RNA Aptamer Delivery through Intact Human Skin

Jon D Lenn, Jessica Neil, Christine Donahue, Kellie Demock, Caitlin Vestal Tibbetts, Javier Cote-Sierra, Susan H Smith, David Rubenstein, Jean-Philippe Therrien, P Shannon Pendergrast, Jason Killough, Marc B Brown, Adrian C Williams

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
42 Downloads (Pure)

Abstract

It is generally recognized that only relatively small molecular weight (typically < ∼ 500 Da) drugs can effectively permeate through intact stratum corneum. Here, we challenge this orthodoxy using a 62-nucleotide (molecular weight = 20,395 Da) RNA-based aptamer, highly specific to the human IL-23 cytokine, with picomolar activity. Results demonstrate penetration of the aptamer into freshly excised human skin using two different fluorescent labels. A dual hybridization assay quantified aptamer from the epidermis and dermis, giving levels far exceeding the cellular half maximal inhibitory concentration values (>100,000-fold), and aptamer integrity was confirmed using an oligonucleotide precipitation assay. A T helper 17 response was stimulated in freshly excised human skin resulting in significantly upregulated IL-17f, and IL-22; topical application of the IL-23 aptamer decreased both IL-17f and IL-22 by approximately 45% but did not result in significant changes to IL-23 mRNA levels, confirming that the aptamer did not globally suppress mRNA levels. This study demonstrates that very-large-molecular-weight RNA aptamers can permeate across the intact human skin barrier to therapeutically relevant levels into both the epidermis and dermis and that the skin-penetrating aptamer retains its biologically active conformational structure capable of binding to endogenous IL-23.
Original languageEnglish
Pages (from-to)282-290
Number of pages9
JournalJournal of Investigative Dermatology
Volume138
Issue number2
Early online date12 Dec 2017
DOIs
Publication statusPublished - 1 Feb 2018

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