Cellular association and cytotoxicity of anti-CD74-targeted lipid drug-carriers in B lymphoma cells.
The ability to selectively target anti-cancer drugs via specific ligands against antigens expressed on malignant cells could greatly improve the therapeutic indices of the drugs. In this paper an anti-CD74 antibody (Ab), LL1, was covalently attached to the surface of sterically stabilized lipid drug-carriers (emulsions and liposomes) by use of a PEG-based heterobifunctional coupling agent. Target cells internalize LL1 very fast and that was found to be true for the LL1-lipid drug-carrier complexes as well. During a 24 h in vitro incubation with the target Raji B-lymphoma cells about 30% of the added complexes were associated with the cells. The corresponding value for drug-carrier without targeting ligand was near 0.6%. Displacement experiments showed that free LL1 competed well with LL1-complexes indicating preserved immunoreactivity. Non-target cells showed only unspecific association of LL1-complexes. A dioleoylated derivative of the anti-cancer drug 3',5'-O-dioleoyl-FUdR (FUdR) (FUdR-dO) loaded into LL1-lipid drug-carriers showed good cytotoxic activity. In vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cytotoxicity tests against neoplastic B-cells gave IC30 values of 0.45, 1.25, 5.30 and 7.30 microM for the prodrug FUdR-dO in LL1-emulsions, LL1-liposomes, emulsions and liposomes, respectively. The value for the parent drug FUdR was calculated to 4.35 microM. In the light of the extensive and specific delivery of LL1-lipid drug-carriers to B-cells and the selective cytotoxicity of the incorporated drug, we infer that the complexes may be useful in the selective elimination of circulating malignant B-cells in vivo.
Lundberg
Bo B
BB
Department of Biochemistry and Pharmacy, Abo Akademi University, BioCity, PO Box 66, FIN-20521, Abo, Finland. bolundbe@abo.fi
Griffiths
Gary
G
Hansen
Hans J
HJ
D000912:Antibodies, Neoplasm / Q000008:administration & dosage* / Q000633:toxicity; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D002051:Burkitt Lymphoma / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage / Q000633:toxicity; D016503:Drug Delivery Systems / Q000379:methods*; D018922:HL-60 Cells; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D008055:Lipids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016393:Lymphoma, B-Cell / Q000188:drug therapy*
D000912:Antibodies, Neoplasm; D000944:Antigens, Differentiation, B-Lymphocyte; D004337:Drug Carriers; D000949:Histocompatibility Antigens Class II; D008055:Lipids; C045084:invariant chain