Characterization of organ-specific immunoliposomes for delivery of 3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine in a mouse lung-metastasis model.
A previous study has shown that lipophilic prodrugs can be delivered efficiently to normal lung endothelium by incorporation into liposomes covalently conjugated to monoclonal antibody (mAb) 34A against the lung endothelial anticoagulant protein thrombomodulin. In the present study, the potential use of these lung-targeted immunoliposomes (34A-liposomes) for delivery of a lipophilic prodrug, 3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine (dpFUdR), to the tumor-bearing lung was examined using BALB/c mice bearing experimental lung metastasis induced by i.v. injection of EMT-6 mouse mammary tumor cells. Immunohistochemical examination of the tumor-bearing lung showed specificity of mAb 34A to lung endothelium. Tumor cells appeared to localize just outside of the normal blood vessels and were within a small diffusion distance from the mAb 34A-binding sites. 111In-labeled 34A-liposomes containing monosialoganglioside (GM1) were prepared that included [3H]-dpFUdR at 3.0 mol% in the lipid mixture. In vitro cell binding studies further demonstrated that 34A-liposomes bound specifically to normal mouse lung cells that expressed thrombomodulin but not to EMT-6 cells. Biodistribution study showed efficient and immunospecific accumulation of [3H]-dpFUdR incorporated into 34A-liposomes in the lung at a level parallel with that of 111In-labeled 34A-liposomes, indicating that the drug is delivered to the target organ in intact liposomes. Liposomal dpFUdR appeared to be metabolized in the lung to the parent drug FUdR at a rate slower than in the liver and spleen. Furthermore, treatment of lung-metastasis-bearing mice with dpFUdR incorporated into 34A-liposomes on days 1 and 3 after tumor cell injection resulted in a significant increase in the median survival time of treated mice as compared with control mice (%T/C value, 165%). dpFUdR either dispersed in emulsion or incorporated into antibody-free liposomes was ineffective in prolonging the survival of mice. These results indicate the potential effectiveness of organ-specific immunoliposomes containing a lipophilic prodrug for the targeted therapy of metastatic tumors.
Mori
A
A
Department of Pharmacology, University of Pittsburgh School of Medicine, PA 15261.
Kennel
S J
SJ
van Borssum Waalkes
M
M
Scherphof
G L
GL
Huang
L
L
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001666:Binding Sites, Antibody; D004195:Disease Models, Animal; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D007150:Immunohistochemistry; D008081:Liposomes; D008168:Lung / Q000276:immunology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D015674:Mammary Neoplasms, Animal / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011355:Prodrugs / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D011355:Prodrugs; D005467:Floxuridine; C044351:3',5'-O-dipalmitoyl-5-fluoro-2'-deoxyuridine