Reduction-Cleavable Polymeric Vesicles with Efficient Glutathione-Mediated Drug Release Behavior for Reversing Drug Resistance
Reduction-Cleavable Polymeric Vesicles with Efficient Glutathione-Mediated Drug Release Behavior for Reversing Drug Resistance
复制标题
具有有效谷胱甘肽介导的药物释放行为以逆转耐药性的还原可裂解聚合物囊泡
DOI：
10.1021/am402860v
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发表时间：
2013-11-13
影响因子：
9.5
通讯作者：
Ou, Zhouluo
中科院分区：
文献类型：
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作者：
Ren, Tianbin;Wu, Wei;Ou, Zhouluo
在肿瘤治疗中，多药耐药（MDR）已成为化疗成功的主要障碍。潜在的机制依赖于药物外排转运蛋白的过表达，其阻止药物的细胞内转运。在这项研究中，还原切割囊泡的设计和开发具有有效的谷胱甘肽介导的药物释放行为逆转耐药性。聚合物囊泡自组装从三嵌段共聚物与二硫键连接的聚（乙二醇）（PEG）和聚（ε-苄氧羰基-L-赖氨酸）（PzLL）。透射电子显微镜（TEM）和共聚焦激光扫描显微镜（CLSM）的观察结果显示，囊泡周围有一个明显的中空结构，外层很薄，表明囊泡成功形成。使用荧光可检测的盐酸阿霉素（DOX中心点HCl）作为模型药物，发现由谷胱甘肽（GSH）调节的药物释放的显著加速（>3倍差异）。在孵育的DOX中心点HCl负载的聚合物囊泡与HeLa宫颈癌细胞系暴露于谷胱甘肽，增强的核积累的DOX中心点HCl被观察到，引起的囊泡结构在还原条件下的优选解体。重要的是，通过使用盐酸吉西他滨（GC中心点HCl）抗性乳腺癌细胞系MDA-MB-231，发现用GC处理后细胞活力显著降低。盐酸负载的聚合物囊泡，表明这些囊泡可以帮助逆转耐药性。
In the treatment of cancer, multidrug resistance (MDR) has been the major obstacle to the success of chemotherapy. The underlying mechanism relies on the overexpression of drug-efflux transporters that prevent the intracellular transport of the drug. In this study, reduction-cleavable vesicles were designed and developed with efficient glutathione-mediated drug-release behavior for reversing drug resistance. Polymeric vesicles were self-assembled from triblock copolymers with disulfide-bond-linked poly(ethylene glycol) (PEG) and poly(epsilon-benzyloxycarbonyl-L-lysine) (PzLL). Observations from transmission electron microscopy (TEM) and confocal laser scanning microscopy (CLSM) outline an obvious hollow structure surrounded by a thin outer layer, indicating the successful formation of the vesicles. Using fluorescently detectable doxorubicin hydrochloride (DOX center dot HCl) as the model drug, a significant acceleration of drug release regulated by glutathione (GSH) was found (>3-fold difference). Upon incubation of the DOX center dot HCl-loaded polymeric vesicles with the HeLa cervical cancer cell line exposed to glutathione, an enhanced nuclear accumulation of DOX center dot HCl was observed, elicited by the preferred disassembly of the vesicle structure under reducing conditions. Importantly, by using the gemcitabine hydrochloride (GC center dot HCl)-resistant breast cancer cell line MDA-MB-231, it was found that cell viability was significantly reduced after treatment with GC. HCl-loaded polymeric vesicles, indicating that these vesicles can help to reverse the drug resistance.