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An experimental model for interpreting percutaneous penetration of oligonucleotides that incorporates the role of keratinocytes.
J Invest Dermatol. 1998 Dec; 111(6):1166-71.JI

Abstract

Oligonucleotides have been extensively studied for their potential as therapeutic agents. Phosphorothioate oligonucleotides have been demonstrated to be particularly useful due to their stability against nucleases, their ability to be internalized by many cell types, and the ease with which they hybridize with target mRNA. These compounds have previously been delivered across the skin with the aid of iontophoresis. During transdermal delivery, the first viable cells exposed to the oligonucleotides are the keratinocytes. The purpose of this study was to determine the relationship between internalization of these compounds by keratinocytes and their transport across the skin. The in vitro uptake of 15 different fluorescently labeled phosphorothioate oligonucleotides into human keratinocytes was quantitatively measured with a fluorometer. Photomicrographs of keratinocytes indicate diffuse cytoplasmic and nuclear localization. The ability of these molecules to enter cells was linearly related to size. Cellular uptake data were inversely correlated with previously reported steady-state transport levels of oligonucleotides that had been transdermally delivered by iontophoresis across hairless mouse skin. Oligonucleotides that readily entered keratinocytes had a decreased ability to penetrate skin under iontophoretic conditions. The results indicate that oligonucleotide sequences may be designed for treating skin diseases (high uptake, low transport) or systemic disorders (low uptake, high transport).

Authors+Show Affiliations

Department of Biological Systems Engineering, University of Nebraska, Lincoln 68583-0726, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9856834

Citation

Brand, R M., et al. "An Experimental Model for Interpreting Percutaneous Penetration of Oligonucleotides That Incorporates the Role of Keratinocytes." The Journal of Investigative Dermatology, vol. 111, no. 6, 1998, pp. 1166-71.
Brand RM, Haase K, Hannah TL, et al. An experimental model for interpreting percutaneous penetration of oligonucleotides that incorporates the role of keratinocytes. J Invest Dermatol. 1998;111(6):1166-71.
Brand, R. M., Haase, K., Hannah, T. L., & Iversen, P. L. (1998). An experimental model for interpreting percutaneous penetration of oligonucleotides that incorporates the role of keratinocytes. The Journal of Investigative Dermatology, 111(6), 1166-71.
Brand RM, et al. An Experimental Model for Interpreting Percutaneous Penetration of Oligonucleotides That Incorporates the Role of Keratinocytes. J Invest Dermatol. 1998;111(6):1166-71. PubMed PMID: 9856834.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An experimental model for interpreting percutaneous penetration of oligonucleotides that incorporates the role of keratinocytes. AU - Brand,R M, AU - Haase,K, AU - Hannah,T L, AU - Iversen,P L, PY - 1998/12/18/pubmed PY - 1998/12/18/medline PY - 1998/12/18/entrez SP - 1166 EP - 71 JF - The Journal of investigative dermatology JO - J Invest Dermatol VL - 111 IS - 6 N2 - Oligonucleotides have been extensively studied for their potential as therapeutic agents. Phosphorothioate oligonucleotides have been demonstrated to be particularly useful due to their stability against nucleases, their ability to be internalized by many cell types, and the ease with which they hybridize with target mRNA. These compounds have previously been delivered across the skin with the aid of iontophoresis. During transdermal delivery, the first viable cells exposed to the oligonucleotides are the keratinocytes. The purpose of this study was to determine the relationship between internalization of these compounds by keratinocytes and their transport across the skin. The in vitro uptake of 15 different fluorescently labeled phosphorothioate oligonucleotides into human keratinocytes was quantitatively measured with a fluorometer. Photomicrographs of keratinocytes indicate diffuse cytoplasmic and nuclear localization. The ability of these molecules to enter cells was linearly related to size. Cellular uptake data were inversely correlated with previously reported steady-state transport levels of oligonucleotides that had been transdermally delivered by iontophoresis across hairless mouse skin. Oligonucleotides that readily entered keratinocytes had a decreased ability to penetrate skin under iontophoretic conditions. The results indicate that oligonucleotide sequences may be designed for treating skin diseases (high uptake, low transport) or systemic disorders (low uptake, high transport). SN - 0022-202X UR - https://www.unboundmedicine.com/medline/citation/9856834/An_experimental_model_for_interpreting_percutaneous_penetration_of_oligonucleotides_that_incorporates_the_role_of_keratinocytes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-202X(15)40335-5 DB - PRIME DP - Unbound Medicine ER -