Chlorotoxin Fused to IgG-Fc Inhibits Glioblastoma Cell Motility via Receptor-Mediated Endocytosis.
Chlorotoxin Fused to IgG-Fc Inhibits Glioblastoma Cell Motility via Receptor-Mediated Endocytosis.
复制标题
DOI：
10.1155/2012/975763
复制
发表时间：
2012
影响因子：
--
通讯作者：
Seno M
中科院分区：
文献类型：
--
作者：
Kasai T;Nakamura K;Vaidyanath A;Chen L;Sekhar S;El-Ghlban S;Okada M;Mizutani A;Kudoh T;Murakami H;Seno M
Chlorotoxin是一种来源于Leiurus quinquestriatus（蝎子）毒液的36-氨基酸肽，已显示其抑制结肠上皮细胞中的低电导氯离子通道。氯毒素还与胶质瘤细胞表面的基质金属蛋白酶-2和其他蛋白质结合。胶质瘤细胞被认为在侵袭和迁移过程中需要基质金属蛋白酶-2的激活。在这项研究中，针对胶质瘤，我们设计了两种类型的重组chlorotoxin融合到人IgG-Fc与/不铰链区。将与IgG-Fc融合的氯毒素设计为具有铰链区的60 kDa的二聚体和不具有铰链区的30 kDa的单体。氯毒素的单体和二聚体形式在300 nM时抑制细胞增殖，并诱导人脑胶质瘤A172细胞的内化。单体具有比二聚体更大的抑制作用;因此，融合到IgG-Fc的单体氯毒素多价地展示在生物纳米胶囊的表面上，以开发靶向基质金属蛋白酶-2的药物递送系统。在A172细胞中，当氯毒素展示在生物纳米胶囊上时，观察到生物纳米胶囊的靶依赖性内化。本研究表明，融合到IgG-Fc的氯毒素可用于胶质母细胞瘤细胞的主动靶向。
Chlorotoxin is a 36-amino acid peptide derived from Leiurus quinquestriatus (scorpion) venom, which has been shown to inhibit low-conductance chloride channels in colonic epithelial cells. Chlorotoxin also binds to matrix metalloproteinase-2 and other proteins on glioma cell surfaces. Glioma cells are considered to require the activation of matrix metalloproteinase-2 during invasion and migration. In this study, for targeting glioma, we designed two types of recombinant chlorotoxin fused to human IgG-Fcs with/without a hinge region. Chlorotoxin fused to IgG-Fcs was designed as a dimer of 60 kDa with a hinge region and a monomer of 30 kDa without a hinge region. The monomeric and dimeric forms of chlorotoxin inhibited cell proliferation at 300 nM and induced internalization in human glioma A172 cells. The monomer had a greater inhibitory effect than the dimer; therefore, monomeric chlorotoxin fused to IgG-Fc was multivalently displayed on the surface of bionanocapsules to develop a drug delivery system that targeted matrix metalloproteinase-2. The target-dependent internalization of bionanocapsules in A172 cells was observed when chlorotoxin was displayed on the bionanocapsules. This study indicates that chlorotoxin fused to IgG-Fcs could be useful for the active targeting of glioblastoma cells.