title: Increased liposome extravasation in selected tissues: effect of substance P.
abstract: We have used a pharmacologic mediator to open intercellular connections in selected vessels to allow liposomes to escape from the blood stream and to extravasate into tissues that have appropriate receptors. We have examined the effects of substance P (SP), a peptide known to increase vascular permeability in selected tissues, such as trachea, esophagus, and urinary bladder in rats. We used quantitative fluorescence analysis of tissues to measure two fluorescent markers, one attached to the lipid (rhodamine-phosphatidylethanolamine) and another, doxorubicin (an anti-tumor drug), encapsulated within the aqueous interior. We have also examined the deposition of liposomes microscopically by the use of encapsulated colloidal gold and silver enhancement. Analysis of the biochemical and morphological observations indicate the following: (i) Injection of SP produces a striking increase in both liposome labels, but only in tissues that possess receptors for SP in postcapillary venules; (ii) liposome material in these tissues has extravasated and is found extracellularly near a variety of cells beyond the endothelial layer over the first few hours; (iii) 24 h following injection of liposomes and SP, liposome material is found in these tissues, localized intracellularly in both endothelial cells and macrophages. We propose that appropriate application of tissue-specific mediators can result in liposome extravasation deep within tissues that normally do not take up significant amounts of liposomes from the blood. Such liposomes are able to carry a variety of pharmacological agents that can be released locally within selected target tissues for therapeutic purposes.
authors.affiliation: Cardiovascular Research Institute, San Francisco, CA 94143-0130, USA.
authors.forename: J
authors.initials: J
authors.lastname: Rosenecker
authors.forename: W
authors.initials: W
authors.lastname: Zhang
authors.forename: K
authors.initials: K
authors.lastname: Hong
authors.forename: J
authors.initials: J
authors.lastname: Lausier
authors.forename: P
authors.initials: P
authors.lastname: Geppetti
authors.forename: S
authors.initials: S
authors.lastname: Yoshihara
authors.forename: D
authors.initials: D
authors.lastname: Papahadjopoulos
authors.forename: J A
authors.initials: JA
authors.lastname: Nadel
mesh_terms: D000818:Animals; D003102:Colloids; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004337:Drug Carriers; D005119:Extravasation of Diagnostic and Therapeutic Materials; D006046:Gold; D008081:Liposomes; D008297:Male; D010714:Phosphatidylethanolamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D012235:Rhodamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D012834:Silver; D013373:Substance P / Q000494:pharmacology*; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D003102:Colloids; D004337:Drug Carriers; D008081:Liposomes; D010714:Phosphatidylethanolamines; D012235:Rhodamines; D013373:Substance P; D012834:Silver; C027305:Lissamine Rhodamine B sulfonyl chloride; D006046:Gold; D004317:Doxorubicin