INCREASED LIPOSOME EXTRAVASATION IN SELECTED TISSUES - EFFECT OF SUBSTANCE-P

We have used a pharmacologic mediator to open intercellular connection s in selected vessels to allow liposomes to escape from the blood stre am and to extravasate into tissues that have appropriate receptors. We have examined the effects of substance P (SP), a peptide known to inc rease vascular permeability in selected tissues, such as trachea, esop hagus, and urinary bladder in rats. We used quantitative fluorescence analysis of tissues to measure two fluorescent markers, one attached t o the lipid (rhodamine-phosphatidylethanolamine) and another, doxorubi cin (an antitumor 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 la bels, but only in tissues that possess receptors for SP in postcapilla ry venules; (ii) liposome material in these tissues has extravasated a nd is found extracellularly near a variety of cells beyond the endothe lial layer over the first few hours; (iii) 24 h following injection of liposomes and SP, liposome material is found in these tissues, locali zed intracellularly in both endothelial cells and macrophages. We prop ose that appropriate application of tissue-specific mediators can resu lt in liposome extravasation deep within tissues that normally do not take up significant amounts of liposomes from the blood. Such liposome s are able to carry a variety of pharmacological agents that can be re leased locally within selected target tissues for therapeutic purposes .