PCSK9) 
      for hypercholesterolemia therapy, and evaluated its pharmacokinetics using PET 
      imaging. As expected, the (18)F-labeled cholesterol-modified PS-BNA-type 
      oligodeoxynucleotide showed much higher and more rapid accumulation in the 
      delivery target organ, that is, the liver, which encourages us to develop this 
      drug. These results suggest that dynamic PET studies using (18)F-incorporated 
      oligodeoxynucleotide synthesized by stoichiometry-focused Huisgen-type labeling 
      is useful for quantitative pharmacokinetic evaluation of nucleic acid drugs and 
      their delivery systems.
CI  - Copyright (c) 2014 Elsevier B.V. All rights reserved.
FAU - Mukai, Hidefumi
AU  - Mukai H
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan.
FAU - Ozaki, Daiki
AU  - Ozaki D
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan.
FAU - Cui, Yilong
AU  - Cui Y
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan.
FAU - Kuboyama, Takeshi
AU  - Kuboyama T
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan; Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 
      Yamadaoka, Suita, Osaka 565-0871, Japan.
FAU - Yamato-Nagata, Hiroko
AU  - Yamato-Nagata H
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan; Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 
      Yamadaoka, Suita, Osaka 565-0871, Japan.
FAU - Onoe, Kayo
AU  - Onoe K
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan.
FAU - Takahashi, Maiko
AU  - Takahashi M
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan.
FAU - Wada, Yasuhiro
AU  - Wada Y
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan.
FAU - Imanishi, Takeshi
AU  - Imanishi T
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, 
      Suita, Osaka 565-0871, Japan.
FAU - Kodama, Tetsuya
AU  - Kodama T
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, 
      Suita, Osaka 565-0871, Japan.
FAU - Obika, Satoshi
AU  - Obika S
AD  - Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, 
      Suita, Osaka 565-0871, Japan. Electronic address: obika@phs.osaka-u.ac.jp.
FAU - Suzuki, Masaaki
AU  - Suzuki M
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan.
FAU - Doi, Hisashi
AU  - Doi H
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan.
FAU - Watanabe, Yasuyoshi
AU  - Watanabe Y
AD  - Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science 
      Technologies (CLST), 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047, 
      Japan. Electronic address: yywata@riken.jp.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20140222
PL  - Netherlands
TA  - J Control Release
JT  - Journal of controlled release : official journal of the Controlled Release 
      Society
JID - 8607908
RN  - 0 (Drug Carriers)
RN  - 0 (Fluorine Radioisotopes)
RN  - 0 (Nucleic Acids)
RN  - 0 (Oligodeoxyribonucleotides, Antisense)
RN  - 0 (Organothiophosphorus Compounds)
RN  - 97C5T2UQ7J (Cholesterol)
SB  - IM
MH  - Animals
MH  - Cholesterol/analogs & derivatives
MH  - Drug Carriers/*chemistry
MH  - Fluorine Radioisotopes/administration & dosage/chemistry/*pharmacokinetics
MH  - Nucleic Acids/administration & dosage/chemistry/*pharmacokinetics
MH  - Oligodeoxyribonucleotides, Antisense/administration & 
      dosage/chemistry/*pharmacokinetics
MH  - Organothiophosphorus Compounds/chemistry
MH  - Positron-Emission Tomography/*methods
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Tissue Distribution
OTO - NOTNLM
OT  - (18)F-labeling
OT  - Oligodeoxynucleotides
OT  - Pharmacokinetics
OT  - Positron emission tomography imaging
EDAT- 2014/02/26 06:00
MHDA- 2014/12/24 06:00
CRDT- 2014/02/26 06:00
PHST- 2013/07/14 00:00 [received]
PHST- 2013/12/27 00:00 [revised]
PHST- 2014/02/16 00:00 [accepted]
PHST- 2014/02/26 06:00 [entrez]
PHST- 2014/02/26 06:00 [pubmed]
PHST- 2014/12/24 06:00 [medline]
AID - S0168-3659(14)00102-3 [pii]
AID - 10.1016/j.jconrel.2014.02.014 [doi]
PST - ppublish
SO  - J Control Release. 2014 Apr 28;180:92-9. doi: 10.1016/j.jconrel.2014.02.014. Epub 
      2014 Feb 22.