RNAi mediated IL-6 in vitro knockdown in psoriasis skin model with topical siRNA delivery system based on liquid crystalline phase

Author(s)

Depieri, Livia Vieira ; Borgheti-Cardoso, Livia Neves ; Campos, Patricia Mazureki ; Otaguiri, Katia Kaori ; Moura de Carvalho Vicentini, Fabiana Testa ; Lopes, Luciana Biagini ; Vieira Fonseca, Maria Jose ; Vitoria Lopes Badra Bentley, M.

• Document type: Journal article
• Source: EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS; v. 105, p. 50-58, AUG 2016.
• Web of Science Citations: 15

Abstract

Gene therapy by RNA interference (RNAi) is a post-transcriptional silencing process that can suppress the expression of a particular gene and it is a promising therapeutic approach for the treatment of many severe diseases, including cutaneous disorders. However, difficulties related to administration and body distribution limit the clinical use of small interfering RNA (siRNA) molecules. In this study, we proposed to use nanocarriers to enable siRNA application in the topical treatment of skin disorders. A siRNA nanodispersion based on liquid crystalline phase and composed of monoolein (MO), oleic acid (OA) and polyethylenimine (PEI) was developed and its physicochemical properties, efficiency of complexation and carrieris/RNA stability were assessed. Subsequently, cell viability, cellular uptake, in vitro skin irritation test using reconstructed human epidermis (RHE) and in vitro IL-6 knockdown in psoriasis skin model were evaluated. The results showed that the liquid crystalline nanodispersion is a promising topical delivery system for administration of siRNA, being able to overcome the limitations of the route of administration, as well those resulting from the characteristics of siRNA molecules. The formulation was effective at complexing the siRNA, presented high rate of cell uptake (similar to 90%), increased the skin penetration of siRNA in vitro, and did not cause skin irritation compared with Triton-X (a moderate irritant), resulting in a 4-fold higher viability of reconstructed human epidermis and a 15.6-fold lower release of IL-1 alpha. A single treatment with the liquid crystalline nanodispersion carrying IL-6 siRNA for 6 h was able to reduce the extracellular IL-6 levels by 3.3-fold compared with control treatment in psoriasis skin model. Therefore, liquid crystalline nanodispersion is a suitable nanocarrier for siRNA with therapeutic potential to suppress skin disease-specific genes. This study also highlights the applicability of reconstructed skin models in pharmaceutical field to evaluate the performance of delivery systems without the use of animal models. (C) 2016 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 12/09125-8 - Liquid crystalline nanodispersions as a carrier of siRNA in the topical treatment of psoriasis: In vitro and in vivo evaluation and elucidation of the mechanisms of cellular uptake
• Grantee: Lívia Vieira Depieri
• Support Opportunities: Scholarships in Brazil - Doctorate