Dual responsive micelles capable of modulating miRNA-34a to combat taxane resistance in prostate cancer.
Dual responsive micelles capable of modulating miRNA-34a to combat taxane resistance in prostate cancer.
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DOI：
10.1016/j.biomaterials.2018.10.036
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发表时间：
2019-02
期刊：
影响因子：
14
通讯作者：
Feng Lin;D. Wen;Xiaofang Wang;R. Mahato
中科院分区：
文献类型：
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作者：
Feng Lin;D. Wen;Xiaofang Wang;R. Mahato
癌症干细胞数量的增加与阻碍成功化疗的化学抗性之间存在直接相关性。通过靶向大块肿瘤细胞和CSC的协同疗法在逆转化学抗性和治疗抗性前列腺癌方面显示出前景。在此，我们证明了用于共递送多西他赛（DTX）和柔红霉素（RUB）（一种用于靶向CSC的miR-34激活剂）的pH和谷胱甘肽（GSH）敏感性纳米载体的制造，用于治疗紫杉烷抗性（TXR）前列腺癌。通过将DTX包封到pH响应性二异丙基氨基乙醇（DIPAE）和GSH响应性RUB前药缀合的聚碳酸酯基胶束中，制备了负载DTX的P-RUB（DTX/P-RUB）胶束。结果表明，自组装的DTX/P-RUB胶束具有良好的体外稳定性，并能通过增强的渗透和滞留效应（EPR）有效靶向肿瘤。胶束被肿瘤细胞内吞后，由于DIPAE的质子化和GSH诱导酸性内吞囊泡中二硫键的断裂，胶束发生膨胀和解体，导致DTX和RUB的快速释放。然后，释放的RUB上调细胞内miR-34 a，其然后影响参与化学抗性的蛋白质的表达，从而使肿瘤细胞对DTX敏感，并进一步导致显著抑制TXR肿瘤进展。因此，DTX/P-RUB胶束具有治疗TXR前列腺癌的潜力。通过利用这种双重响应策略，可以实现许多其他疏水药物的成功递送用于癌症治疗。
There is a direct correlation between increase in the number of cancer stem cells CSCs and chemoresistance that impedes successful chemotherapy. Synergistic therapy by targeting both bulk tumor cells and CSCs has shown promise in reversing chemoresistance and treating resistant prostate cancer. Herein, we demonstrated the fabrication of a pH and glutathione (GSH) sensitive nanocarrier for co-delivery of docetaxel (DTX) and rubone (RUB), a miR-34 activator for targeting CSCs, for the treatment of taxane resistant (TXR) prostate cancer. DTX loaded P-RUB (DTX/P-RUB) micelles were prepared by encapsulating DTX into pH responsive diisopropylaminoethanol (DIPAE) and GSH responsive RUB prodrug conjugated polycarbonate based micelles. The self-assembled DTX/P-RUB micelles displayed good stability in vitro and could efficiently target to tumors by enhanced permeability and retention (EPR) effect. After endocytosis by tumor cells, the micelles underwent expansion and disassembly due to the protonation of DIPAE and GSH induced cleavage of disulfide bond in acidic endocytic vesicles, resulting in fast release of DTX and RUB. The released RUB then upregulated the intracellular miR-34a, which then affected the expression of proteins involved in chemoresistance, thus sensitizing the tumor cells towards DTX and further leading to significant inhibition of TXR tumor progression. Thus, DTX/P-RUB micelles have the potential to treat TXR prostate cancer. By taking advantage of this dual responsive strategy, the successful delivery of many other hydrophobic drugs can be achieved for cancer treatment.