Targeting of daunomycin using biotinylated immunoliposomes: pharmacokinetics, tissue distribution and in vitro pharmacological effects.
Biotinylated immunoliposomes were prepared by a non-covalent (biotin-streptavidin) coupling procedure and conjugated to the OX26 monoclonal antibody directed against the rat transferrin receptor. In vitro, these biotinylated immunoliposomes were used to by-pass P-glycoprotein in multidrug-resistant RBE4 brain capillary endothelial cells and thereby to achieve 2- to 3-fold higher intracellular accumulation of liposomal daunomycin as compared to free drug. The extent of cellular uptake of liposomal daunomycin was dose- and time-dependent, was inhibited by competition with unbound OX26 and was associated with a pharmacological (i.e. cytotoxic) effect. Cytotoxic effects of liposomal formulations of daunomycin, in contrast to the free drug, were apparent only after prolonged incubation periods being indicative of a slow intracellular unpacking and release of liposomal daunomycin. Pharmacokinetics and tissue distribution studies in the rat revealed brain accumulation of daunomycin in OX26-immunoliposomes to higher levels as compared to brain uptake of free daunomycin, or daunomycin incorporated within pegylated liposomes or within unspecific IgG(2a) isotype control immunoliposomes. Such OX26-mediated effects were not observed in other tissues such as spleen, liver, muscle or kidney.
Schnyder
Anita
A
University Hospital Basel, Department of Research and Division of Clinical Pharmacology, CH-4031, Basel, Switzerland.
Krähenbühl
Stephan
S
Drewe
Jürgen
J
Huwyler
Jörg
J
D000465:Algorithms; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001710:Biotin; D002478:Cells, Cultured; D003630:Daunorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D016503:Drug Delivery Systems; D007120:Immunochemistry; D007074:Immunoglobulin G / Q000276:immunology; D008081:Liposomes; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012235:Rhodamines / Q000633:toxicity; D014018:Tissue Distribution
D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D007074:Immunoglobulin G; D008081:Liposomes; D012235:Rhodamines; C022027:lissamine rhodamine B; D001710:Biotin; D003630:Daunorubicin