ENHANCED HEPATIC-CLEARANCE OF INTRAVENOUSLY ADMINISTERED STERICALLY STABILIZED MICROSPHERES IN ZYMOSAN-STIMULATED RATS

The blood clearance and organ deposition of sterically stabilized (pol oxamine-908 coated) polystyrene microspheres of two different sizes (6 0 and 220 nm in diameter) were compared in control and zymosan-stimula ted rats 3 h after intravenous administration. Poloxamine coating dram atically decreased the uptake of 60-nm microspheres by organs of the r eticuloendothelial system and, concomitantly, kept microspheres in the blood. Large poloxamine-coated microspheres (220 nm) initially remain ed in the blood, but eventually a large fraction of these microspheres was filtered by the spleen. Daily administration of zymosan produced a marked increase in the intravascular clearance of the large, but not the small, poloxamine-coated microspheres. The enhanced intravascular clearance of large poloxamine-coated microspheres in zymosan-treated rats was the result of hepatic sequestration. On the other hand, the s plenic filtration of these microspheres was depressed by 225% below th e control values, despite the dramatic increase in spleen size of zymo san-treated rats. Preincubation of large poloxamine-coated microsphere s in serum derived from both the control and zymosan-treated animals s uggested that the enhanced hepatic uptake of large sterically stabiliz ed microspheres following zymosan stimulation was not the result of '' specific opsonization'' processes. Instead, the changes in the prolife rative as well as the phagocytic response of Kupffer cells appeared to be responsible for these observations. The preferred hepatic uptake o f large poloxamine-coated microspheres, as opposed to smaller particle s, is suggested to be due to differences in surface characteristics an d the properties of microspheres. These may include differences in pol ymer density and the surface conformation of the polyoxyethylene segme nts of the polymer in the biological environment and the way they inte ract with both plasma components and the macrophage surface. These obs ervations could be of importance in the use of sterically stabilized d rug carriers for delivery of therapeutic agents to sites other than th e reticuloendothelial system in clinical conditions associated with gl obally or regionally enhanced reticuloendothelial activity.