title: A single dose of intravenously injected poloxamine-coated long-circulating particles triggers macrophage clearance of subsequent doses in rats.
abstract: 1. Adsorption of the block copolymer non-ionic surfactant poloxamine-908 on to the surface of polystyrene nanospheres (60 nm in diameter) produced 'phagocyte-resistant' particles (otherwise known as long-circulating particles). This was reflected by a profound reduction in uptake of such engineered nanospheres by macrophages of the reticuloendothelial system and extended blood circulation time, after intravenous administration to rats. 2. A single intravenous administration of poloxamine-908-coated particles dramatically affected the circulation half-life and body distribution of a second subsequent dose. The degree of alteration depended on the interval between the two doses. At 3 days after a single intravenous injection of poloxamine-coated particles, Kupffer cells and spleen macrophages could clear a second dose of long-circulating beads from the blood. When tested at day 14, the second dose of intravenously injected poloxamine-coated particles avoided rapid uptake by liver and spleen macrophages and remained in the blood. 3. The coating polymer (poloxamine-908) apparently triggered bead clearance by resident Kupffer cells and certain sub-populations of spleen macrophages, since a single intravenous dose of an endotoxin-free solution of poloxamine 3 days before the administration of long-circulating particles induced similar effects. When the interval between the two injections was 2 weeks, poloxamine-coated particles again exhibited long circulation half-life. This cycle could be repeated after intravenous administration of a second poloxamine dose 2 weeks after the first poloxamine injection. 4. The mechanism of particle recognition by resident tissue macrophages was found to be independent of opsonization processes. 5. These studies could have important implications in biomedical application, design and engineering of poloxamine-based long-circulating drug carriers for repeated intravenous administration.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nottingham, U.K.
authors.forename: S M
authors.initials: SM
authors.lastname: Moghimi
authors.forename: T
authors.initials: T
authors.lastname: Gray
mesh_terms: D000818:Animals; D004337:Drug Carriers; D005029:Ethylenediamines; D005260:Female; D006207:Half-Life; D007728:Kupffer Cells / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008863:Microspheres; D011092:Polyethylene Glycols; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000166:cytology / Q000502:physiology; D013501:Surface-Active Agents; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D005029:Ethylenediamines; D013501:Surface-Active Agents; C012571:tetronic 701; D011092:Polyethylene Glycols