RNA Aptamer Delivery through Intact Human Skin
| Autor: | Jessica Neil, Caitlin Vestal Tibbetts, Kellie Marie Demock, Susan H. Smith, Christine Patricia Donahue, Jon D. Lenn, Javier Cote-Sierra, P. Shannon Pendergrast, Jason R. Killough, Adrian C. Williams, Marc B. Brown, Jean-Philippe Therrien, David Rubenstein |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Aptamer Skin Absorption Endogeny Human skin Dermatology Biology Administration Cutaneous Biochemistry Interleukin-23 03 medical and health sciences Dermis medicine Humans Molecular Biology Epidermis (botany) Oligonucleotide Interleukins Interleukin-17 RNA Biological activity Cell Biology Aptamers Nucleotide Molecular biology Up-Regulation 030104 developmental biology medicine.anatomical_structure Epidermal Cells Epidermis |
| Zdroj: | The Journal of investigative dermatology. 138(2) |
| ISSN: | 1523-1747 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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