Selective targeting of immunoliposomal doxorubicin against human multiple myeloma in vitro and ex vivo.
Circulating malignant CD19(+) B cells have been implicated in the pathogenesis and relapse of multiple myeloma (MM). This study investigated the therapeutic applicability of using long-circulating liposome-encapsulated doxorubicin (DXR) targeted against the internalizing CD19 antigens present on human MM cells. In vitro binding studies using the CD19(+) MM cell line ARH77 demonstrated that CD19-directed immunoliposomes (SIL[anti-CD19]) specifically attached to these cells. Formulations of immunoliposomal doxorubicin (DXR-SIL[anti-CD19]) showed a higher association with, and higher cytotoxicity against, ARH77 cells than did non-targeted liposomal doxorubicin (DXR-SL) or isotype-matched controls (DXR-NSIL[IgG2a]). By using the pH-sensitive fluorophore, 1-hydroxypyrene-3,6, 8-trisulfonic acid, binding of SIL[anti-CD19] to CD19 antigens was shown to trigger receptor-mediated internalization of the antibody-antigen complexes into endosomes. Targeting of SIL[anti-CD19] to CD19(+) B cells was also demonstrated in a heterogeneous mixture of peripheral blood mononuclear cells (PBMC) from MM patients. A decrease in cellular DNA (which is an indicator of apoptosis) caused by the cytotoxicity of DXR-SIL[anti-CD19] to myeloma PBMC was determined by using flow cytometry. While PBMC treatment with free DXR resulted in non-specific cytotoxicity to both B and T cells, DXR-SL were only minimally cytotoxic to either. In contrast, DXR-SIL[anti-CD19] were selectively cytotoxic for B cells in PBMC, indicating that this treatment may be effective in eliminating circulating malignant B cells in MM patients.
Lopes de Menezes
D E
DE
Department of Pharmacology, University of Alberta, Edmonton, Alta., Canada.
Pilarski
L M
LM
Belch
A R
AR
Allen
T M
TM
D000818:Animals; D015703:Antigens, CD / Q000145:classification / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004317:Doxorubicin / Q000494:pharmacology*; D004337:Drug Carriers; D006801:Humans; D016130:Immunophenotyping; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008081:Liposomes; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy*; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000970:Antineoplastic Agents; D004337:Drug Carriers; D008081:Liposomes; D004317:Doxorubicin