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Cross‐Linking of Thiolated Paclitaxel–Oligo(p‐phenylene vinylene) Conjugates Aggregates inside Tumor Cells Leads to “Chemical Locks” That Increase Drug Efficacy
Advanced Materials ( IF 27.4 ) Pub Date : 2018-01-17 , DOI: 10.1002/adma.201704888 Lingyun Zhou 1, 2 , Fengting Lv 1, 2 , Libing Liu 1, 2 , Guizhi Shen 3 , Xuehai Yan 3 , Guillermo C. Bazan 4 , Shu Wang 1, 2
Advanced Materials ( IF 27.4 ) Pub Date : 2018-01-17 , DOI: 10.1002/adma.201704888 Lingyun Zhou 1, 2 , Fengting Lv 1, 2 , Libing Liu 1, 2 , Guizhi Shen 3 , Xuehai Yan 3 , Guillermo C. Bazan 4 , Shu Wang 1, 2
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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 IC50 of OPV‐S‐PTX for tumor cell line A549 is reduced down to 0.33 × 10−9m from 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.
中文翻译：
硫代紫杉醇-寡聚（对亚苯基亚乙烯基）的交联会聚集肿瘤细胞内的聚集物，从而导致“化学锁”，从而提高药物功效
如何降低某些肿瘤细胞对紫杉醇（PTX）和相关紫杉类抗癌药物的耐药性是提高治愈率的主要挑战。因此，设计了具有巯基的寡聚（对-亚苯基亚乙烯基）单元和增强药物功效并逆转耐药性的PTX（OPV-S-PTX）单元。该机制涉及OPV-S-PTX扩散到细胞中，其中π-π相互作用导致聚集。由于较高的活性氧（ROS）浓度，在肿瘤细胞中聚集体通过硫醇基团的氧化交联是有利的。交联的聚集体可“化学锁定”多发色团颗粒，从而产生更持久的效果。肿瘤细胞系A549的OPV‐S‐PTX的IC 50降低至0.33×10 -9 m与PTX本身的观测值相比（41×10 -9 m）。建议通过加速微管束的形成来提高OPV‐S‐PTX的功效。A549 / T接种的异种移植小鼠实验显示，OPV-S-PTX处理可抑制肿瘤生长。总而言之，这些结果表明，OPV-S-PTX通过ROS的内部交联提供了一种区分肿瘤细胞与健康细胞的方法，化学锁定颗粒的形成增强了药物功效并有助于降低耐药性。
更新日期：2018-01-17
中文翻译：
硫代紫杉醇-寡聚（对亚苯基亚乙烯基）的交联会聚集肿瘤细胞内的聚集物，从而导致“化学锁”，从而提高药物功效
如何降低某些肿瘤细胞对紫杉醇（PTX）和相关紫杉类抗癌药物的耐药性是提高治愈率的主要挑战。因此，设计了具有巯基的寡聚（对-亚苯基亚乙烯基）单元和增强药物功效并逆转耐药性的PTX（OPV-S-PTX）单元。该机制涉及OPV-S-PTX扩散到细胞中，其中π-π相互作用导致聚集。由于较高的活性氧（ROS）浓度，在肿瘤细胞中聚集体通过硫醇基团的氧化交联是有利的。交联的聚集体可“化学锁定”多发色团颗粒，从而产生更持久的效果。肿瘤细胞系A549的OPV‐S‐PTX的IC 50降低至0.33×10 -9 m与PTX本身的观测值相比（41×10 -9 m）。建议通过加速微管束的形成来提高OPV‐S‐PTX的功效。A549 / T接种的异种移植小鼠实验显示，OPV-S-PTX处理可抑制肿瘤生长。总而言之，这些结果表明，OPV-S-PTX通过ROS的内部交联提供了一种区分肿瘤细胞与健康细胞的方法，化学锁定颗粒的形成增强了药物功效并有助于降低耐药性。
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