Selective targeting of immunoliposomal doxorubicin against human multiple myeloma in vitro and ex vivo

被引:0
作者
de Menezes, DEL
Pilarski, LM
Belch, AR
Allen, TM
机构
[1] Univ Alberta, Dept Pharmacol, Edmonton, AB T6G 2H7, Canada
[2] Univ Alberta, Cross Canc Inst, Dept Oncol, Edmonton, AB T6G 1Z2, Canada
来源
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES | 2000年 / 1466卷 / 1-2期
关键词
liposome; CD19; doxorubicin; targeted drug delivery; multiple myeloma;
D O I
暂无
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2000 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:205 / 220
页数:16
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