In vitro efficacy of a sterically stabilized immunoliposomes targeted to membrane type 1 matrix metalloproteinase (MT1-MMP)
In vitro efficacy of a sterically stabilized immunoliposomes targeted to membrane type 1 matrix metalloproteinase (MT1-MMP)
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DOI：
10.1248/bpb.30.972
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发表时间：
2007-05-01
影响因子：
2
通讯作者：
Kiwada, Hiroshi
中科院分区：
文献类型：
--
作者：
Atobe, Kazutaka;Ishida, Tatsuhiro;Kiwada, Hiroshi
抗癌药物选择性细胞毒性差，导致剂量限制性不良反应，影响临床疗效。实体肿瘤招募新的血管以支持其生长，肿瘤细胞和肿瘤内皮细胞（ECs）上独特表达的表位可作为免疫脂质体抗癌药物的靶点。膜型1基质金属蛋白酶（MT1 - MMP）是一种与肿瘤生长和血管生成相关的重要蛋白质，在恶性肿瘤细胞和活化的内皮细胞上表达。通过靶向MT1 - MMP以及其他血管生成内皮细胞可实现选择性递送。在这方面，一种抗MT1 - MMP Fab'抗体被用于制备一种靶向MT1 - MMP的空间稳定免疫脂质体（SIL[抗MT1 - MMP（Fab'）]）。使用人纤维肉瘤HT - 1080细胞检测了SIL[抗MT1 - MMP（Fab'）]和非靶向空间稳定脂质体（SL）的结合及细胞内分布。SIL[抗MT1 - MMP（Fab'）]以脂质浓度、温度和时间依赖的方式被细胞摄取，最终在溶酶体中积累。含多柔比星（DXR）的SIL[抗MT1 - MMP（Fab'）]（DXR - SIL[抗MT1 - MMP（Fab'）]）的细胞毒性显著高于含DXR的SL。内吞作用抑制剂抑制了SIL[抗MT1 - MMP（Fab'）]的细胞内化，表明其内化是通过网格蛋白或小窝依赖的内吞作用介导的。此外，在人脐静脉内皮细胞（HUVEC）上观察到SIL[抗MT1 - MMP（Fab'）]的有效结合。基于这些结果，预计DXR - SIL[抗MT1 - MMP（Fab'）]在体内可能通过破坏肿瘤内皮实现直接杀伤肿瘤细胞和间接杀伤肿瘤细胞。这种策略可能有潜力克服体内常规化疗的一些主要局限性。
The poor selective cytotoxicity of anticancer drugs lead to dose-limiting adverse effects which compromise the clinical outcome. Solid tumors recruit new blood vessels to support their growth, and epitopes that are uniquely expressed on tumor cells and tumor endothelial cells (ECs) can function as targets for immunoliposomal anticancer drugs. Membrane type 1 matrix metalloproteinase (MT1-MMP), an important protein related to tumor growth and angiogenesis, is expressed on malignant tumor cells and is activated ECs. Selective delivery could be achieved by targeting MT1-MMP, as well as other angiogenic ECs. In this regard, an anti-MT1-MMP Fab' antibody was used to prepare a MT1-MMP targeted sterically stabilized immunoliposomes (SIL[anti-MT1-MMP(Fab')]). The binding and intracellular distribution of S1L[anti-MT1-MMP(Fab')] and a non-targeted sterically stabilized liposomes (SL) were examined using human fibrosarcoma HT-1080 cells. SIL[anti-MT1-MMP(Fab')] was taken up by the cells in a lipid concentration, temperature, and time dependent manner, ultimately accumulating in the lysosomes. The cytotoxicity of doxorubicin (DXR)-containing SIL[anti-MT1-MMP(Fab')] (DXR-SIL[anti-MT1-MMP(Fab')1) was significantly higher than that of DXR-containing SL. The cellular internalization of S1L[anti-MT1-MMP(Fab')I was inhibited by endocytosis inhibitors, suggesting that their internalization was mediated via clathrin- or caveolae-depen dent endocytosis. Furthermore, the efficient binding of S1L[anti-MT1-MMP(Fab')1 was observed on human umbilical vein endothelial cells (HUVEC). Based on these results, it would be expected that DXR-SIL[anti-MT1-MMP(Fab')] may achieve direct tumor cell kill and indirect tumor cell kill via the destruction of the tumor endothelium in vivo. This strategy may have the potential for overcoming some major limitations in conventional chemotherapy in vivo.