title: Comparison of anti-Tac and anti-transferrin receptor-conjugated liposomes for specific drug delivery to adult T-cell leukemia.
abstract: Adult T-cell leukemia (ATL) is a rapidly progressive and usually fatal malignancy of mature T cells characterized by the expression of large numbers of interleukin-2 (IL-2) receptors on the cell surface. Anti-Tac, a monoclonal antibody directed against the IL-2 receptor, was conjugated to liposomes and compared with anti-transferrin receptor (anti-TFR) conjugates for specific binding, internalization, and intracellular drug delivery to ATL cells. Two independent assays were used: a fluorimetric assay with liposome encapsulated 1-hydroxypyrene-3,6,8-trisulfonic acid, a pH-sensitive fluorescent dye, and a growth inhibition assay using methotrexate-gamma-aspartate, a liposome-dependent cytotoxic drug. MT-1 and HUT-102 cell lines derived from patients with ATL were compared with Molt-4, a leukemia cell line that does not express IL-2 receptors in an uninduced state. Fluorimetric studies showed specific binding and internalization of anti-Tac-conjugated liposomes by HUT-102 and MT-1 but not by the Tac-negative cell line Molt-4, demonstrating the lack of nonspecific or Fc receptor-mediated uptake. Anti-TFR-conjugated liposomes were effectively bound and internalized by all three cell lines and consistently showed the highest degree of cellular liposome uptake. Drug-containing liposomes conjugated to anti-Tac were more than tenfold more effective in causing growth inhibition of ATL cells than the nonspecific control conjugates. Anti-Tac conjugates caused minimal growth inhibition of Molt-4 cells over the concentration range effective against the ATL cells. Anti-TFR-coupled liposomes gave better growth inhibition of HUT-102 and MT-1 cells (40- to 60-fold) than anti-Tac conjugates. Both anti-Tac-directed and anti-TFR-directed liposomes are effective for intracellular drug delivery to ATL cells and may represent a useful method of treatment in this disease.
authors.affiliation: Department of Pediatrics, University of California, San Francisco 94143.
authors.forename: K M
authors.initials: KM
authors.lastname: Hege
authors.forename: D L
authors.initials: DL
authors.lastname: Daleke
authors.forename: T A
authors.initials: TA
authors.lastname: Waldmann
authors.forename: K K
authors.initials: KK
authors.lastname: Matthay
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D004705:Endocytosis; D005455:Fluorescent Antibody Technique; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D008081:Liposomes / Q000008:administration & dosage*; D008856:Microscopy, Fluorescence; D015375:Receptors, Interleukin-2 / Q000276:immunology* / Q000502:physiology; D011990:Receptors, Transferrin / Q000276:immunology* / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D008081:Liposomes; D015375:Receptors, Interleukin-2; D011990:Receptors, Transferrin