Autor: Peter J. Ludovice, Mark R. Prausnitz, Arthi Krishnan, Shilpa Kaushik
Rok vydání: 2001
Předmět:
Zdroj: Pharmaceutical Research. 18:894-896
ISSN: 0724-8741
DOI: 10.1023/a:1011013218494
Popis: Drug delivery across the skin has had great success for drugs such as nicotine, estradiol, and a few others (1,2). However, the vast majority of drugs cannot cross skin at therapeutic rates, due primarily to the formidable barrier presented by skin’s outer layer, the stratum corneum. This barrier to transdermal transport is formed primarily by a series of multilamellar lipid bilayers found in stratum corneum’s extracellular spaces. Strategies to enhance drug delivery across the skin have focused to a large extent on chemical and physical methods to disrupt lipid structure (1,2). However, most enhancers have side effects, including irritation or safety concerns. The ideal enhancer for transdermal drug delivery would be one that is specifically targeted to disrupt stratum corneum lipids without damaging cells found deeper within the skin. The use of magainin peptides may present an opportunity to do this. Magainins are a family of peptides originally isolated from the skin of the African clawed frog, Xenopus laevis (3), which show a broad spectrum of antimicrobial activity. They exhibit potent antibacterial behavior at low concentrations (4,5) and belong to a class of antimicrobial peptides that interact directly with the lipid bilayer as opposed to specific membrane proteins (6,7). This antimicrobial activity appears to be derived from the peptides’ ability to increase the porosity of the membrane. Magainins specifically target bacteria because of the favorable interaction between the positivelycharged magainins and the typically negatively-charged bacterial membranes. Bacterial membranes generally contain large amounts of lipid with negatively-charged head groups such as phosphatidylserine and phosphatidylglycerol. In contrast, magainins are generally not as effective against most eukaryotic cells because of unfavorable interaction with the positive charges residing on their numerous zwitterionic lipid head groups such as phosphatidylethanolamine and phosphatidylcholine. Given this charge-dependent mechanism of magainins’ effect, we sought to determine if magainins could disrupt bilayers made of lipids found in human stratum corneum. Although analysis of stratum corneum lipids is complicated by spatial and inter-individual variation, they are reported to contain fewer zwitterionic phospholipids (∼5 wt. %) than typical eukaryotic cells, while containing ∼16 wt. % negativelycharged fatty acids (8). Given the significant negative charge and limited zwitterion content of stratum corneum, we propose the hypothesis that magainins can disrupt stratum corneum lipid bilayers.
Databáze: OpenAIRE
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