Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation.
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.
Rothbard
J B
JB
CellGate, Sunnyvale, California 94086, USA. Khavari@cmgm.stanford.edu
Garlington
S
S
Lin
Q
Q
Kirschberg
T
T
Kreider
E
E
McGrane
P L
PL
Wender
P A
PA
Khavari
P A
PA
D000287:Administration, Topical; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001692:Biological Transport; D019921:Biotinylation; D016572:Cyclosporine / Q000008:administration & dosage / Q000737:chemistry; D003524:Cyclosporins / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000517:prevention & control*; D007376:Interleukin-2 / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D019169:Jurkat Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012867:Skin / Q000166:cytology / Q000378:metabolism*; D012869:Skin Absorption; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D003524:Cyclosporins; D007376:Interleukin-2; D011355:Prodrugs; D015759:Ionomycin; D016572:Cyclosporine; D001120:Arginine; D013755:Tetradecanoylphorbol Acetate