Codelivery of a π–π Stacked Dual Anticancer Drug Combination with Nanocarriers for Overcoming Multidrug Resistance and Tumor Metastasis
Codelivery of a π–π Stacked Dual Anticancer Drug Combination with Nanocarriers for Overcoming Multidrug Resistance and Tumor Metastasis
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DOI：
10.1002/adfm.201603336
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发表时间：
2016-12
影响因子：
19
通讯作者：
Xiao Wei;Yi Wang;Xiang Xiong;Xing Guo;Lei Zhang;Xiaobin Zhang;Shaobing Zhou
中科院分区：
文献类型：
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作者：
Xiao Wei;Yi Wang;Xiang Xiong;Xing Guo;Lei Zhang;Xiaobin Zhang;Shaobing Zhou
肿瘤细胞的多药耐药（MDR）是肿瘤化疗的主要障碍，目前几乎没有克服MDR的策略。本研究开发了一种新的策略，将π-π堆叠的双重抗癌药物组合与主动靶向的、pH和还原敏感的聚合物胶束平台共同递送，以对抗多药耐药和肿瘤转移。与其他方法相比，两种传统的化疗药物，多柔比星（DOX）和10-羟基喜树碱具有复杂的芳香族π-π共轭结构，通过π-π堆积相互作用整合到一个药物递送系统中，这使得释放的药物能够由于药物分子结构的微小变化而逃避药物泵的识别。该胶束表现出对DOX耐药的人乳腺癌MCF-7细胞（MCF-7/ADR）的主动靶向作用，并具有响应肿瘤细胞的微环境刺激而控制药物释放的能力。因此，π-π堆叠的双重抗癌药物组合的共递送在MCF-7/ADR肿瘤模型中显示出高治疗功效，并成功地防止了肿瘤细胞的肺转移。研究了MDR逆转的潜在机制，结果表明π-π堆叠的双重药物的协同作用促进线粒体依赖性凋亡。
The multidrug resistance (MDR) of cancer cells is a major obstacle in cancer chemotherapy and very few strategies are available to overcome it. Here, a new strategy is developed to codeliver a π–π stacked dual anticancer drug combination with an actively targeted, pH‐ and reduction‐sensitive polymer micellar platform for combating multidrug resistance and tumor metastasis. In contrast to other methods, two traditional chemotherapeutics, doxorubicin (DOX) and 10‐hydroxycamptothecin with complex aromatic π–π conjugated structures, are integrated into one drug delivery system via a π–π stacking interaction, which enables the released drugs to evade the recognition of drug pumps due to a slight change in the drug's molecular structure. The micelles exhibit active targeting of DOX‐resistant human breast cancer MCF‐7 cells (MCF‐7/ADR) and have the ability to control the release of the drug in response to the microenvironmental stimuli of tumor cells. As a result, the codelivery of the π–π stacked dual anticancer drug combination displays high therapeutic efficacy in the MCF‐7/ADR tumor model and successfully prevents the lung metastasis of tumor cells. The mechanism underlying the reversal of MDR is investigated, and the results reveal that the synergistic effect of the π–π stacked dual drugs promotes mitochondria‐dependent apoptosis.