Abstract
As a new category of therapeutics for skin diseases including atopic dermatitis (AD), nucleic acids are gaining importance in the clinical setting. Intradermal administration is noninvasive and improves patients′ quality of life. However, intradermal small interfering RNA (siRNA) delivery is difficult because of two barriers encountered in the skin: intercellular lipids in the stratum corneum and tight junctions in the stratum granulosum. Tight junctions are the major barrier in AD; therefore, we focused on functional peptides to devise an intradermal siRNA delivery system for topical skin application. In this study, we examined intradermal siRNA permeability in the tape-stripped (20 times) back skin of mice or AD-like skin of auricles treated with 6-carboxyfluorescein-aminohexyl phosphoramidite (FAM)-labeled siRNA, the tight junction modulator AT1002, and the functional cytoplasm-responsive stearylated peptide STR-CH2R4H2C by using confocal laser microscopy. We found that strong fluorescence was observed deep and wide in the epidermis and dermis of back skin and AD-like ears after siRNA with STR-CH2R4H2C and AT1002 treatment. After 10 h from administration, brightness of FAM-siRNA was significantly higher for STR-CH2R4H2C + AT1002, compared to other groups. In addition, we confirmed the nontoxicity of STR-CH2R4H2C as a siRNA carrier using PAM212 cells. Thus, our results demonstrate the applicability of the combination of STR-CH2R4H2C and AT1002 for effective intradermal siRNA delivery.
Highlights
Intradermal drug administration is commonly used because of its easy application and removal of applied drugs
We have reported that the application of AT1002 can reversibly open tight junctions and increase intradermal small interfering RNA (siRNA) delivery [22]
We investigated the intradermal FAM-siRNA delivery using stearic acid (STR)-CH2 R4 H2 C and AT1002 in tape-stripped back skin of normal mice after treatment for 1, 5, or 10 h with naked FAM-siRNA, STR-CH2 R4 H2 C, and STR-CH2 R4 H2 C + AT1002 solutions (Figure 1)
Summary
Intradermal drug administration is commonly used because of its easy application and removal of applied drugs. The skin consists of three layers: epidermis, dermis, and hypodermis. Macrophages, Langerhans cells, and mast cells related to the immune response are found in the epidermis and dermis. It is speculated that intradermal administration improves treatment by efficiently triggering small interfering RNA (siRNA) to these intradermal inflammatory cells. The epidermis contains strong barriers, including subcorneal intercellular lipid structures and tight junctions in the stratum granulosum. The intradermal delivery of hydrophilic macromolecules like siRNA is difficult, necessitating the use of absorption enhancers
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