Transdermal delivery of interferon-γ (IFN-γ) mediated by penetratin, a cell-permeable peptide

IFN-γ (interferon-γ) has several applications in the treatment of IFN-γ-related skin disorders. While systemic delivery - the major route used to administer IFN-γ - results in significant side effects and toxicity, including fever, fatigue, nausea, vomiting and neurotoxicity, transdermal delivery has a very low transduction efficiency. In order to improve the efficiency of transdermal IFN-γ delivery, we introduced a Pen (penetratin) peptide, a 16-amino-acid-long polypeptide corresponding to the third helix of the DNA-binding domain (homoeodomain) of Antennapedia (a Drosophila transcription factor). The human IFN-γ gene was then fused with a gene fragment that encodes the Pen of Antennapedia in a bacterial expression vector, producing a genetic in-frame Pen-IFN-γ. The expressed and purified Pen-IFN-γ was then found to have a much more efficient transduction profile than native IFN-γ. In addition, compared with native IFN-γ, Pen-IFN-γ exhibited similar activities when added exogenously to a culture medium: (i) induction of IRF-1 gene expression, and (ii) NF-κB (nuclear factor κB) luciferase reporter activation. These results indicate that the transdermal delivery system using Pen may be an excellent way to replenish IFN-γ in the various disorders related to this cytokine.