Docetaxel loaded oleic acid-coated hydroxyapatite nanoparticles enhance the docetaxel-induced apoptosis through activation of caspase-2 in androgen independent prostate cancer cells
Docetaxel loaded oleic acid-coated hydroxyapatite nanoparticles enhance the docetaxel-induced apoptosis through activation of caspase-2 in androgen independent prostate cancer cells
复制标题
负载多西紫杉醇的油酸包被的羟基磷灰石纳米颗粒通过激活雄激素非依赖性前列腺癌细胞中的 caspase-2 增强多西紫杉醇诱导的细胞凋亡
DOI：
10.1016/j.jconrel.2010.07.108
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发表时间：
2010-10-15
影响因子：
10.8
通讯作者：
Gao, Xin
中科院分区：
文献类型：
--
作者：
Luo, Yun;Ling, You;Gao, Xin
多西紫杉醇(DtXl)仍然是改善激素难治性前列腺癌(HRPC)患者生存的首选方案，但许多患者的药物反应轻微，毒性大。在本研究中，我们研究了新型DtXl-loaded-[1，2-distearoyl-sn-glycero-3-phosphoethanolamine-N-carboxy(polyethylene)2000(DSPE-PEGCOOH2000)稳定油酸(OA)包覆羟基磷灰石(HA)纳米颗粒(DtXl-NPs)的效率，并深入探讨了这些新型DtXl纳米颗粒诱导细胞凋亡的分子机制。DtX1的包封率为83.6%，药物缓释时间超过30d。与DtX1相比，DtXl-NPs对PC3和DU145两种前列腺癌细胞株具有更强的体外细胞毒作用，并增强了DtX1诱导的PC3细胞的凋亡。细胞周期分析显示，与DtX1相比，DtX1-NPs处理的PC3细胞明显停滞在G2-M期，但亚G(0)/G(1)细胞比例较高。DtXl-NPs对PC3细胞的促凋亡作用与线粒体膜电位的改变有关，可能与caspase-2激活有关。Caspase的动力学研究表明，在DtX1-NPs诱导的PC3细胞凋亡中，caspase-2被提前激活，这与DtX1诱导的PC3细胞凋亡不同。小干扰RNA(SiRNA)抑制caspase-2的激活可显著抑制DtXl-NPs诱导的线粒体膜电位的破坏和DtXl-NPs诱导的细胞凋亡，提示caspase-2的激活是PC3细胞线粒体去极化之前的关键事件。我们的发现表明，纳米颗粒，而不是简单的药物载体，可能在介导生物效应方面发挥积极作用。(C)2010爱思唯尔B.V.保留所有权利。
Docetaxel (Dtxl) remains the preferred choice of improving the survival of patients with hormone refractory prostate cancer (HRPC), but many patients suffer from modest drug response and significant toxicity. In the present study, we investigated the efficiency of novel Dtxl loaded-[1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-carboxy(polyethylene glycol)]2000 (DSPE-PEG-COOH) stabilized-oleic acid (OA) coated hydroxyapatite (HA) nanoparticles (Dtxl-NPs) and gained insights into the molecular mechanism of the apoptosis induced by these novel Dtxl-loaded nanoparticles. The drug encapsulation efficiency of Dtxl was 83.6% and the sustained drug release was observed over 30 days. The Dtxl-NPs exhibited significantly more cytotoxicity in both prostate cancer cell lines (PC3 and DU145) compared with Dtxl in vitro and increased the Dtxl-induced apoptosis in the PC3 cells. Cell cycle analysis showed that the PC3 cells treated with Dtxl-NPs exhibited significant arrest in the G2-M phase but a higher sub-G(0)/G(1) population when compared with Dtxl. The enhanced apoptosis induced by Dtxl-NPs in the PC3 cells was associated with the changes in mitochondrial membrane potential (MMP) and seemed to involve the activation of caspase-2. The kinetic studies of caspases demonstrated an early activation of caspase-2 in Dtxl-NPs-induced apoptosis in PC3 cells, which differs from Dtxl-induced apoptosis. The inhibition of caspase-2 activation by small interfering RNA (siRNA) knockdown resulted in the significant inhibition of Dtxl-NPs-induced disruption of MMP and Dtxl-NPs-induced apoptosis, indicating that the activation of caspase-2 was the critical event before the mitochondrial depolarization in the PC3 cells. Our findings showed that nanoparticles, more than simple drug carriers, may play an active role in mediating the biological effects. (C) 2010 Elsevier B.V. All rights reserved.