A human anti-c-Met Fab fragment conjugated with doxorubicin as targeted chemotherapy for hepatocellular carcinoma.
A human anti-c-Met Fab fragment conjugated with doxorubicin as targeted chemotherapy for hepatocellular carcinoma.
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与阿霉素缀合的人抗 c-Met Fab 片段作为肝细胞癌的靶向化疗
DOI：
10.1371/journal.pone.0063093
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Zhu J
中科院分区：
文献类型：
--
作者：
Chen X;Ding G;Gao Q;Sun J;Zhang Q;Du L;Qiu Z;Wang C;Zheng F;Sun B;Ni J;Feng Z;Zhu J
c-Met 在肝细胞癌 (HCC) 中过度表达，但在正常组织中不存在或表达水平较低。因此，我们生成了一种新型人抗 c-Met Fab 片段 (MetFab) 与阿霉素 (DOX) 的缀合物，并评估其是否具有针对 HCC 的靶向抗肿瘤活性并减少 DOX 的副作用。从人噬菌体库中筛选MetFab，通过化学合成与DOX缀合，并通过HPLC确认MetFab-DOX的缀合。评估了 MetFab-DOX 的药物释放模式、结合功效和细胞分布。 MetFab-DOX在pH7.2 PBS下稳定，而在pH4.0下快速释放阿霉素，MetFab-DOX的结合功效与MetFab相似，并且MetFab-DOX的细胞分布与游离DOX不同。通过MTT法和裸鼠HCC模型分析MetFab-DOX的细胞毒性。 MetFab-DOX 对表达 c-Met 的肿瘤细胞表现出细胞毒性作用，但对不表达 c-Met 的细胞没有细胞毒性作用。 MetFab-DOX在小鼠模型中发挥抗肿瘤作用，并显着降低游离DOX的副作用。此外，分别通过肿瘤组织切片的免疫荧光染色和光学肿瘤成像证实了缀合物的定位，并通过分光荧光计比较了游离 DOX 和 MetFab-DOX 治疗之间药物的组织分布。 MetFab-DOX可以定位于肿瘤组织，并且施用MetFab-DOX后肿瘤中阿霉素的浓度比施用DOX后更高。综上所述，MetFab-DOX能够有效靶向表达c-Met的HCC细胞，在HCC临床前模型中具有明显的抗肿瘤活性，且副作用减少。
c-Met is over-expressed in hepatocellular carcinoma(HCC) but is absent or expressed at low levels in normal tissues. Therefore we generated a novel conjugate of a human anti-c-Met Fab fragment (MetFab) with doxorubicin (DOX) and assessed whether it had targeted antitumor activity against HCC and reduced the side-effects of DOX. The MetFab was screened from human phage library, conjugated with DOX via chemical synthesis, and the conjugation MetFab-DOX was confirmed by HPLC. The drug release patterns, the binding efficacy, and cellular distribution of MetFab-DOX were assessed. MetFab-DOX was stable at pH7.2 PBS while release doxorubicin quickly at pH4.0, the binding efficacy of MetFab-DOX was similarly as MetFab, and the cellular distribution of the MetFab-DOX is distinct from free DOX. The cytotoxicity of MetFab-DOX was analyzed by the MTT method and the nude mouse HCC model. The MetFab-DOX demonstrated cytotoxic effects on c-Met expressing-tumor cells, but not on the cells without c-Met expression. MetFab-DOX exerted anti-tumor effect and significantly reduced the side effect of free DOX in mice model. Furthermore, the localization of conjugate was confirmed by immunofluorescence staining of tumor tissue sections and optical tumor imaging, respectively, and the tissue-distribution of drug was compared between free DOX and MetFab-DOX treatment by spectrofluorometer. MetFab-DOX can localize to the tumor tissue, and the concentration of doxorubicin in the tumor was higher after MetFab-DOX administration than after DOX administration. In summary, MetFab-DOX can target c-Met expressing HCC cells effectively and have obvious antitumor activity with decreased side-effects in preclinical models of HCC.
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影响因子：
3.7
作者：
Huan M;Zhang B;Teng Z;Cui H;Wang J;Liu X;Xia H;Zhou S;Mei Q
通讯作者：
Mei Q
影响因子：
3.2
作者：
Huang, Yu-Fen;Shangguan, Dihua;Liu, Haipeng;Phillips, Joseph A.;Zhang, Xiaoling;Chen, Yan;Tan, Weihong
通讯作者：
Tan, Weihong
影响因子：
--
作者：
Ayla S;Seckin I;Tanriverdi G;Cengiz M;Eser M;Soner BC;Oktem G
通讯作者：
Oktem G
影响因子：
11.5
作者：
Hay, RV;Cao, B;Vande Woude, GF
通讯作者：
Vande Woude, GF
影响因子：
2.6
作者：
Liao, YJ;Zhao, P;Cao, B
通讯作者：
Cao, B