Weiqi Lin

Transdermal Delivery of Antisense Oligonucleotides with Microprojection Patch (macroflux®) Technology

In recent years, antisense oligodeoxynucleotide (ODN) technology has emerged as one of the most promising functional genomic therapies. Several clinical trials have demonstrated its therapeutic value and low toxicity (1). To date, parenteral infusion has been the primary mode of ODN delivery. However, efforts to develop more convenient routes of administration are being explored. Transdermal iontophoresis increased ODNs across the skin; however, delivery of a therapeutically relevant dose was not achieved (2–5). The major barrier for transdermal delivery is the stratum corneum, the outermost “dead” layer of the skin. In human skin, the stratum corneum is 10–20 m thick, whereas in mice and rats it is significantly thinner. Removal of the stratum corneum by mechanical abrasion, tape stripping, or chemical treatment has been shown to significantly enhance permeation through the skin for a wide range of pharmaceuticals, including phosphorothioated (PS) ODNs (5–8). However, these approaches may be limited due to the lack of control and reproducibility, as well as the irritancy potential (9). Microprojection patch is a novel microfabrication technology for controlled transdermal drug delivery. The patch system incorporates a stainless steel or titanium microprojection array. When applied onto the skin manually or by an applicator, microprojections penetrate and create superficial pathways through the skin barrier layer to allow drug delivery. The array can be combined either with passive or iontophoretic delivery systems. In this study, we demonstrate that microprojection patch technology can facilitate the controlled transdermal ODN delivery. MATERIALS AND METHODS

Transdermal Delivery of Antisense Oligonucleotides

In recent years, antisense oligodeoxynucleotides (ODNs) have emerged as promising biopharmaceutical therapeutics. These agents specifically target genes or gene transcripts involved in pathogenesis. Several clinical trials have demonstrated the therapeutic value and low toxicity of ODNs (1–5). Because ODNs, like most biopharmaceuticals, are highly susceptible to degradation in the gastrointestinal environment and only poorly absorbed through biomembranes, they have been delivered primarily by parenteral infusion. This route of administration, however, is invasive and inconvenient, and repeated injections or lengthy infusions can be painful and disruptive to normal life. Therefore, transdermal delivery is being explored as a more patient-friendly alternative (6).