Enhanced hepatic clearance of intravenously administered sterically stabilized microspheres in zymosan-stimulated rats

Abstract

The blood clearance and organ deposition of sterically stabilized (poloxamine-908 coated) polystyrene microspheres of two different sizes (60 and 220 nm in diameter) were compared in control and zymosan-stimulated rats 3 h after intravenous administration. Poloxamine coating dramatically decreased the uptake of 60-nm microspheres by organs of the reticuloendothelial system and, concomitantly, kept microspheres in the blood. Large poloxamine-coated microspheres (220 nm) initially remained 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 splenic filtration of these microspheres was depressed by 225% below the control values, despite the dramatic increase in spleen size of zymosan-treated rats. Preincubation of large poloxamine-coated microspheres in serum derived from both the control and zymosan-treated animals suggested that the enhanced hepatic uptake of large sterically stabilized microspheres following zymosan stimulation was not the result of "specific opsonization" processes. Instead, the changes in the proliferative as well as the phagocytic response of Kupffer cells appeared to be responsible for these observations. The preferred hepatic uptake of large poloxamine-coated microspheres, as opposed to smaller particles, is suggested to be due to differences in surface characteristics and the properties of microspheres. These may include differences in polymer density and the surface conformation of the polyoxyethylene segments of the polymer in the biological environment and the way they interact with both plasma components and the macrophage surface. These observations could be of importance in the use of sterically stabilized drug carriers for delivery of therapeutic agents to sites other than the reticuloendothelial system in clinical conditions associated with globally or regionally enhanced reticuloendothelial activity.

Surface engineered nanospheres with enhanced drainage into lymphatics and uptake by macrophages of the regional lymph nodes

“…Therefore, it is not surprising that lymph node macrophages can efficiently filter the drained poloxamine 901-and 904-coated particles rather than that of poloxamine 908-coated particles during the course of the experiment. This concept is further supported by the observation that the interstitially administered poloxamine 908-coated nanospheres can reach the systemic circulation, remain within the blood, and avoid extensive clearance by Kupffer cells and spleen macrophages [4,5,8] even at 24 h post-administration (Fig. la).…”

“…Polystyrene nanospheres, 60 nm in diameter, were purchased from Polysciences (UK) and surface labelled with Na[12'I] (Amersham International, UK) as described in detail elsewhere [4,5]. All poloxamines and poloxamers were a gift from BASF, USA.…”

“…These conditions are best met for poloxamine 908, rather than that of poloxamine 901 and 904, and as a result the drainage from the injection site of poloxamine 908 is most rapid when compared to that of other poloxamines ( Fig. la and b) at all time points (poloxamines 901, 904 and 908 contain 4, 15 and 119 ethylene oxide units, respectively, per POE chain, whereas they all share a central POP region consisting of 68 propylene oxide units) [4,5]. These observations can also be reproduced with the related poloxamer series 401, 402 and 407 (Fig.…”

“…This observed difference in lymph node sequestration among the poloxaminecoated particles may be attributed to their different surface characteristics. The steric barrier imposed by hydrophilic POE chains of the poloxamines has been shown to suppress both opsonization processes and interaction of particles with phagocytic cells; a process which is directly proportional to its chain length (the shorter the POE chain, the lesser the steric-barrier activity) [4,5]. Therefore, it is not surprising that lymph node macrophages can efficiently filter the drained poloxamine 901-and 904-coated particles rather than that of poloxamine 908-coated particles during the course of the experiment.…”

Lipid-Based Drug Delivery Systems in Cancer Therapy: What Is Available and What Is Yet to Come

“…For larger particles that are not subjected to renal clearance, it is believed that these particles accumulate within the spleen and to a larger extent within the liver (Moghimi et al, 1993a;Moghimi et al, 1993b). Regardless of whether nanoparticles are coated with a stealth component or not, particles with a hydrodynamic diameter of more than 200 nm exhibit a faster rate of intravascular clearance via splenic filtration and hepatic sequestration than those with a hydrodynamic diameter of less than 200 nm (Moghimi et al, 1993b).…”