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Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation

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.

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Figure 1: Heptamers of D-arginine penetrate the skin barrier.
Figure 2: Biotinylated r7–CsA conjugates enter the epidermis and dermis of mouse and human skin.
Figure 3: Biotinylated r7-CsA enters dermal T cells in inflamed skin.
Figure 4: Conjugate synthesis and chemical release.
Figure 5: Functional activity of releasable R7-CsA.

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Correspondence to Jonathan B. Rothbard or Paul A. Khavari.

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Rothbard, J., Garlington, S., Lin, Q. et al. Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nat Med 6, 1253–1257 (2000). https://doi.org/10.1038/81359

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