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By taking advantage of a monoclonal IgG antibody, 34A, which is highly specific to pulmonary endothelial cells, we have prepared liposomes containing various amounts of antibody molecules (immunoliposomes). These immunoliposomes accumulate specifically in the lung when injected i.v. Two lipid compositions were used: phosphatidylcholine/cholesterol/phosphatidylserine (PS), 10:5:1 (mol/mol), a composition that allows liposomes to be readily taken up by the reticuloendothelial system (RES) (liver and spleen), and phosphatidylcholine/cholesterol/ganglioside GM1, 10:5:1 (mol/mol), a composition that allows liposomes to avoid or delay the RES uptake (the so-called stealth liposomes). Although an increase in the number of antibody molecules per liposome was accompanied by an increased level of lung binding of the immunoliposomes, differences due to the lipid composition were more profound. For example, stealth immunoliposomes containing an antibody/lipid ratio = 1:37 (wt/wt) accumulated in lung to a level of 60% of the injected dose, whereas PS-containing immunoliposomes with a higher antibody/lipid ratio (1:8) only accumulated 50% of the injected dose in the lung. Conjugation of antibody to the stealth liposome did not increase the rate of liposome uptake by liver; this rate was approximately 10-fold lower than that of the PS-containing liposomes without antibody. Stealth immunoliposomes with high antibody content also showed long retention in the lung. The t1/2 of lung residence for the stealth immunoliposomes with an antibody/lipid ratio = 1:11 (wt/wt) was approximately 24 hr. The fact that stealth immunoliposomes showed a longer retention time in the lung than the PS-containing immunoliposomes of similar antibody content suggests that macrophages may play a role in the removal of the bound immunoliposomes from the pulmonary endothelium. Alternatively, dissociated stealth immunoliposomes may reenter the circulation and rebind to the lung target, causing an apparent slow overall dissociation rate. These results can be understood on the basis of two competing kinetic processes: lung binding whose rate is directly proportional to the antibody content of the immunoliposomes and uptake by RES whose rate is significantly reduced in the case of the stealth liposomes. Even for a modest level of antibody content, the half-life for target binding of immunoliposomes was significantly shorter than the half-life of liver uptake of the liposomes, resulting in a favorable target binding. Significant immunoliposome binding to the lung is not due to the fact that tail vein-injected liposomes flow through the lung capillary bed before they encounter the liver, because portal vein-injected immunoliposomes showed the same rate and extent of target binding as the tail vein-injected ones.

Lipid composition is important for highly efficient target binding and retention of immunoliposomes.