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Gene silencing following siRNA delivery to skin via coated steel microneedles: In vitro and in vivo proof-of-concept

Chong, Rosalind, Gonzalez-Gonzalez, E., Lara, Maria F., Speaker, Tycho J., Contag, Christopher H., Kaspar, Roger L., Coulman, Sion, Hargest, Rachel and Birchall, James Caradoc 2013. Gene silencing following siRNA delivery to skin via coated steel microneedles: In vitro and in vivo proof-of-concept. Journal of Controlled Release 166 (3) , pp. 211-219. 10.1016/j.jconrel.2012.12.030

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Abstract

The development of siRNA-based gene silencing therapies has significant potential for effectively treating debilitating genetic, hyper-proliferative or malignant skin conditions caused by aberrant gene expression. To be efficacious and widely accepted by physicians and patients, therapeutic siRNAs must access the viable skin layers in a stable and functional form, preferably without painful administration. In this study we explore the use of minimally-invasive steel microneedle devices to effectively deliver siRNA into skin. A simple, yet precise microneedle coating method permitted reproducible loading of siRNA onto individual microneedles. Following recovery from the microneedle surface, lamin A/C siRNA retained full activity, as demonstrated by significant reduction in lamin A/C mRNA levels and reduced lamin A/C protein in HaCaT keratinocyte cells. However, lamin A/C siRNA pre-complexed with a commercial lipid-based transfection reagent (siRNA lipoplex) was less functional following microneedle coating. As Accell-modified 'self-delivery' siRNA targeted against CD44 also retained functionality after microneedle coating, this form of siRNA was used in subsequent in vivo studies, where gene silencing was determined in a transgenic reporter mouse skin model. Self-delivery siRNA targeting the reporter (luciferase/GFP) gene was coated onto microneedles and delivered to mouse footpad. Quantification of reporter mRNA and intravital imaging of reporter expression in the outer skin layers confirmed functional in vivo gene silencing following microneedle delivery of siRNA. The use of coated metal microneedles represents a new, simple, minimally-invasive, patient-friendly and potentially self-administrable method for the delivery of therapeutic nucleic acids to the skin.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Medicine
Subjects: Q Science > QH Natural history > QH426 Genetics
Q Science > QR Microbiology > QR180 Immunology
R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords: Microneedles; Coating; Lipoplex; Self-delivery siRNA; Keratinocytes; RNA interference
Publisher: Elsevier
ISSN: 0168-3659
Date of Acceptance: 30 December 2012
Last Modified: 13 May 2019 19:55
URI: http://orca.cf.ac.uk/id/eprint/46920

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