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First published on July 30, 2008; DOI: 10.1124/mol.108.050153

0026-895X/08/7405-1183-1192$20.00
Mol Pharmacol 74:1183-1192, 2008

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Enhanced Anti-Inflammation of Inhaled Dexamethasone Palmitate Using Mannosylated Liposomes in an Endotoxin-Induced Lung Inflammation Model

Wassana Wijagkanalan, Yuriko Higuchi, Shigeru Kawakami, Mugen Teshima, Hitoshi Sasaki, and Mitsuru Hashida

Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan (W.W., Y.H., S.K., M.H.); Department of Hospital Pharmacy, Nagasaki University Hospital of Medicine and Dentistry, Nagasaki, Japan (M.T., H.S.); and Institute of Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan (M.H.)

Inhalation of bacterial endotoxin induces pulmonary inflammation by activation of nuclear factor {kappa}B (NF{kappa}B), production of cytokines and chemokines, and neutrophil activation. Although glucocorticoids are the drugs of choice, administration of free drugs results in adverse effects as a result of a lack of selectivity for the inflammatory effector cells. Because alveolar macrophages play a key role in the inflammatory response in the lung, selective targeting of glucocorticoids to alveolar macrophages offers efficacious pharmacological intervention with minimal side effects. We have demonstrated previously the selective targeting of mannosylated liposomes to alveolar macrophages via mannose receptor-mediated endocytosis after intratracheal administration. In this study, the anti-inflammatory effects of dexamethasone palmitate incorporated in mannosylated liposomes (DPML) at 0.5 mg/kg via intratracheal administration were investigated in lipopolysaccharide-induced lung inflammation in rats. DPML significantly inhibited tumor necrosis factor {alpha}, interleukin-1β, and cytokine-induced neutrophil chemoattractant-1 levels, suppressed neutrophil infiltration and myeloperoxidase activity, and inhibited NF{kappa}B and p38 mitogen-activated protein kinase activation in the lung. These results prove the value of inhaled mannosylated liposomes as powerful targeting systems for the delivery of anti-inflammatory drugs to alveolar macrophages to improve their efficacy against lung inflammation.

Received for publication July 2, 2008.

Accepted for publication July 28, 2008.

Address correspondence to: Dr. Mitsuru Hashida, Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. E-mail: hashidam{at}pharm.kyoto-u.ac.jp






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