Dermal Delivery of Topically Applied Oligonucleotides via Follicular Transport in Mouse Skin

Antisense oligodeoxynucleotides formulated in cream preparations are being examined in the clinic as topical therapy for psoriasis. To produce their intended anti-inflammatory effects, these large anionic molecules must penetrate the stratum corneum and reach the living epidermis and dermis. A topic...

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Published in:Journal of investigative dermatology 2005-05, Vol.124 (5), p.971-975
Main Authors: Dokka, Sujatha, Cooper, Scott R., Kelly, Susan, Hardee, Gregory E., Karras, James G.
Format: Article
Language:English
Subjects:
Administration, Topical
Animals
Biological and medical sciences
Biological Transport
Delivery. Postpartum. Lactation
Dermatology
Gynecology. Andrology. Obstetrics
hair follicle
Hair Follicle - metabolism
Medical sciences
Mice
Mice, Hairless
Mice, Inbred BALB C
oligonucleotide
Oligonucleotides, Antisense - administration & dosage
Oligonucleotides, Antisense - pharmacokinetics
Skin - metabolism
Time Factors
topical delivery
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Cooper, Scott R.
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Karras, James G.
description Antisense oligodeoxynucleotides formulated in cream preparations are being examined in the clinic as topical therapy for psoriasis. To produce their intended anti-inflammatory effects, these large anionic molecules must penetrate the stratum corneum and reach the living epidermis and dermis. A topically applied phosphorothioate antisense oligonucleotide targeted to intercellular adhesion molecule-1 recently was shown to modulate cytokine-inducible target gene expression in engrafted human skin. In this study, we examined the route of entry into mouse skin of fluorochrome-tagged or naked second-generation 2′-O-methoxyethyl-modified oligonucleotides that react specifically with an antibody, using topical cream-based formulations. In hairless mouse skin, immunohistochemical analysis and fluorescence microscopy were unable to detect the presence of oligonucleotide in the epidermis or dermis following topical application although immunostaining was associated with the stratum corneum and fluorescein isothiocyanate-labeled oligonucleotide was observed in hair follicles. Kinetic analysis of oligonucleotide topically applied to hair-clipped BALB/c mouse skin showed early follicular localization, diffusion of oligonucleotide from the mid-follicle, and subsequent dermal accumulation. Saline formulation resulted in oligonucleotide remaining within the hair follicle. These results suggest that oligonucleotide penetration in skin involves a follicular route and further, that topical oligonucleotide therapy may be particularly well suited for altering physiology within the hair follicle and related structures.
doi_str_mv 10.1111/j.0022-202X.2005.23672.x
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To produce their intended anti-inflammatory effects, these large anionic molecules must penetrate the stratum corneum and reach the living epidermis and dermis. A topically applied phosphorothioate antisense oligonucleotide targeted to intercellular adhesion molecule-1 recently was shown to modulate cytokine-inducible target gene expression in engrafted human skin. In this study, we examined the route of entry into mouse skin of fluorochrome-tagged or naked second-generation 2′-O-methoxyethyl-modified oligonucleotides that react specifically with an antibody, using topical cream-based formulations. In hairless mouse skin, immunohistochemical analysis and fluorescence microscopy were unable to detect the presence of oligonucleotide in the epidermis or dermis following topical application although immunostaining was associated with the stratum corneum and fluorescein isothiocyanate-labeled oligonucleotide was observed in hair follicles. 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Kinetic analysis of oligonucleotide topically applied to hair-clipped BALB/c mouse skin showed early follicular localization, diffusion of oligonucleotide from the mid-follicle, and subsequent dermal accumulation. Saline formulation resulted in oligonucleotide remaining within the hair follicle. These results suggest that oligonucleotide penetration in skin involves a follicular route and further, that topical oligonucleotide therapy may be particularly well suited for altering physiology within the hair follicle and related structures.</abstract><cop>Danvers, MA</cop><pub>Elsevier Inc</pub><pmid>15854038</pmid><doi>10.1111/j.0022-202X.2005.23672.x</doi><tpages>5</tpages><oa>free_for_read</oa></addata></record>
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subjects Administration, Topical
Animals
Biological and medical sciences
Biological Transport
Delivery. Postpartum. Lactation
Dermatology
Gynecology. Andrology. Obstetrics
hair follicle
Hair Follicle - metabolism
Medical sciences
Mice
Mice, Hairless
Mice, Inbred BALB C
oligonucleotide
Oligonucleotides, Antisense - administration & dosage
Oligonucleotides, Antisense - pharmacokinetics
Skin - metabolism
Time Factors
topical delivery
title Dermal Delivery of Topically Applied Oligonucleotides via Follicular Transport in Mouse Skin
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