Topical delivery of siRNA into skin using SPACE-peptide carriers

Short-interfering RNAs (siRNAs) offer a potential tool for the treatment of skin disorders. However, applications of siRNA for dermatological conditions are limited by their poor permeation across the stratum corneum of the skin and low penetration into the skin's viable cells. In this study, we report the use of SPACE-peptide in combination with a DOTAP-based ethosomal carrier system to enhance skin delivery of siRNA. A DOTAP-based SPACE Ethosomal System significantly enhanced siRNA penetration into porcine skin in vitro by 6.3 ± 1.7-fold (p < 0.01) with an approximately 10-fold (p < 0.01) increase in epidermis accumulation of siRNA compared to that from an aqueous solution. Penetration of siRNA was also enhanced at the cellular level. Internalization of SPACE-peptide occurred in a concentration dependent manner marked by a shift in intracellular distribution from punctate spots to diffused cytoplasmic staining at a peptide concentration of 10 mg/mL. In vitro delivery of GAPDH siRNA by SPACE peptide led to 83.3 ± 3.0% knockdown relative to the control. In vivo experiments performed using female BALB/C mice also confirmed the efficacy of DOTAP-SES in delivering GAPDH-siRNA into skin. Topical application of DOTAP-SES on mice skin resulted in 63.2% ± 7.7% of GAPDH knockdown, which was significantly higher than that from GAPDH-siRNA PBS (p < 0.05). DOTAP-SES formulation reported here may open new opportunities for cutaneous siRNA delivery.

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