AN INVESTIGATION OF THE FILTRATION CAPACITY AND THE FATE OF LARGE FILTERED STERICALLY-STABILIZED MICROSPHERES IN RAT SPLEEN

Earlier we demonstrated that coating the surface of large model polyst yrene microspheres (220-300 nm in diameter) with the block co-polymer polyoxyethylene/polyoxypropylene poloxamine-908 triggered their accumu lation in the rat spleen by a filtration mechanism following intraveno us administration [Moghimi, S.M., Porter, C.J.H., Muir, I.S., Illum. L . and Davis, S.S. (1991) Biochem. Biophys. Res. Commun. 177, 861-866]. We have now demonstrated that the macrophages of the red-pulp can eff ectively phagocytose the filtered poloxamine-coated microspheres 24 h post-administration. This could be the result of either the loss of th e surface adsorbed poloxamine, and hence the steric barrier, or 'neutr alization' of the effect of the anti-phagocytic material poloxamine-90 8 within the spleen. In order to assess the capacity of the splenic up take mechanism(s), rats received daily intravenous administration of u nlabelled large poloxamine-908 coated microspheres (220 nm in diameter ) for 4 days (daily-dosed animals). Control rats received daily saline injection. On the fifth day all animals were injected with either rad iolabelled large (220 nm) or small (60 nm in diameter) poloxamine-coat ed polystyrene microspheres. Predosing dramatically decreased the sple nic uptake of the large test microspheres but had no effect on the upt ake of small test-microspheres. The failure of the spleen to take up p articles was not associated with an increased circulatory level of mic rospheres. Surprisingly, both small and large coated microspheres were sequestered by the liver and accumulated in Kupffer cells as demonstr ated by electron microscopy in daily-dosed animals. In contrast, the l iver of control animals did not effectively sequester poloxamine-coate d microspheres. Here, microspheres predominantly remained in blood. Se questration of poloxamine-908 coated microspheres by Kupffer cells of the liver of daily-dosed animals was the result of opsonization by an unknown serum component.