Redox-Activatable ATP-Depleting Micelles with Dual Modulation Characteristics for Multidrug-Resistant Cancer Therapy
Redox-Activatable ATP-Depleting Micelles with Dual Modulation Characteristics for Multidrug-Resistant Cancer Therapy
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DOI：
10.1002/adhm.201601293
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发表时间：
2017-04-19
影响因子：
10
通讯作者：
Ping, Yuan
中科院分区：
文献类型：
--
作者：
Wang, Hebin;Li, Yang;Ping, Yuan
开发了一种通过细胞内氧化还原激活的快速三磷酸腺苷（ATP）耗尽胶束系统，用于抗癌药物紫杉醇（PTX）和靶向polo样激酶1（PLK 1）的小干扰RNA（siRNA）的共递送，以解决多药耐药（MDR）癌症治疗的关键挑战。ATP消耗胶束由氧化还原响应性两亲聚合物（称为bPEG-SS-P123-PEI（PSPP））自组装而成，所述两亲聚合物由生物相容的具有8个臂的支链聚乙二醇（PEG）（bPEG）、ATP消耗Pluronic P123（P123）和阳离子低分子量聚乙烯亚胺（PEI）嵌段组成。在临界胶束浓度下，PSPP单聚体自组装成有序的多层纳米结构，并能够负载PTX和靶向PLK 1的siRNA。在细胞内富含谷胱甘肽的还原环境中二硫键的裂解不仅促进PTX和siRNA释放，而且还激活快速ATP消耗作用，这在防止多药耐药癌细胞的细胞内PTX流出中至关重要。发现通过PSPP胶束的ATP消耗和siRNA抑制的组合提供了双重调节，用于使多药耐药癌细胞对PTX治疗再敏感。因此，PTX和PLK 1 siRNA的共递送在体内MDR肿瘤模型中发挥更强的抗肿瘤生长的组合效应。快速ATP消耗纳米胶束的发展代表了具有空间和时间控制的独特的双重调节癌症MDR的原始递送策略。
A fast adenosine triphosphate (ATP)-depleting micellar system that is activated by intracellular redox for the codelivery of anticancer drug paclitaxel (PTX) and small interference RNA (siRNA) targeting polo-like kinase1 (PLK1) is developed to address the key challenges of multidrug-resistant (MDR) cancer therapy. The ATP-depleting micelle is self-assembled from a redox-responsive amphiphilic polymer (termed as bPEG-SS-P123-PEI (PSPP)) that is composed of biocompatible branched polyethylene glycol (PEG) with 8 arms (bPEG), ATP-depleting Pluronic P123 (P123), and cationic low molecular weight polyethylenimine (PEI) blocks. Upon critical micelle concentration, the PSPP unimer self-assembles into a well-ordered multilayered nanostructure and is able to load PTX and siRNA targeting PLK1. The cleavage of disulfide linkages at intracellular glutathione-rich reduction milieu not only promotes PTX and siRNA release, but also activates the fast ATP-depletion action that is critical in preventing intracellular PTX efflux by multidrug-resistant cancer cells. The combination of ATP depletion and siRNA inhibition by PSPP micelles is found to provide dual modulations for resensitizing multidrug-resistant cancer cells for PTX treatment. As a result, the codelivery of PTX and PLK1 siRNA exerts a stronger combinational effect against tumor growth in MDR tumor models in vivo. The development of fast ATP-depleting nanomicelle represents an original delivery strategy for the distinctive dual modulation of cancer MDR with spatial and temporal control.