Overcoming drug resistance by cell-penetrating peptide-mediated delivery of a doxorubicin dimer with high DNA-binding affinity
Overcoming drug resistance by cell-penetrating peptide-mediated delivery of a doxorubicin dimer with high DNA-binding affinity
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DOI：
10.1016/j.ejmech.2017.02.056
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发表时间：
2017-04-21
影响因子：
6.7
通讯作者：
Peneva, Kalina
中科院分区：
文献类型：
--
作者：
Lelle, Marco;Freidel, Christoph;Peneva, Kalina
我们描述了一种新的生物结合物的合成和表征，它由一个八精氨酸细胞穿透肽和一个高度DNA仿射的阿霉素二聚体组成。这两个组分之间的连接是由一个可切割的二硫键组成的，它通过谷胱甘肽介导在胞浆的还原环境中有效地在细胞内传递细胞毒性有效载荷。为了确定二聚体药物分子的DNA结合亲和力，采用了微尺度热电泳法。这是第一次利用这种方法来评估蒽环类药物与核酸的结合作用。多肽-药物结合物对药物敏感和阿霉素耐药的癌细胞的细胞毒性作用表明，该生物结合物可以成功地克服神经母细胞瘤细胞的耐药性。(C)2017年爱思唯尔·马森公司。版权所有。
We describe the synthesis and characterization of a novel bioconjugate, consisting of an octaarginine cell-penetrating peptide and a highly DNA-affine doxorubicin dimer. The linkage between the two components is composed of a cleavable disulfide bond, which enables the efficient intracellular delivery of the cytotoxic payload within the reductive environment of the cytosol, mediated through glutathione. To determine the DNA-binding affinity of the dimeric drug molecule, microscale thermophoresis was applied. This is the first utilization of this method to assess the binding interactions of an anthracycline drug with nucleic acids. The cytotoxic effect of the peptide-drug conjugate, studied with drug-sensitive and doxorubicin-resistant cancer cells, demonstrates that the bioconjugate can successfully overcome drug resistance in neuroblastoma cells. (c) 2017 Elsevier Masson SAS. All rights reserved.