In vitro drug delivery mediated by ecto-NAD+-glycohydrolase ligand-targeted liposomes.
We have studied the growth-inhibitory potency of methotrexate and methotrexate-gamma-aspartate encapsulated in liposomes conjugated to ligands of ecto-NAD+-glycohydrolase (Salord, J. et al., Biochim. Biophys. Acta 886 (1986) 64-75). The ability of targeted liposomes to enhance growth inhibition, which amounted to a 4-fold reduction of the drug concentration required to inhibit cell growth by 50% as compared to nontargeted liposomes, was observed only with cells expressing this ecto-enzyme activity, i.e., Swiss 3T3 fibroblasts and RAJI, a Burkitt-type lymphoma cell line. Delivery of the encapsulated drugs was inhibited by NH4Cl and varied with the endocytic capacity of the cells. Only small unilamellar vesicles affected the growth of the lymphoma cells, whereas the fibroblasts were more sensitive to large unilamellar vesicles. With vesicles of appropriate size, there was a good correlation between the specific binding of the targeted liposomes to cells and drug delivery. Our results suggest that ecto-NAD+-glycohydrolase can provide a recognition site on target cells and mediate the internalization of targeted liposomes by a mechanism most probably related to adsorptive endocytosis.
Salord
J
J
Laboratoire de Chimie Enzymatique (CNRS UA 1182), Université Louis Pasteur, Strasbourg, France.
Schuber
F
F
D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents; D002051:Burkitt Lymphoma / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003857:Deoxyuridine / Q000378:metabolism; D004337:Drug Carriers; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D007700:Kinetics; D008081:Liposomes; D008727:Methotrexate / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D009699:N-Glycosyl Hydrolases / Q000378:metabolism*; D009243:NAD / Q000031:analogs & derivatives* / Q000378:metabolism; D009244:NAD+ Nucleosidase; D013438:Sulfhydryl Compounds; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D013438:Sulfhydryl Compounds; D000643:Ammonium Chloride; D009243:NAD; C048482:3,4-dimethylpyridine adenine dinucleotide; C037394:methotrexate-gamma-aspartate; D009699:N-Glycosyl Hydrolases; D009244:NAD+ Nucleosidase; D003857:Deoxyuridine; D008727:Methotrexate