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

The architecture of the liver constitutes a favorable condition for cell-specific delivery of drugs by means of targeted delivery systems due to the presence of a fenestrated endothelium. This allows access of particulate drug carriers such as liposomes to not only the sinusoidally located Kupffer cells and the endothelial cells but also to the trans-endothelial hepatocytes and stellate cells. Relatively small liposomes are known to accumulate in hepatocytes to much larger extents than larger ones. However, we found that even substantial amounts of relatively large liposomes can be taken up by hepatocytes after i.v, administration, provided they have the proper lipid composition, i.e. containing the negatively charged phospholipid phosphatidylserine (PS) and consisting of fluid-phase lipids. Liposomes containing phosphatidylglycerol (PG) as a negatively charged constituent or PS-containing liposomes consisting of rigid bilayer lipids were shown not to gain access to the hepatocytes. We propose that the mechanism responsible for this transendothelial passage of large fluid-type liposomes involves a PS-specific transient interaction with the endothelial cells followed by a forced squeezing of the fluid liposomes 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 and nonlabeled PS liposomes were simultaneously injected: under those conditions 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-adsorbed plasma proteins.