Co-delivery of PLK1-specific shRNA and doxorubicin via core-crosslinked pH-sensitive and redox ultra-sensitive micelles for glioma therapy
Co-delivery of PLK1-specific shRNA and doxorubicin via core-crosslinked pH-sensitive and redox ultra-sensitive micelles for glioma therapy
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通过核心交联 pH 敏感和氧化还原超敏感胶束共同递送 PLK1 特异性 shRNA 和阿霉素，用于神经胶质瘤治疗
DOI：
10.1039/c7tb02160g
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发表时间：
2018
影响因子：
7
通讯作者：
Zhou Shaobing
中科院分区：
文献类型：
--
作者：
Wang Pu;Yu Nengwei;Wang Yi;Sun Huili;Yang Zhenglin;Zhou Shaobing
抗肿瘤药物在体内转运时会遇到许多生物屏障，包括粘膜屏障、非特异性摄取和细胞内耐药。因此，用纳米载体将治疗剂有效递送至靶细胞和包封药物的受控细胞内释放是实现高治疗效率的关键。在这项研究中，我们开发了一个肿瘤微环境敏感的聚合物胶束系统从pH值和谷胱甘肽（GSH）的双重响应的共聚物，每个重复单元含有一个二硫键。为了防止药物在血液循环中过早释放，通过UV光照射使核心区域化学交联。在肿瘤细胞中，由于“质子海绵效应”，胶束能够通过迅速膨胀从酸性溶酶体逃逸到细胞质中。随后，实现了超灵敏的氧化还原反应，因为胶束基质的丰富的二硫键可以被高水平的GSH切割，导致包封的多柔比星（DOX）和PLK1特异性shRNA的快速细胞内释放。在U87胶质瘤荷瘤小鼠中的抗肿瘤活性表明，该新系统对实体瘤具有高治疗功效，对正常组织的副作用可忽略不计。因此，这种胶束纳米平台在递送药物用于增强胶质瘤治疗方面具有巨大的潜力。
Anticancer drug delivery encounters many biological barriers, including mucosal barriers, nonspecific uptake and intracellular drug resistance. Consequently, efficient delivery of therapeutic agents with nanocarriers to the target cell and controlled intracellular release of encapsulated drugs are key to achieving high therapeutic efficiency. In this study, we develop a tumor microenvironment-sensitive polymer micelle system from a pH- and glutathione (GSH) dual-responsive copolymer with each repeating unit containing a disulfide bond. To prevent premature drug release within the blood circulation, the core region was chemically crosslinked via UV light irradiation. In tumor cells, the micelles are able to escape from the acidic lysosome into the cytoplasm via a prompt expansion due to the “proton sponge effect”. Subsequently, ultra-sensitive redox responsiveness is realized since the abundant disulfide bonds of the micellar matrix can be cleaved by a high level of GSH, leading to a rapid intracellular release of encapsulated doxorubicin (DOX) and PLK1-specific shRNA. The antitumor activity in U87 glioma tumor-bearing mice reveals that this novel system possesses a high therapeutic efficacy against solid tumors with negligible side effects on normal tissues. Therefore, this micellar nanoplatform has great potential in delivering drugs for enhanced glioma therapy.