title: CXCL1 gene silencing in skin using liposome-encapsulated siRNA delivered by microprojection array.
abstract: The barrier morphology of skin provides major obstacles for the application of siRNA for gene silencing, which current delivery technologies do not effectively overcome. Emerging technologies utilise microprojection array devices to penetrate into the skin epidermis and dermis for delivery of drug payloads. Delivery of siRNA by such devices has been proven in principle, yet requires optimisation for clinical applications. Herein, we demonstrate the use of Nanopatch™ microprojection arrays to deliver liposome-encapsulated siRNA to overcome skin barrier, and in vivo siRNA delivery hurdles. This application provided effective silencing of CXCL1 expression induced by the co-delivery of Fluvax 2012® by microprojection array. Liposomes encapsulating siRNA were dry-coated onto microprojection arrays, and remained intact after elution from arrays in vitro. Microprojection arrays facilitated the delivery of fluorescently-labelled nucleic acids through murine ear stratum corneum to the epidermis and dermis, with diffusion from microprojections into adjacent skin evident within 30s. CXCL1 mRNA, induced by delivery of Fluvax by microprojection array, was reduced by 75% up to 20 h post-treatment by co-delivery of liposome-encapsulated CXCL1-specific siRNA, but not by arrays co-delivering liposome-encapsulated control siRNA. CXCL1 protein expression in explant cultures from skin treated with arrays bearing CXCL1 specific or control siRNA was similarly reduced. These results as a test case have many implications for gene silencing in skin and inflammation, with the benefit of targeted delivery using microprojection arrays to deliver liposome-encapsulated siRNA.
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St. Lucia, QLD 4072, Australia; University of Queensland Diamantina Institute, Woolloongabba, QLD 4102, Australia.
authors.forename: Oscar
authors.initials: O
authors.lastname: Haigh
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Alexandra C I
authors.initials: AC
authors.lastname: Depelsenaire
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Stefano C
authors.initials: SC
authors.lastname: Meliga
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Sally R
authors.initials: SR
authors.lastname: Yukiko
authors.affiliation: Cancer Research Centre, Griffith Health Institute, Griffith University, Southport, QLD 4222, Australia.
authors.forename: Nigel A J
authors.initials: NA
authors.lastname: McMillan
authors.affiliation: University of Queensland Diamantina Institute, Woolloongabba, QLD 4102, Australia.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Frazer
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, St. Lucia, QLD 4072, Australia; University of Queensland Diamantina Institute, Woolloongabba, QLD 4102, Australia. Electronic address: m.kendall@uq.edu.au.
authors.forename: Mark A F
authors.initials: MA
authors.lastname: Kendall
mesh_terms: D000199:Actins / Q000008:administration & dosage / Q000494:pharmacology; D000287:Administration, Topical; D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics*; D004339:Drug Compounding; D016503:Drug Delivery Systems; D004431:Ear, External / Q000378:metabolism; D005260:Female; D020868:Gene Silencing / Q000187:drug effects*; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology*; D012869:Skin Absorption
chemical_list: D000199:Actins; D054360:Chemokine CXCL1; D008081:Liposomes; D034741:RNA, Small Interfering
keywords: CXCL1; Liposome; Microneedle; Microprojection; Skin; siRNA