pH-sensitive immunoliposomes as an efficient and target-specific carrier for antitumor drugs.

pH-sensitive immunoliposomes composed of dioleoylphosphatidyl-ethanolamine and oleic acid (8:2) significantly enhanced the cytotoxic effect of the entrapped drug 1-beta-D-arabinofuranosylcytosine (ara-C) to target L-929 cells, as compared to free drug, drug encapsulated in antibody-free liposomes, or in pH-insensitive immunoliposomes. These pH-sensitive immunoliposomes were ineffective against nontarget A-31 cells. The enhanced cytotoxic effect could be blocked by excess free antibody or excess drug-free immunoliposomes. Pretreatment of target cells with the weak bases chloroquine or NH4Cl, which raise the internal pH of cellular acidic organelles such as endosomes and lysosomes, inhibited the cell killing activity of ara-C encapsulated in the pH-sensitive immunoliposomes. Since it is known that ara-C is rapidly inactivated in the lysosomes, our results suggest that the release of ara-C from the pH-sensitive immunoliposomes occurs in a prelysosomal compartment, i.e., the endosome. Parallel experiments using methotrexate as a cytotoxic drug confirm the enhanced ability of the pH-sensitive liposomes for cytoplasmic drug delivery over that of free drug. These results indicate that pH-sensitive immunoliposomes can be used as an efficient and target-specific carrier for antitumor drugs.