Smart pH-Sensitive and Temporal-Controlled Polymeric Micelles for Effective Combination Therapy of Doxorubicin and Disulfiram
Smart pH-Sensitive and Temporal-Controlled Polymeric Micelles for Effective Combination Therapy of Doxorubicin and Disulfiram
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用于阿霉素和双硫仑有效联合治疗的智能 pH 敏感和时间控制聚合物胶束
DOI：
10.1021/nn4010796
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发表时间：
2013-07-01
期刊：
影响因子：
17.1
通讯作者：
Li, Yaping
中科院分区：
文献类型：
--
作者：
Duan, Xiaopin;Xiao, Jisheng;Li, Yaping
化疗药物与多药耐药（MDR）调节剂的组合已成为治疗MDR癌症的有前途的策略。为了确保两种药物能够以最佳比例同时递送到肿瘤区域，并且MDR调节剂能够比化疗药物更早和更快地释放到Pip-糖蛋白（Pip）并随后抑制化疗药物的泵出，设计并制备了一种高载药量、精确配比的pH敏感型聚合物胶束体系将苯乙烯-马来酸酐（SMA）衍生物与己二酰肼（ADH）通过可加成的腙键连接在一起，然后将P-gp抑制剂和凋亡诱导剂双硫仑（DSF）包封在SMA-ADH-DOX（SAD）偶联物自组装形成的胶束中。pH敏感的聚合物胶束系统能够实现两种药物的时间释放：包封的DSF快速释放以抑制P-gp的活性并恢复细胞凋亡信号通路，而缀合的DOX以持续和pH依赖性的方式释放并在耐药细胞中高度累积，由于DSF使Pip失活而发挥治疗作用。智能共递送系统通过增加DOX的细胞内积累和促进凋亡反应在增强细胞毒性方面非常有效，并且与两种药物的其他组合相比，对耐药乳腺癌异种移植物的生长显示出最有效的抑制作用。总之，这种智能共给药系统对于MDR肿瘤的临床治疗具有重要的应用前景。
The combination of a chemotherapeutic drug with a multidrug resistance (MDR) modulator has emerged as a promising strategy for treating MDR cancer. To ensure two drugs could be simultaneously delivered to tumor region at the optimum ratio, and the MDR modulator could be released earlier and faster than the chemotherapeutic drug to inactivate P-glycoprotein (Pip) and subsequently inhibit the pumping out of the chemotherapeutic drug, a smart pH-sensitive polymeric micelles system with high drug loading and precise drug ratio was designed and prepared by conjugating doxorubicin (DOX) to poly(styrene-co-maleic anhydride) (SMA) derivative with adipic dihydrazide (ADH) through a add-cleavable hydrazone bond, and then encapsulating disulfiram (DSF), a P-gp inhibitor as well as an apoptosis inducer, into the micelles formed by the self-assembly of SMA-ADH-DOX (SAD) conjugate. The pH-sensitive polymeric micelles system enabled a temporal release of two drugs: encapsulated DSF was released fast to inhibit the activity of P-gp and restore cell apoptotic signaling pathways, while conjugated DOX was released in a sustained and pH-dependent manner and highly accumulated in drug resistant cells to exert therapeutic effect, due to the inactivation of Pip by DSF. The smart co-delivery system was very effective in enhancing the cytotoxicity by increasing the intracellular accumulation of DOX and promoting the apoptotic response, and showed the most effective inhibitory effect on the growth of drug-resistant breast cancer xenografts as compared to other combinations of both drugs. In a word, this smart co-delivery system has significant promise for the clinical therapy of MDR cancer.