Inhibition of tracheal vascular extravasation by liposome-encapsulated albuterol in rats.
OBJECTIVE
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 i.v., 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 i.v. 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.
Zhang
W
W
Cardiovascular Research Institute, University of California at San Francisco 94143-0130 USA.
Guo
L
L
Nadel
J A
JA
Papahadjopoulos
D
D
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005070:Evans Blue; D007275:Injections, Intravenous; D008081:Liposomes; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D013047:Specific Pathogen-Free Organisms; D013373:Substance P / Q000494:pharmacology; D014132:Trachea / Q000098:blood supply* / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D004337:Drug Carriers; D008081:Liposomes; D013373:Substance P; D005070:Evans Blue; D000420:Albuterol