Synthesis, Characterization, and Evaluation of Near-IR Boron Dipyrromethene Bioconjugates for Labeling of Adenocarcinomas by Selectively Targeting the Epidermal Growth Factor Receptor
Synthesis, Characterization, and Evaluation of Near-IR Boron Dipyrromethene Bioconjugates for Labeling of Adenocarcinomas by Selectively Targeting the Epidermal Growth Factor Receptor
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DOI：
10.1021/acs.jmedchem.8b01746
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发表时间：
2019-04-11
影响因子：
7.3
通讯作者：
Vicente, M. Graca H.
中科院分区：
文献类型：
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作者：
Kaufman, Nichole E. M.;Meng, Qianli;Vicente, M. Graca H.
合成了一系列含有表皮生长因子受体（EGFR）靶向的聚乙二醇化LARLLT肽和/或葡萄糖或生物素乙二胺基团的五种硼二吡咯亚甲基（BODIPY）生物缀合物，并使用分子建模、表面等离子体共振、荧光显微镜、竞争性结合测定和动物研究来研究新缀合物与EGFR胞外结构域的结合能力。发现具有LARLLT肽的BODIPY缀合物与EGFR特异性结合，而缺乏肽的那些缀合物弱且非特异性地结合。所有BODIPY结合物在HT-29细胞中显示出低的细胞毒性（IC 50> 94 μ M），无论是在黑暗中还是在光激活（1.5 J/cm（2））时。对携带皮下人HT-29异种移植物的裸鼠的研究显示，仅携带LARLLT肽的BODIPY缀合物在静脉内施用后24小时显示肿瘤定位。我们的研究结果表明，携带EGFR靶向肽3 PEG-LARLLT的BODIPY生物缀合物显示出作为过表达EGFR的结肠癌的近红外荧光成像剂的前景。
A series of five boron dipyrromethene (BODIPY) bioconjugates containing an epidermal growth factor receptor (EGFR)-targeted pegylated LARLLT peptide and/or a glucose or biotin ethylene diamine group were synthesized, and the binding capability of the new conjugates to the extracellular domain of EGFR was investigated using molecular modeling, surface plasmon resonance, fluorescence microscopy, competitive binding assays, and animal studies. The BODIPY conjugates with a LARLLT peptide were found to bind specifically to EGFR, whereas those lacking the peptide bound weakly and nonspecifically. All BODIPY conjugates showed low cytotoxicity (IC50 > 94 mu M) in HT-29 cells, both in the dark and upon light activation (1.5 J/cm(2)). Studies of nude mice bearing subcutaneous human HT-29 xenografts revealed that only BODIPY conjugates bearing the LARLLT peptide showed tumor localization 24 h after intravenous administration. The results of our studies demonstrate that BODIPY bioconjugates bearing the EGFR-targeting peptide 3PEG-LARLLT show promise as near-IR fluorescent imaging agents for colon cancers overexpressing EGFR.