Hepatic uptake of polystyrene microspheres in rats: Effect of particle size on intrahepatic distribution

Abstract

The in vivo disposition of polystyrene microsphere (MS) with the particle size of 50 nm (MS-50) or 500 nm (MS-500) was characterized after intravenous administration to rats. A rapid elimination from systemic circulation was observed for both MSs. Tissue distribution of MS-50 and MS-500 at 1 h after intravenous injection indicated that both MSs were exclusively distributed to liver and that small but significant amounts of MS-50 and MS-500 were also distributed to lung and spleen, respectively. To investigate the intrahepatic distribution of MS, liver was separated into liver parenchymal cells (PC) and non-parenchymal cells (NPC) at 1 or 6 h after intravenous administration. The contribution of each cell fraction was dependent on both the size of MS and the time after administration. Furthermore, by separating the NPC into endothelial cells and Kupffer cells using a centrifugal elutriation method, their contribution was also evaluated. For both MSs, Kupffer cells were recognized to be mostly responsible for the hepatic uptake, although a significant amount of MS-50 (about 28% of total uptake) was taken up by PC. On the other hand, there was little contribution of PC (about 5%) to the hepatic uptake of MS-500. The endothelial cells were contributed larger to the uptake of MS-500 (about 24%) than that of MS-50 (13%).

Introduction

Although colloidal particles are good candidates for efficient drug carriers, the rapid clearance by the macrophages of the reticuloendothelial system (RES), mainly Kupffer cells of liver and to a lesser extent the macrophages of the spleen and the bone marrow, limits their application as carriers to other tissues and/or cells 1, 2, 3. In general, Kupffer cells are thought to play a major role in clearing the particulate materials from the systemic circulation. However, it has been recently shown that liver endothelial cells are also very important scavengers for a number of circulating macromolecular waste products 4, 8. The disposition characteristics of colloidal particles in the body after intravenous injection are largely dependent upon their sizes and surface properties [5]. Small particles are taken up by the RES whereas larger particles (>7 μm) are normally trapped mechanically in the smallest pulmonary vessels. Since the majority of particulate materials are mainly captured by liver, it is important to elucidate the kinetics of hepatic uptake and intrahepatic distribution of the carrier. Although the intrahepatic distribution of particulate materials has been investigated after intravenous administration 28, 29, there is little information about time-dependent change in intrahepatic distribution of the carrier.

To achieve a rational design of particulate carrier system, the basic information about in vivo disposition and time-dependent intrahepatic distribution of particle itself should be required. Therefore, in the present study, in vivo distribution studies were performed to assess the tissue distribution of MS-50 and MS-500 in rats. Furthermore, liver cells were separated into PC and NPC at 1 or 6 h after intravenous injection and the time dependency of intrahepatic distribution was investigated for MS-50 and MS-500. As for polystyrene microspheres, there is little quantitative information about the relative contributions of Kupffer cells, liver endothelial cells and parenchymal cells to their hepatic uptake. Therefore, NPC was further separated into liver sinusoidal endothelial cells and Kupffer cells to assess the extent of their contributions to the hepatic uptake of both MSs.