Cross-Linking of Thiolated Paclitaxel-Oligo(p-phenylene vinylene) Conjugates Aggregates inside Tumor Cells Leads to "Chemical Locks" That Increase Drug Efficacy
Cross-Linking of Thiolated Paclitaxel-Oligo(p-phenylene vinylene) Conjugates Aggregates inside Tumor Cells Leads to "Chemical Locks" That Increase Drug Efficacy
复制标题
肿瘤细胞内硫醇化紫杉醇-寡聚体（对亚苯基亚乙烯基）结合物的交联形成“化学锁”，从而提高药效
DOI：
10.1002/adma.201704888
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发表时间：
2018
影响因子：
29.4
通讯作者：
Wang Shu
中科院分区：
文献类型：
--
作者：
Zhou Lingyun;Lv Fengting;Liu Libing;Shen Guizhi;Yan Xuehai;Bazan Guillermo C.;Wang Shu
如何降低某些肿瘤细胞对紫杉醇(PTX)及相关紫杉醇类抗癌药物的耐药性是提高治愈率的主要挑战。由此设计了一种含硫醇基团的低聚对苯乙炔单元和一种能提高药物疗效和逆转耐药性的PTX单元(OPV-S-PTX)。其机制涉及OPV-S-PTX在细胞内的扩散，在那里π-π相互作用导致聚集。在肿瘤细胞中，由于较高的活性氧物种(ROS)浓度，通过硫醇基团的氧化使聚集体发生交联是很受欢迎的。交联的聚集体以化学方式“锁定”多个发色团粒子，以获得更持久的效果。OPV-S-PTX对肿瘤细胞株A549的IC50由PTX本身的41×10−9M降至0.33×10−9M。OPV-S-PTX的增效作用可能是通过加速微管束的形成而实现的。接种A549/T的异种移植小鼠实验显示，OPV-S-PTX治疗对肿瘤生长有抑制作用。总之，这些结果表明，OPV-S-PTX通过ROS的内部交联为区分肿瘤和健康细胞提供了一种手段，化学锁定颗粒的形成提高了药物疗效并有助于降低耐药性。
How to reduce the resistance of certain tumor cells to paclitaxel (PTX) and related taxoid anticancer drugs is a major challenge for improving cure rates. An oligo(p‐phenylenevinylene) unit with thiol groups and a PTX unit (OPV‐S‐PTX), which enhances drug efficacy and reverses resistance is thus designed. The mechanism involves diffusion of OPV‐S‐PTX into the cell, where π–π interactions lead to aggregation. Cross‐linking of the aggregates via oxidation of thiol groups is favored in tumor cells because of the higher reactive oxygen species (ROS) concentration. Cross‐linked aggregates “chemically lock” the multichromophore particle for a more persistent effect. The IC50of OPV‐S‐PTX for tumor cell line A549 is reduced down to 0.33 × 10−9mfrom that observed for PTX itself (41 × 10−9m). Enhanced efficacy by OPV‐S‐PTX is proposed to proceed via acceleration of microtubule bundle formation. A549/T‐inoculated xenograft mice experiments reveal suppression of tumor growth upon OPV‐S‐PTX treatment. Altogether, these results show that the internal cross‐linking of OPV‐S‐PTX through ROS provides a means to discriminate between tumor and healthy cells and the formation of the chemically locked particles enhances drug efficacy and helps in reducing resistance.