Combination delivery of Adjudin and Doxorubicin via integrating drug conjugation and nanocarrier approaches for the treatment of drug-resistant cancer cells.
Combination delivery of Adjudin and Doxorubicin via integrating drug conjugation and nanocarrier approaches for the treatment of drug-resistant cancer cells.
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通过整合药物偶联和纳米载体方法联合递送 Adjudin 和多柔比星来治疗耐药癌细胞
DOI：
10.1039/c4tb01764a
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发表时间：
2015-02-28
期刊：
影响因子：
--
通讯作者：
Zhang Z
中科院分区：
文献类型：
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作者：
Li X;Gao C;Wu Y;Cheng CY;Xia W;Zhang Z
联合治疗被认为是克服多药耐药（MDR）的有效策略。本研究采用线粒体抑制剂Adjudin（ADD）和常用化疗药物阿霉素（DOX）联合治疗耐药肿瘤细胞（MCF-7/ADR）。鉴于ADD和DOX的不同理化性质，我们开发了一种新的药物制剂（ADD-DOX（M）），通过整合药物缀合和纳米载体方法来实现两种药物的共递送。我们证明了ADD和DOX通过形成酸敏感的腙键结合，然后通过DSPE-PEG 2000胶束包封ADD-DOX结合物，具有高药物包封率和良好可控的载药效率。发现所获得的ADD-DOX（M）胶束在生理条件下是稳定的，但在酸性环境中可以快速释放药物。以下细胞实验证实，ADD-DOX（M）媒介物可以通过内吞途径被MCF-7/ADR癌细胞内化，并存在于中等酸性的内溶酶体内，从而加速ADD-DOX的水解和游离ADD和DOX的释放。结果，ADD-DOX（M）制剂显示出优异的抗MDR效果。总之，我们首次报道了ADD和DOX的组合使用与用于治疗MDR癌细胞的有效共递送策略。
Combination therapy has been regarded as a potent strategy to overcome multidrug resistance (MDR). In this study, we adopt Adjudin (ADD), a mitochondria inhibitor, and Doxorubicin (DOX), a common chemo-drug, to treat drug-resistant cancer cells (MCF-7/ADR) in combination. Given the different physico-chemical properties of ADD and DOX, we develop a novel drug formulation (ADD–DOX (M)) by integrating drug conjugation and nanocarrier approaches to realize the co-delivery of the two drugs. We demonstrate the conjugation of ADD and DOX via formation of an acid-sensitive hydrazone bond, and then the encapsulation of ADD–DOX conjugates by DSPE-PEG2000 micelles with high drug encapsulation efficiency and well-controllable drug loading efficiency. The obtained ADD–DOX (M) micelles are found to be stable under physiological conditions, but can rapidly release drugs within acidic environments. Following cellular experiments confirm that ADD–DOX (M) vehicles can be internalized by MCF-7/ADR cancer cells through an endocytic pathway and exist within the moderate acidic endolysosomes, thus accelerating the hydrolysis of ADD–DOX and the release of free ADD and DOX. As a result, the ADD–DOX (M) formulation exhibits an excellent anti-MDR effect. In summary, we for the first time report the combinational use of ADD and DOX with an effective co-delivery strategy for the treatment of MDR cancer cells.