Endothelial and transendothelial delivery of pharmaceutically active agents; potential of liposomes

The architecture of the liver constitutes a favorable condition for cell-sp ecific delivery of drugs by means of targeted delivery systems due to the p resence of a fenestrated endothelium. This allows access of particulate dru g carriers such as liposomes to not only the sinusoidally located Kupffer c ells and the endothelial cells but also to the trans-endothelial hepatocyte s and stellate cells. Relatively small liposomes are known to accumulate in hepatocytes to much l arger extents than larger ones. However, we found that even substantial amo unts of relatively large liposomes can be taken up by hepatocytes after i.v , administration, provided they have the proper lipid composition, i.e. con taining the negatively charged phospholipid phosphatidylserine (PS) and con sisting of fluid-phase lipids. Liposomes containing phosphatidylglycerol (P G) as a negatively charged constituent or PS-containing liposomes consistin g of rigid bilayer lipids were shown not to gain access to the hepatocytes. We propose that the mechanism responsible for this transendothelial passag e of large fluid-type liposomes involves a PS-specific transient interactio n with the endothelial cells followed by a forced squeezing of the fluid li posomes through the fenestrations, possibly mediated by an endothelial cell -surface-located scavenger receptor. An alternative explanation, involving a pharmacological widening effect of the PS on the fenestrations, could be discarded on the basis of experiments in which radiolabeled PG liposomes an d nonlabeled PS liposomes were simultaneously injected: under those conditi ons still no uptake of large PG liposomes by hepatocytes was observed. The endothelial scavenger receptor is able to recognize and internalize PS liposomes in vitro but not in vivo, due to the masking effect of liposome-a dsorbed plasma proteins.