Dr. Hui and his group propose to develop transdermal delivery methods based on recent advances in electroporation and liposome technologies. Their long range goal is to develop convenient, safe, and effective methodologies that can be applied to introduce drugs and genes across the skin barrier, for the purpose of gene therapy, controlled drug release, and topical treatment of local ailments including skin carcinoma. The stratum corneum (SC), the top layer of skin, is the major barrier of transdermal transport, and contributes to most of the electrical resistance of the skin. Electroporation of the SC enhances the transdermal transport by several orders of magnitude. It is proposed to use prior knowledge and experience of Dr. Hui's group in cell electroporation to broaden understanding of the skin electroporation mechanism, and to use this as a basis to devise efficient electroporation protcols for transdermal delivery. It is proposed to study the changes in ultrastructure, electrical impedance, and molecular transport through the skin by electric pulses, using surface electrodes on the whole skin. Liposomes have been found to preferentially partition into hair follicles, which offer another route of transdermal transport. It is proposed to investigate the mechanism of liposome-mediated transdermal transport, in order to utilize liposomes to enhance transdermal delivery, alone or in association with electroporation. In particular, charged liposomes will be utilized as carriers of DNA or uncharged molecules, for the purpose of drug and gene transfer. In feasibility studies, it is proposed to apply electroporation and/or liposome methods to deliver photodynamic therapy (PDT) drugs through excised porcine skin, live murine skin, and biopsied human skin with multiple basal cell carcinomas or squamous cell carcinomas, to enhance localized drug delivery for PDT. As a model for gene delivery, it is proposed to apply these methods to deliver plasmids coding for tyrosinase to transfect mutant melanocytes in mice, to establish an assay for platelet storage pool deficiency gene products.
