Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University , Changzhou, 213164, China.
ACS Appl Mater Interfaces. 2017 Feb 8;9(5):4843-4850. doi: 10.1021/acsami.7b00643. Epub 2017 Jan 30.
Supramolecular construction of multistimuli platform for drug delivery is a challenging task. In this work, a pH and GSH (glutathione) dual-responsive bola-type supramolecular amphiphile was successfully fabricated by the complexation between a water-soluble pillar[5]arene (WP5) and a bolaform naphthalimide guest (G) in water. The resulting bola-type amphiphile further self-assembled into supramolecular binary vesicles, which could be disassembled by low pH, a high-GSH-concentration environment, or both. Furthermore, the results of drug loading and releasing tests showed that doxorubicin (DOX), the hydrophobic anticancer drug, could be successfully encapsulated into the Stern region of the obtained supramolecular vesicles and generated the DOX-loaded vesicles with good drug-loading efficiency. Moreover, the obtained DOX-loaded vesicles displayed efficient and rapid DOX release at a simulated tumor microenvironment with low-pH or excess-GSH conditions or both. Significantly, cytotoxicity experiments revealed that the DOX-loaded supramolecular vesicles could obviously improve the anticancer efficiency of free DOX for tumor cells while remarkably reducing its side effects for normal cells. In vitro cellular uptake and subcellular localization assays further proved that these smart drug nanovehicles, entering cancer cells mainly via endocytosis, could cause excellent drug accumulation in cancer cells. The present study provides a successful example with which to rational design an effective bola-type stimuli-responsive supramolecular nanocarrier, which might have wide potential applications in the construction of various controlled drug-delivery systems.
超分子构建用于药物输送的多刺激响应平台是一项具有挑战性的任务。在这项工作中，通过水溶性柱[5]芳烃（WP5）和 bola 型萘酰亚胺客体（G）在水中的络合，成功制备了 pH 和 GSH（谷胱甘肽）双重响应的 bola 型超分子两亲体。所得的 bola 型两亲体进一步自组装成超分子二元囊泡，这些囊泡可以通过低 pH 值、高 GSH 浓度环境或两者的共同作用而解组装。此外，载药和释药实验结果表明，疏水性抗癌药物阿霉素（DOX）可以成功地封装到所得超分子囊泡的疏水性内核中，并生成具有良好载药效率的 DOX 载药囊泡。而且，在模拟肿瘤微环境中，具有低 pH 值或过量 GSH 条件或两者共同作用的情况下，所得 DOX 载药囊泡能够实现高效、快速的 DOX 释放。值得注意的是，细胞毒性实验表明，DOX 载药超分子囊泡能够明显提高游离 DOX 对肿瘤细胞的抗癌效率，同时显著降低其对正常细胞的副作用。体外细胞摄取和亚细胞定位实验进一步证明，这些智能药物纳米载体主要通过内吞作用进入癌细胞，能够在癌细胞中引起优异的药物积累。本研究提供了一个成功的例子，合理设计了一种有效的 bola 型刺激响应超分子纳米载体，可能在构建各种控制药物输送系统方面具有广泛的应用潜力。
