Inhibition of cell proliferation with antibody-targeted liposomes containing methotrexate-gamma-dimyristoylphosphatidylethanolamine.
We have prepared liposomes containing methotrexate-gamma-dimyristoylphosphatidylethanolamine (MTX-DMPE liposomes), to which protein A was covalently coupled, permitting specific association of these liposomes in vitro with murine cells preincubated with relevant protein A-binding monoclonal antibodies. In the absence of antibody the presence of externally-oriented methotrexate (MTX) in MTX-DMPE liposomes did not result in greater binding to cells than liposomes made without MTX-gamma-DMPE. Derivation of methotrexate with phospholipid permits enhanced drug-liposome association. These liposomes are more resistant than conventional liposomes to repeated cycles of freezing and thawing. MTX-DMPE liposomes are comparable to antibody-targeted liposomes made with encapsulated water-soluble methotrexate both with respect to specific binding to target cells and drug effect. The inhibitory effects of MTX-liposomes, as well as free MTX, were reversible by either thiamin pyrophosphate (Tpp) or N5-formyltetrahydrofolate (F-THF), while the effects of MTX-DMPE liposomes were reversed only by N5-formyltetrahydrofolate. This suggests that the toxicity of non-targeted MTX-liposomes may be due to leakage of the encapsulated MTX. The absence of an effect of thiamin pyrophosphate on non-targeted MTX-DMPE liposomes indicates that they do not enter into the cell via the normal folate transport system.
Noé
C
C
Centre d'Immunologie INSERM-CNRS de Marseille-Luminy, France.
Hernandez-Borrell
J
J
Kinsky
S C
SC
Matsuura
E
E
Leserman
L
L
D000643:Ammonium Chloride / Q000008:administration & dosage; D000911:Antibodies, Monoclonal; D002455:Cell Division / Q000187:drug effects; D004337:Drug Carriers; D005434:Flow Cytometry; D005615:Freezing; D008081:Liposomes / Q000008:administration & dosage*; D008213:Lymphocyte Activation / Q000187:drug effects; D008727:Methotrexate / Q000008:administration & dosage*; D010714:Phosphatidylethanolamines; D011355:Prodrugs / Q000008:administration & dosage*; D013205:Staphylococcal Protein A
D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D008081:Liposomes; D010714:Phosphatidylethanolamines; D011355:Prodrugs; D013205:Staphylococcal Protein A; D000643:Ammonium Chloride; D008727:Methotrexate; C018525:1,2-dimyristoylphosphatidylethanolamine