Transdermal drug delivery by iontophoresis

Kogure Kentaro, Fukuta Tatsuya

doi:10.2745/dds.36.198

Functional macromolecules, such as siRNA, are expected as the ideal drugs to induce immune response and suppress specific genes for therapy of skin disorders and cancer. However, delivery of the macromolecules into skin is difficult due to large molecular weight and high hydrophilicity. Since iontophoresis is known to accelerate transdermal permeation of charged molecules by applying a weak electric current to the skin, we paid attention to iontophoresis as an ideal technology for transdermal delivery, and attempted transdermal delivery of macromolecules. siRNA is expected as novel nucleic acid medicines. Thus, we examined iontophoresis of naked siRNA on rat skin in vivo. Naked siRNA was effectively accumulated in the skin after iontophoresis. In addition, iontophoretic delivery of siRNA significantly reduced the target mRNA. From this result, it was suggested that siRNA was delivered into not only the skin tissue, but also cytoplasm of target cells. Then, we analyzed the in vitro intracellular delivery of fluorescent-labeled siRNA by weak electric current（WEC）, and found that cellular uptake of fluorescent-labeled siRNA was increased by WEC, while endocytosis inhibitors significantly prevented siRNA uptake. These results indicate that the cellular uptake mechanism by WEC is endocytosis. Moreover, we compared the intracellular trafficking of macromolecule FITC-dextran, which has different molecular weight, 10,000 and 70,000, taken up by weak electric current. The 10,000 dextran spread to cytoplasm, but 70,000 dextran remained in endosome/lysosomes. This result suggested that WEC treatment induced very unique endosome that leaked macromolecules with a molecular weight of less than 70,000. Transmission electron microscopy of cells treated by WEC showed that the WEC-induced endosomes exhibited an elliptical shape. In the WEC-induced endosomes, ceramide, which makes pore structures in the membrane, was localized. Interestingly, we found that WEC accelerates the production of exosomes as a result of stimulation of the endocytosis. In this review, we also introduce recent findings regarding IP-mediated transdermal drug delivery of bio-macromolecules such as antibody and WEC-mediated increases in vascular permeability.

Transdermal drug delivery by iontophoresis

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