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pH-sensitive Immunoliposomes as an Efficient and Target-specific Carrier for Antitumor Drugs¹

Department of Biochemistry, University of Tennessee, Knoxville, Tennessee 37996-0840

pH-sensitive immunoliposomes composed of dioleoylphosphatidylethanolamine and oleic acid (8:2) significantly enhanced the cytotoxic effect of the entrapped drug 1-ß-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.

¹ Supported by NIH Grant CA 24553.

² Research Career Development Awardee (CA 00718). To whom requests for reprints should be addressed.

Received 11/ 4/85. Revised 1/29/86. Accepted 4/ 7/86.

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