BRAIN DRUG-DELIVERY OF SMALL MOLECULES USING IMMUNOLIPOSOMES

Immunoliposomes (antibody-directed liposomes) were used in the present study for delivery of the antineoplastic agent daunomycin to the rat brain, A coupling procedure was Introduced, which allows conjugation o f a thiolated antibody to maleimide-grafted 85-nm liposomes sterically stabilized with PEG, Antibody was thereby coupled to the terminal end of a PEG-conjugated linker lipid, No brain uptake of PEG-conjugated l iposomes carrying [H-3]daunomycin was observed, However, brain targeti ng of immunoliposomes carrying [H-3]daunomycin was mediated by the OX2 6 monoclonal antibody to the rat transferrin receptor, which is select ively enriched at the brain microvascular endothelium that comprises t he blood-brain barrier in vivo. Coupling of 30 OX26 antibodies per lip osome resulted in optimal brain delivery, Saturation of delivery was o bserved at higher antibody densities, Determination of brain levels of immunoliposomes over 24 h revealed that immunoliposomes accumulate in brain tissue, Brain targeting of immunoliposomes was not observed in immunoliposomes conjugated with a mouse IgG(2a) isotype control, In ad dition, coinjection of free OX26 saturated plasma clearance of immunol iposomes. Since a single liposome may carry greater than or equal to 1 0,000 drug molecules, the use of PEG-conjugated immunoliposomes Increa ses the drug carrying capacity of the monoclonal antibody by up to 4 l ogarithmic orders in magnitude, In summary, specific OX26-mediated tar geting of daunomycin to the rat brain was achieved by the use of an im munoliposome-based drug delivery system.