Possibility of active targeting to tumor tissues with liposomes

lIn terms of active targeting by immunoliposomes, two anatomical compartmen ts are considerable for targeting sites. One is located a readily accessibl e site in intravascular, and another is a much less accessible target site located in the extravascular. However, it was made clear that the active ta rgeting with immunoliposomes is determined by two kinetically competing pro cesses, such as binding to the target site and uptake by the RES. To overco me these contradictions, we have designed a new type of long-circulating im munoliposome, which was PEG-immunoliposome attached antibodies at the dista l end of PEG chain, so called the pendant type immunoliposome. The pendant type immunoliposome showed much higher targetability than the ordinary immu noliposomes to both targeting sites of lung endothelial cells and solid tum or tissue. This is due to the free PEG chains (not linked to the antibody) effectively avoiding the RES uptake of liposomes, resulting in elevated the blood concentration and enhanced the target binding of immunoliposomes. Th e presence of free PEG does not interfere with the binding of the terminall y linked antibody to the antigen. For targeting to the vascular endothelial surface in the lung, 34A antibody, which is highly specific to mouse pulmo nary endothelial cells, was conjugated to make the pendant type immunolipos omes (34A-PEG-ILP). 34A-PFG-ILP showed significantly higher targeting degre e than the ordinary type of immunoliposomes. For targeting to the solid tum or tissue, Fab' fragment of 21B2 antibody which is anti-human CFA and trans ferrin (TF) were used. Both pendant type immunoliposomes (Fab'-PFG-ILP and TF-PEG-ILP) showed the low RES uptake and the long circulation time, and re sulted in enhanced accumulation of the liposomes in the solid tumor. TF-PEG -ILP was internalized into tumor cells with receptor mediated endocytosis, after extravasation into tumor tissue. The pendant type immunoliposome can escape from the gaps between adjacent endothelial cells and openings at the vessel termini during tumor angiogenesis by passive convective transport m uch rather than ligand directed targeting. Active targeting to tumor tissue with the pendant type immunoliposome is particularly important for many hi ghly toxic anticancer drugs for cancer chemotherapy. An ultimate goal of pe ndant type immunoliposome is the incorporation of a fusogenic molecule that would induce fusion of Liposome following their binding to the target cell s or their internalization by endocytosis. Such liposomal formulations shou ld be useful for endocytotic internalization of plasmid DNA and other bioac tive materials. (C) 1999 Published by Elsevier Science B.V. All rights rese rved.