| The delivery of macromolecules has proved challenging in the fields of transdermal and intracellular delivery. In particular, the delivery of short interfering RNA (siRNA) remains a major hurdle. Since the discovery of siRNA in the late 1990s, the potential of siRNA to treat many skin diseases including atopic dermatitis, priorasis, and skin cancer has been acknowledged. The use of siRNA as a therapeutic agent however has been limited due to the obstacle of delivering siRNA into skin. In order for a therapeutic effect to be realized, the intact siRNA must be delivered across the skin barrier and the cellular membrane barrier into the cell cytoplasm. While great efforts have been made to deliver siRNA through skin, the few examples of successful siRNA delivery into skin have used invasive methods which are not feasible for the treatment of large skin surface areas and result in patient noncompliance. There is a great need for a delivery method which is effective and patient friendly to realize the potential of siRNA as a therapeutic for skin diseases. The use of peptides has the potential to overcome the obstacles present in siRNA delivery into skin.;In this dissertation, we present the identification of a novel peptide, SPACE (Skin Penetrating And Cell Entering) peptide, through the use of in vitro phage display. Through our studies, SPACE was shown to have the ability to penetrate mouse, porcine, and human skin and was observed to penetrate into all major human cell types. The ability to penetrate both the skin barrier and the cellular membrane barriers made SPACE a good candidate for aiding the delivery of siRNA through skin. In vivo studies in mice verified the ability of SPACE to aid in the topical delivery of siRNA through skin and result in significant knockdown of a protein of interest. These results demonstrate the possibility of effective topical siRNA delivery with SPACE for the treatment of various skin diseases in a patient friendly manner. |
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