A SINGLE-DOSE OF INTRAVENOUSLY INJECTED POLOXAMINE-COATED LONG-CIRCULATING PARTICLES TRIGGERS MACROPHAGE CLEARANCE OF SUBSEQUENT DOSES IN RATS

1. adsorption of the block copolymer non-ionic surfactant poloxamine-9 08 on to the surface of polystyrene nanospheres (60 nm in diameter) pr oduced 'phagocyte-resistant' particles (otherwise known as long-circul ating particles). This was reflected by a profound reduction in uptake of such engineered nanospheres by macrophages of the reticuloendothel ial system and extended blood circulation time, after intravenous admi nistration to rats. 2. A single intravenous administration of poloxami ne-908-coated particles dramatically affected the circulation half-lif e and body distribution of a second subsequent dose. The degree of alt eration depended on the interval between the two doses. At 3 days afte r a single intravenous injection of poloxamine-coated particles, Kupff er cells and spleen macrophages could clear a second dose of long-circ ulating beads from the blood. When tested at day 14, the second dose o f intravenously injected poloxamine-coated particles avoided rapid upt ake by liver and spleen macrophages and remained in the blood. 3. The coating polymer (poloxamine-908) apparently triggered bead clearance b y resident Kupffer cells and certain sub-populations of spleen macroph ages, since a single intravenous dose of an endotoxin-free solution of poloxamine 3 days before the administration of long-circulating parti cles induced similar effects. When the interval between the two inject ions was 2 weeks, poloxamine-coated particles again exhibited long cir culation half-life. This cycle could be repeated after intravenous adm inistration of a second poloxamine dose 2 weeks after the first poloxa mine injection. 4. The mechanism of particle recognition by resident t issue macrophages was found to be independent of opsonization processe s. 5. These studies could have important implications in biomedical ap plication, design and engineering of poloxamine-based long-circulating drug carriers for repeated intravenous administration.