Abstract
Distearoyl-N-(3-carboxypropionoyl polyethyleneglycol succinyl) phosphatidylethanolamine (PEG-COOH) was newly synthesized and used to prepare novel immunoliposomes carrying monoclonal antibodies at the distal ends of the PEG chains (Type C). Liposomes were prepared from egg phosphatidylcholine and cholesterol (2 : 1, m/m) containing 6 mol% of PEG-COOH, and a monoclonal antibody, 34A, which is highly specific to pulmonary endothelial cells, was conjugated to the carboxyl groups of PEG-COOH to give various amounts of antibody molecules per liposome. Other immunoliposomes with PEG coating(Type B) or without PEG coating(an earlier type of immunoliposome, Type A) were prepared for comparison. Type B and Type C liposomes without antibodies showed prolonged circulation time and reduced reticulo-endothelial system(RES) uptake owing to the presence of PEG. These three different types of 34A-immunoliposomes with 30-35 antibody molecules per vesicle and 2000 in the average molecular weight of PEG in Type B or C immunoliposomes were injected into mice to test the immuno targetability to the lung. The efficiency of lung binding of Type B-was one half of that of 34A-Type A, though a large amount of Type B remained in the blood circulation for a long time, suggesting that the steric hindrance of PEG chains reduced not only the immunospecific antibody-antigen binding, but also the RES uptake. The degree of lung binding of Type C was about 1. 3-fold higher than that of Type A, indicating that recognition by the antibodies attached to the PEG terminal was not sterically hindered and that the free PEG (i.e., that not carrying antibody) was effective in increasing the blood concentration of immunoliposomes by enabling them to evade RES uptake. It was shown that antibody density is an important factor for target binding of Type C. However, their immunotagetability was not affected by the molecular weight of PEG-COOH. Our approach provides a simple means of conjugating antibodies directly to the distal end of PEG which is already bound to the liposome membrane, and should contribute to the development of superior targetable drug delivery vehicles for use in diagnostics and therapy.
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