HPMA copolymer-bound doxorubicin targeted to tumor-specific antigen of BCL1 mouse B cell leukemia
HPMA copolymer-bound doxorubicin targeted to tumor-specific antigen of BCL1 mouse B cell leukemia
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DOI：
10.1016/s0168-3659(03)00340-7
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发表时间：
2003-10-30
影响因子：
10.8
通讯作者：
Ríhová, B
中科院分区：
文献类型：
--
作者：
Kovár, M;Mrkvan, T;Ríhová, B
合成了含抗癌药物阿霉素的N-（2-羟丙基）甲基丙烯酰胺（HPMA）共聚物载体，并将B I单克隆抗体（mAb）靶向于BCL 1白血病细胞。选择在同系Balb/c小鼠中生长的BCL 1白血病作为肿瘤模型系统。识别BCL 1细胞表面IgM独特型的B I mAb用作靶向部分。通过Gly-Phe（D，L）-Leu-Gly四肽间隔区的氨解将B1 mAb和阿霉素偶联到HPMA共聚物载体上，以确保药物的细胞内递送和控制释放。B1 mAb靶向偶联物在体外显示出对靶向BCL 1细胞具有严格的肿瘤特异性结合能力。类似的缀合物，但含有人非特异性IG（Hulg）而不是B1 mAb，不能与BCL 1细胞结合。在体外，B1 mAb靶向结合物的细胞毒作用比非靶向或含人非特异性Ig的HPMA共聚物结合阿霉素高40倍。B1 mAb靶向偶联物也显示在体内与靶BCL 1细胞结合。B1 mAb靶向偶联物在治疗已建立的BCL 1白血病方面比游离阿霉素、非靶向偶联物和含人非特异性Ig的偶联物更有效。因此，抗体靶向聚合物药物是用于癌症治疗的有前景的缀合物。(C)2003 Elsevier B. V.保留所有权利。
N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer carrier containing the anticancer drug doxorubicin and targeted with B I monoclonal antibody (mAb) to BCL1 leukemia cells was synthesised and tested in vitro and in vivo. BCL1 leukemia growing in syngenic Balb/c mice was selected as a tumor model system. B I mAb recognising the idiotype of surface IgM on BCL1 cells was used as a targeting moiety. Both B1 mAb and doxorubicin were conjugated to HPMA copolymer carrier by aminolysis through a tetrapeptidic Gly-Phe(D,L)-Leu-Gly spacer to ensure the intracellular delivery and controlled release of the drug. B1 mAb-targeted conjugate was shown to possess strictly tumor-specific binding capacity to target BCL1 cells in vitro. A similar conjugate, but containing human nonspecific Ig (Hulg) instead of B1 mAb, failed to bind to BCL1 cells. In vitro, B1 mAb-targeted conjugate demonstrated 40-fold higher cytotoxic effect than nontargeted or human nonspecific Ig-containing HPMA copolymer-bound doxorubicin. Conjugate targeted with B1 mAb was also shown to bind to target BCL1 cells in vivo. B1 mAb-targeted conjugate was shown to be more efficient in the treatment of established BCL1 leukemia than free doxorubicin, nontargeted and human nonspecific Ig-containing conjugate. Antibody-targeted polymeric drugs are thus promising conjugates for cancer treatment. (C) 2003 Elsevier B.V. All rights reserved.