Inhibition of Tracheal Vascular Extravasation by Liposome-Encapsulated Albuterol in Rats |
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Authors: | Zhang Weiming Guo Luke Nadel Jay A Papahadjopoulos Demetrios |
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Institution: | (1) Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California, 94143-0130;(2) SEQUUS Pharmaceutical, Inc., Menlo Park, California, 94025;(3) Department of Medicine, University of California at San Francisco, San Francisco, California, 94143-0130;(4) Department of Cellular and Molecular Pharmacology and Cancer Research Institute, University of California at San Francisco, San Francisco, California, 94143-0130;(5) California Pacific Medical Research Institute, Liposome Research Laboratory, 2200 Webster St., 2nd Floor, San Francisco, California, 94115 |
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Abstract: | Purpose. To develop a liposome-based system for systemic delivery of anti-inflammatory drugs to airways and other inflamed tissues.
Methods. Postcapillary venular gap junctions open during airway inflammation and allow fluid accumulation and permit molecules (e.g. complement, kininogen) to enter tissues, initiating inflammatory cascades. Beta-adrenergic agonists prevent inflammatory plasma extravasation, but because of their deleterious side effects, they are not used intravenously. When sterically stabilized "stealth liposomes are injected iv, they remain in the circulation for long periods. Inflammatory mediators e.g., substance P(SP)] open postcapillary venular gaps and allow liposomes and their contents to be deposited selectively in the inflamed tissue.
Results. We hypothesized that liposomes encapsulating a beta-adrenergic agonist, such as albuterol, would deposit selectively in inflamed airway tissue, where the drug would slowly leak out of the liposomes, resulting in closure of the gaps, thus preventing subsequent inflammatory extravasation. To test this hypothesis, we delivered albuterol-loaded liposomes iv in rats. Then we injected SP to open the venular gaps and allow accumulation of the drug-loaded liposomes in airway tissue. We examined whether this treatment resulted in inhibition of subsequent plasma extravasation induced by SP. The results indicate that liposome-encapsulated albuterol inhibits subsequent extravasation, presumably by leaking out of liposomes in airway tissue. This inhibition occurs for prolonged periods of time and with limited side effects compared to the effect of free albuterol.
Conclusions. We conclude that liposomes loaded with appropriate drugs, by migrating to inflamed tissue and subsequently inhibiting inflammatory cascades, may be of therapeutic value in inflammatory diseases. |
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Keywords: | beta-adrenergic agonist endothelial gap junctions antiinflammatory drug liposome drug delivery |
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