Immunotargeting of liposomes containing lipophilic antitumor prodrugs.
Potential therapeutic applications of recently developed liposomes with a reduced affinity to the reticuloendothelial systems and a prolonged circulation time as targeting systems for lipophilic prodrugs were examined. In these studies, liposomes composed of phosphatidylcholine and cholesterol, additionally containing monosialoganglioside (GM1) or polyethylene glycol conjugated to phosphatidylethanolamine (PEG-PE), were used. Three antitumor lipophilic prodrugs, N-trifluoroacetyl-adriamycin-14-valerate (AD32), araC-diphosphate-diglyceride (araCdPdG), and 3',5'-o-dipalmitoyl-5-fluoro-2'-deoxyuridine (dpFUdR), were used to examine the effect of lipophilic prodrug incorporation into long-circulating liposomes and immunoliposomes on their biodistribution in mouse. Biodistribution studies with antibody-free liposomes containing lipophilic prodrugs showed that the activities of GM1 or PEG2000-PE in prolonging the circulation time of liposomes appeared to be preserved in the presence of each of the three lipophilic prodrugs at a drug/lipid molar ratio of 3:97. The effect of lipophilic prodrug incorporation on target binding of immunoliposomes was then examined using a mouse model. Incorporation of AD232 or dpFUdR into immunoliposomes, directed to the normal endothelium, did not affect the targetability of immunoliposomes, suggesting a potential effectiveness of these lipophilic prodrug-containing immunoliposomes in therapy for lung tumors. On the contrary, incorporation of araCdPdG resulted in significantly reduced target binding of immunoliposomes by yet unknown mechanism(s).
Mori
A
A
Department of Pharmacology, University of Pittsburgh School of Medicine, Pennsylvania 15261.
Kennel
S J
SJ
Huang
L
L
D000818:Animals; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001665:Binding Sites; D002784:Cholesterol / Q000737:chemistry; D003561:Cytarabine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D003567:Cytidine Diphosphate Diglycerides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers; D005467:Floxuridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D005732:Gangliosides / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010713:Phosphatidylcholines / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry; D013499:Surface Properties
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D003567:Cytidine Diphosphate Diglycerides; D004337:Drug Carriers; D005732:Gangliosides; D008081:Liposomes; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D011355:Prodrugs; C081046:araC-diphosphate diglyceride; C025447:sialogangliosides; D005467:Floxuridine; D003561:Cytarabine; C067972:dioleoyl-N-(monomethoxypolyethylene glycol succinyl)phosphatidylethanolamine; C016163:valrubicin; D011092:Polyethylene Glycols; C044351:3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine; D004317:Doxorubicin; D002784:Cholesterol