Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 542, Issue 1-2, Pages 213-220Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijpharm.2018.03.026
Keywords
siRNA; Functional peptide; Tight junction; Atopic dermatitis; Topical application; Nuclear factor kappaB
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Funding
- Japan Society for the Promotion of Science (JSPS) [22790049]
- Uehara Memorial Foundation
- Promotion and Mutual Aid Corporation for Private Schools of Japan
- Grants-in-Aid for Scientific Research [22790049] Funding Source: KAKEN
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Nucleic acid-based targeting of nuclear factor kappaB (NF-kappa B) is gaining attention as a treatment option for skin diseases like atopic dermatitis (AD). Transdermal administration improves patient quality of life because of non-invasive; however, siRNA delivery into the skin can be challenging owing to the barrier of tight junctions in the granular layer. Therefore, we aimed to develop a delivery system of siRNA for topical skin application using functional peptides. We previously reported that combined treatment with a cytoplasm-responsive stearylated-arginine-rich peptide (STR-CH2R4H2C) and a tight junction opening peptide (AT1002) showed high siRNA permeability in the skin of AD-induced and normal mice. Here, we used murine macrophage RAW264.7 cells to examine siRNA permeation and the therapeutic effect of anti-NF-kappa B (RelA) siRNA (siRelA) complexed with STRCH2R4H2C and AT1002 for AD-induced mice. We showed that significantly higher siRNA cellular uptake occurs after this treatment as well as decreased TNF-alpha and IL-6 expression. Additionally, we showed that effective siRNA transdermal delivery occurs with the suppression of the tight junction protein ZO-1. Moreover, topical skin application of siRelA with STR-CH2R4H2C and AT1002 improved AD-like symptoms in model mice. Thus, the combined treatment of STR-CH2R4H2C and AT1002 could serve as an effective transdermal siRNA therapeutic system for AD.
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