Design of a doxorubicin-peptidomimetic conjugate that targets HER2-positive cancer cells.
Design of a doxorubicin-peptidomimetic conjugate that targets HER2-positive cancer cells.
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DOI：
10.1016/j.ejmech.2016.10.015
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发表时间：
2017-01-05
影响因子：
6.7
通讯作者：
Jois, Seetharama D.
中科院分区：
文献类型：
--
作者：
Pallerla, Sandeep;Gauthier, Ted;Sable, Rushikesh;Jois, Seetharama D.
阿霉素（DOX）属于蒽环类药物，用于治疗各种癌症。它在治疗剂量下具有有限的膀胱抑制作用，但较高剂量可引起心脏毒性。在当前的方法中，我们将已知与HER2蛋白结合的肽模拟物（Arg-氨基萘基丙酸-Phe，化合物5）通过葡聚糖酐接头缀合至DOX。抗增殖测定表明，DOX-拟肽缀合物在较低微摩尔范围内具有活性。该缀合物在HER2过表达的细胞中表现出比在不过表达HER2蛋白的MCF-7和MCF-10A细胞中更高的毒性。使用共聚焦显微镜实验进行的细胞摄取研究显示，与MCF-7细胞中的缀合物相比，缀合物结合至HER2过表达的细胞，并且DOX在4小时内被摄取到细胞中。使用表面等离子体共振的结合研究表明，与单独的化合物5或DOX相比，缀合物以高亲和力结合至HER2胞外结构域。偶联物在细胞存在下稳定，在人血清中的半衰期接近4 h和1 h。DOX在4小时内从缀合物中释放并内化到细胞中，引起细胞毒性。这些结果表明，该缀合物可用于将DOX靶向HER2过表达细胞，并且可提高DOX对HER2阳性癌症的治疗指数。
Doxorubicin (DOX) belongs to the anthracycline class of drugs that are used in the treatment of various cancers. It has limited cystostatic effects in therapeutic doses, but higher doses can cause cardiotoxicity. In the current approach, we conjugated a peptidomimetic (Arg-aminonaphthylpropionic acid-Phe, compound 5) known to bind to HER2 protein to DOX via a glutaric anhydride linker. Antiproliferative assays suggest that the DOX-peptidomimetic conjugate has activity in the lower micromolar range. The conjugate exhibited higher toxicity in HER2-overexpressed cells than in MCF-7 and MCF-10A cells that do not overexpress HER2 protein. Cellular uptake studies using confocal microscope experiments showed that the conjugate binds to HER2-overexpressed cells and DOX is taken up into the cells in 4 h compared to conjugate in MCF-7 cells. Binding studies using surface plasmon resonance indicated that the conjugate binds to the HER2 extracellular domain with high affinity compared to compound 5 or DOX alone. The conjugate was stable in the presence of cells with a half-life of nearly 4 h and 1 h in human serum. DOX is released from the conjugate and internalized into the cells in 4 h, causing cellular toxicity. These results suggest that this conjugate can be used to target DOX to HER2-overexpressing cells and can improve the therapeutic index of DOX for HER2-positive cancer.
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影响因子：
11.5
作者：
Esserman, Laura J.;DeMichele, Angela
通讯作者：
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