Cell-penetrating-peptide-mediated siRNA lung delivery.
The therapeutic application of siRNA (short interfering RNA) shows promise as an alternative approach to small-molecule inhibitors for the treatment of human disease. However, the major obstacle to its use has been the difficulty in delivering these large anionic molecules in vivo. A potential approach to solving this problem is the chemical conjugation of siRNA to the cationic CPPs (cell-penetrating peptides), Tat-(48-60) (transactivator of transcription) and penetratin, which have been shown previously to mediate protein and peptide delivery in a host of animal models. In this transaction, we review recent studies on the utility of siRNA for the investigation of protein function in the airways/lung. We show that, despite previous studies showing the utility of cationic CPPs in vitro, conjugation of siRNA to Tat-(48-60) and penetratin failed to increase residual siRNA-mediated knockdown of p38 MAPK (mitogen-activated protein kinase) (MAPK14) mRNA in mouse lung in vivo. Significantly, we will also discuss potential non-specific actions and the induction of immunological responses by CPPs and their conjugates and how this might limit their application for siRNA-mediated delivery in vivo.
Moschos
S A
SA
Biopharmaceutics Research Group, Airways Disease, National Heart and Lung Institute, Imperial College London, London SW3 6LY, UK.
Williams
A E
AE
Lindsay
M A
MA
D000818:Animals; D016503:Drug Delivery Systems; D006801:Humans; D008168:Lung / Q000378:metabolism*; D010455:Peptides; D021382:Protein Sorting Signals / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology*; D034741:RNA, Small Interfering / Q000008:administration & dosage*
D010455:Peptides; D021382:Protein Sorting Signals; D034741:RNA, Small Interfering