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Dermal delivery of topically applied oligonucleotides via follicular transport in mouse skin.
J Invest Dermatol. 2005 May; 124(5):971-5.JI

Abstract

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.

Authors+Show Affiliations

Department of Pharmaceutical Development, ISIS Pharmaceuticals, Carlsbad, California 92008, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15854038

Citation

Dokka, Sujatha, et al. "Dermal Delivery of Topically Applied Oligonucleotides Via Follicular Transport in Mouse Skin." The Journal of Investigative Dermatology, vol. 124, no. 5, 2005, pp. 971-5.
Dokka S, Cooper SR, Kelly S, et al. Dermal delivery of topically applied oligonucleotides via follicular transport in mouse skin. J Invest Dermatol. 2005;124(5):971-5.
Dokka, S., Cooper, S. R., Kelly, S., Hardee, G. E., & Karras, J. G. (2005). Dermal delivery of topically applied oligonucleotides via follicular transport in mouse skin. The Journal of Investigative Dermatology, 124(5), 971-5.
Dokka S, et al. Dermal Delivery of Topically Applied Oligonucleotides Via Follicular Transport in Mouse Skin. J Invest Dermatol. 2005;124(5):971-5. PubMed PMID: 15854038.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Dermal delivery of topically applied oligonucleotides via follicular transport in mouse skin. AU - Dokka,Sujatha, AU - Cooper,Scott R, AU - Kelly,Susan, AU - Hardee,Gregory E, AU - Karras,James G, PY - 2005/4/28/pubmed PY - 2005/6/3/medline PY - 2005/4/28/entrez SP - 971 EP - 5 JF - The Journal of investigative dermatology JO - J Invest Dermatol VL - 124 IS - 5 N2 - 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. SN - 0022-202X UR - https://www.unboundmedicine.com/medline/citation/15854038/Dermal_delivery_of_topically_applied_oligonucleotides_via_follicular_transport_in_mouse_skin_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-202X(15)32291-0 DB - PRIME DP - Unbound Medicine ER -