Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-6025, USA.
Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-6025, USA.
Biomaterials. 2019 Feb;192:95-108. doi: 10.1016/j.biomaterials.2018.10.036. Epub 2018 Nov 3.
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.
癌症干细胞（CSC）数量的增加与化疗耐药性直接相关，这阻碍了化疗的成功进行。通过针对肿瘤细胞和 CSC 两者的协同治疗，已经显示出逆转化疗耐药性和治疗耐药性前列腺癌的潜力。在此，我们展示了一种 pH 值和谷胱甘肽（GSH）敏感的纳米载体的制备，用于共递送多西他赛（DTX）和鲁布（RUB），RUB 是一种针对 CSC 的 miR-34 激活剂，用于治疗紫杉烷耐药（TXR）前列腺癌。通过将 DTX 封装到 pH 响应的二异丙醇基乙胺（DIPAE）和 GSH 响应的 RUB 前药共轭碳酸酯基胶束中，制备了负载 DTX 的 P-RUB（DTX/P-RUB）胶束。在体外，DTX/P-RUB 胶束表现出良好的稳定性，并可以通过增强的通透性和保留（EPR）效应有效地靶向肿瘤。进入肿瘤细胞后，由于 DIPAE 的质子化和酸性内吞小泡中二硫键的 GSH 诱导裂解，胶束会发生扩张和解体，导致 DTX 和 RUB 的快速释放。然后，释放的 RUB 上调了细胞内的 miR-34a，从而影响了参与化疗耐药性的蛋白质的表达，从而使肿瘤细胞对 DTX 敏感，并进一步导致 TXR 肿瘤进展的显著抑制。因此，DTX/P-RUB 胶束有可能治疗 TXR 前列腺癌。通过利用这种双重响应策略，可以成功递送至许多其他疏水性药物，用于癌症治疗。
