Abstract
Many systemically effective drugs such as cyclosporin A are ineffective topically because of their poor penetration into skin. To surmount this problem, we conjugated a heptamer of arginine to cyclosporin A through a pH-sensitive linker to produce R7-CsA. In contrast to unmodified cyclosporin A, which fails to penetrate skin, topically applied R7-CsA was efficiently transported into cells in mouse and human skin. R7-CsA reached dermal T lymphocytes and inhibited cutaneous inflammation. These data establish a general strategy for enhancing delivery of poorly absorbed drugs across tissue barriers and provide a new topical approach to the treatment of inflammatory skin disorders.
MeSH terms
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Administration, Topical
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Animals
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Arginine / analogs & derivatives*
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Arginine / chemical synthesis
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Arginine / pharmacokinetics*
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Arginine / therapeutic use
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Biological Transport
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Biotinylation
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Cyclosporine / administration & dosage
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Cyclosporine / chemistry
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Cyclosporins / administration & dosage
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Cyclosporins / chemical synthesis
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Cyclosporins / pharmacokinetics*
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Cyclosporins / therapeutic use
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Humans
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Inflammation / prevention & control*
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Interleukin-2 / biosynthesis
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Ionomycin / pharmacology
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Jurkat Cells
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Mice
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Mice, Inbred BALB C
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Molecular Structure
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Prodrugs / chemical synthesis
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Prodrugs / pharmacokinetics*
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Prodrugs / therapeutic use
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Skin / cytology
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Skin / metabolism*
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Skin Absorption
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Tetradecanoylphorbol Acetate / pharmacology
Substances
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Cyclosporins
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Interleukin-2
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Prodrugs
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Ionomycin
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Cyclosporine
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Arginine
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Tetradecanoylphorbol Acetate