Long-Circulating Immunoliposome Targeting in Animal Models

Abstract

The current status of newly developed PEG-immunoliposomes (Type C), carrying monoclonal antibodies or their fragments (Fab') at the distal ends of the PEG chains, were described in this review. In terms of target binding of Type C, two different anatomical compartments were considered. They are the mouse lung endothelial for a readily accessible site in intravascular and the mouse implanted solid tumor for a much less accessible target site located in extravascular through leaky vascular. Distearoyl phosphatidylethanolamine derivatives of PEG with carboxyl group (DSPE-PEG-COOH) and dipalmitoyl phosphatidylethanolamine derivatives of PEG with maleimidyl group (DPPE-PEG-Mal) at the PEG's terminus were newly synthesized. Small unilamellar liposomes (90 - 130 nm in diameter) were prepared from phosphatidylcholine and cholesterol (2:1, m/m) containing 6 mol% of DSPE-PEG-COOH or DPPE-PEG-Mal. For targeting to the vascular endothelial surface in the lung, 34A antibody, which is highly specific to mouse pulmonary endothelial cells, was conjugated to PEG-liposome (34A-Type C). The degree of lung binding of 34A-Type C in BALB/c mouse was significantly higher than that of 34A-Type A which is an ordinary type of immunoliposome (without PEG derivatives). For targeting to the solid tumor tissue, 21B2 antibody which is anti-human CEA and its Fab' fragment were used. The targeting ability of Fab'-Type C was examined by using CEA-positive human gastric cancer strain MKN-45 cells inoculated into BALB/c nu/nu mice. Fab'-Type C showed the low RES uptake and the long circulation time, and resulted in enhanced accumulation of the liposomes in the solid tumor. The small Fab'-Type C could predominantly pass through the leaky tumor endothelium by passive convective transport. These studies offer some important insights into the potential of target-specific drug delivery.