Peptide nucleic acids conjugated to short basic peptides show improved pharmacokinetics and antisense activity in adipose tissue.
A peptide nucleic acid (PNA) targeting a splice junction of the murine PTEN primary transcript was covalently conjugated to various basic peptides. When systemically administered to healthy mice, the conjugates displayed sequence-specific alteration of PTEN mRNA splicing as well as inhibition of full length PTEN protein expression. Correlating activity with drug concentration in various tissues indicated strong tissue-dependence, with highest levels of activity observed in adipose tissue. While the presence of a peptide carrier was found to be crucial for efficient delivery to tissue, little difference was observed between the various peptides evaluated. A second PNA-conjugate targeting the murine insulin receptor primary transcript showed a similar activity profile, suggesting that short basic peptides can generally be used to effectively deliver peptide nucleic acids to adipose tissue.
Wancewicz
Edward V
EV
Isis Pharmaceuticals, Inc., Carlsbad, California 92008, USA.
Maier
Martin A
MA
Siwkowski
Andrew M
AM
Albertshofer
Klaus
K
Winger
Theodore M
TM
Berdeja
Andres
A
Gaus
Hans
H
Vickers
Timothy A
TA
Bennett
C Frank
CF
Monia
Brett P
BP
Griffey
Richard H
RH
Nulf
Christopher J
CJ
Hu
Jiaxin
J
Corey
David R
DR
Swayze
Eric E
EE
Kinberger
Garth A
GA
D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004337:Drug Carriers; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000737:chemistry*; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis* / Q000235:genetics; D020135:Peptide Nucleic Acids / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D022821:RNA Splice Sites; D012326:RNA Splicing; D016372:RNA, Antisense / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011972:Receptor, Insulin / Q000096:biosynthesis* / Q000235:genetics; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D004337:Drug Carriers; D009842:Oligopeptides; D020135:Peptide Nucleic Acids; D022821:RNA Splice Sites; D016372:RNA, Antisense; D012333:RNA, Messenger; D011972:Receptor, Insulin; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse