Phosphorothioate-stimulated uptake of short interfering RNA by human cells.
The cellular delivery of short interfering RNA (siRNA) is a main hurdle in therapeutic drug development. Here, we describe that phosphorothioate (PTO)-derived oligonucleotides stimulate the physical cellular uptake of siRNA in trans in human cells. This is reflected by an apparent dose-dependent siRNA-mediated suppression of lamin A/C in primary human umbilical vein endothelial cells. The PTO-stimulated cellular uptake in trans is concentration dependent, length dependent, related to the phosphorothioate chemistry but not sequence specific. We provide experimental evidence to support a caveolin-mediated uptake mechanism. In sum, this work strongly suggests the exploration of PTOs as facilitators in the delivery of biologically active siRNA to mammalian cells.
Overhoff
Marita
M
Institut für Molekulare Medizin, Universität zu Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Sczakiel
Georg
G
D022461:Caveolins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D019319:Okadaic Acid / Q000494:pharmacology; D020319:Oligodeoxyribonucleotides, Antisense / Q000737:chemistry* / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology
D022461:Caveolins; D004791:Enzyme Inhibitors; D007797:Laminin; D020319:Oligodeoxyribonucleotides, Antisense; D034741:RNA, Small Interfering; C084098:laminin A; D019319:Okadaic Acid