Hydrodynamic gene delivery in human skin using a hollow microneedle device

M. Dul (1) , M. Stefanidou (1) , P. Porta (1) , J. Serve (1) , C. O'Mahony (2) , Bernard Malissen (3) , S. Henri (3) , Y. Levin , E. Kochba (3) , F. S. Wong (1) , C. Dayan (1) , S. A. Coulman (1) , J. C. Birchall

1 Cardiff University
2 Tyndall National Institute, Cork
3 CIML - Centre d'Immunologie de Marseille - Luminy

Microneedle devices have been proposed as aminimally invasive delivery system for the intradermal administration of nucleic acids, both plasmid DNA (pDNA) and siRNA, to treat localised disease or provide vaccination. Different microneedle types and application methods have been investigated in the laboratory, but limited and irreproducible levels of gene expression have proven to be significant challenges to pre-clinical to clinical progression. This study is the first to explore the potential of a hollow microneedle device for the delivery and subsequent expression of pDNA in human skin. The regulatory approved MicronJet600 (R) (MicronJet hereafter) device was used to deliver reporter plasmids (pCMV beta and pEGFP-N1) into viable excised human skin. Exogenous gene expression was subsequently detected at multiple locations that were distant from the injection site but within the confines of the bleb created by the intradermal bolus. The observed levels of gene expression in the tissue are at least comparable to that achieved by the most invasive microneedle application methods e.g. lateral application of a microneedle. Gene expression was predominantly located in the epidermis, although also evident in the papillary dermis. Optical coherence tomography permitted real time visualisation of the sub-surface skin architecture and, unlike a conventional intradermal injection, MicronJet administration of a 50 mu L bolus appears to create multiple superficial microdisruptions in the papillary dermis and epidermis. These were co-localised with expression of the pCMV beta reporter plasmid. We have therefore shown, for the first time, that a hollow microneedle device can facilitate efficient and reproducible gene expression of exogenous naked pDNA in human skin using volumes that are considered to be standard for intradermal administration, and postulate a hydrodynamic effect as the mechanism of gene delivery. (C) 2017 Elsevier B.V. All rights reserved.

Mots clés: Microneedles; Human skin; DNA; Genetic vaccine; Gene therapy; Hydrodynamic

Domaines: Immunologie

M. Dul, M. Stefanidou, P. Porta, J. Serve, C. O'Mahony, et al.. Hydrodynamic gene delivery in human skin using a hollow microneedle device. Journal of Controlled Release, 2017, 265 (SI), pp.120-131. ⟨10.1016/j.jconrel.2017.02.028⟩. ⟨hal-01764681⟩