Topical delivery of interleukin-13 antisense oligonucleotides with cationic elastic liposome for the treatment of atopic dermatitis.
BACKGROUND
Interleukin (IL)-13, overproduced in the skin of atopic dermatitis (AD), has been shown to play an essential role in the pathogenesis of the disease. Thus, inhibition of IL-13 production should provide a key step to alleviate disease conditions of the atopic skin. In the present study, IL-13 antisense oligonucleotide (ASO) was designed and formulated with cationic elastic liposome (cEL) to improve transdermal delivery.


METHODS
ASOs were generated against murine IL-13 mRNA (+4 to + 23) and complexed with cEL. Physicochemical properties of IL-13 ASO/cEL complex were examined by DNA retardation and DNase I protection assay. An in vitro inhibition study was performed in T-helper 2 (Th2) cells and cytotoxicity was tested by the XTT assay. The in vivo effect of IL-13 ASO/cEL complex was tested in a murine model of AD.


RESULTS
In vitro, the IL-13 ASO/cEL complex showed dose- and ratio-dependent inhibition of IL-13 secretion in Th2 cells. At the IL-13 ASO/cEL ratio of 6, maximum inhibition of IL-13 secretion was observed. When applied to the ovalbumin-sensitized murine model of AD, topically administered IL-13 ASO/cEL complex dramatically suppressed IL-13 production (by up to 70% of the control) in the affected skin region. In addition, the levels of IL-4 and IL-5 were also significantly reduced. Moreover, IL-13 ASO/cEL-treated AD mice showed reduced infiltration of inflammatory cells into the epidermal and dermal areas, with concomitant reduction of skin thickness.


CONCLUSIONS
These data suggests that IL-13 ASO/cEL complex can provide a potential therapeutic tool for the treatment of AD and also be applied to other immune diseases associated with the production of Il-13.
Kim
Sung Tae
ST
Laboratory of Excellency for Drug and Gene Delivery, College of Pharmacy, Seoul National University, Seoul, South Korea.
Lee
Kyung-Mi
KM
Park
Hyun-Joo
HJ
Jin
Su-Eon
SE
Ahn
Woong Shick
WS
Kim
Chong-Kook
CK
D000287:Administration, Topical; D000818:Animals; D003876:Dermatitis, Atopic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015847:Interleukin-4 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D014407:Tumor Cells, Cultured
D018793:Interleukin-13; D015848:Interleukin-5; D008081:Liposomes; D016376:Oligonucleotides, Antisense; D015847:Interleukin-4