Reversal of multidrug resistance phenotype in human breast cancer cells using doxorubicin-liposome-microbubble complexes assisted by ultrasound
Reversal of multidrug resistance phenotype in human breast cancer cells using doxorubicin-liposome-microbubble complexes assisted by ultrasound
复制标题
超声波辅助下使用阿霉素-脂质体-微泡复合物逆转人乳腺癌细胞的多药耐药表型
DOI：
10.1016/j.jconrel.2013.11.018
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发表时间：
2014-01-28
影响因子：
10.8
通讯作者：
Zheng, Hairong
中科院分区：
文献类型：
--
作者：
Deng, Zhiting;Yan, Fei;Zheng, Hairong
多药耐药（MDR）的规避在化疗的成功中起着至关重要的作用。本研究旨在探讨超声辅助阿霉素脂质体微泡复合物（DLMC）逆转人乳腺癌细胞MDR表型的有效性及其可能机制。通过生物素-亲和素连接将阿霉素（DOX）-脂质体（DL）偶联到微泡（MB）表面制备DLMC。然后对所得载药复合物进行表征，并与MCF-7/ADR人乳腺癌细胞一起孵育，然后进行US暴露。结果表明，与DL、DL +维拉帕米（相同剂量）或DL MC + US处理的耐药细胞相比，DL MC + US处理的耐药细胞的细胞摄取更快，核积聚明显增加，药物外排更少。增强的药物递送和细胞摄取还与对MCF-7/ADR细胞的细胞毒性增加、MCF-7/ADR细胞活力降低和凋亡细胞增加相关。机制研究进一步揭示了DLMC + US处理的耐药细胞与DLMC、DL + US或DL +维拉帕米+ US处理的对照细胞相比，活性氧（ROS）水平显著升高，DNA损伤增强，P-糖蛋白表达明显降低。总之，我们的研究表明，DLMC与US组合可以提供有效的药物递送，以使细胞敏感，从而规避MDR，并提高化疗的治疗指数。(C)2013爱思唯尔有限公司版权所有。
The circumvention of multidrug resistance (MDR) plays a critically important role in the success of chemotherapy. The aim of this work is to investigate the effectiveness and possible mechanisms of the reversal of MDR phenotype in human breast cancer cells by using doxorubicin-liposome-microbubble complexes (DLMC) assisted by ultrasound (US). DLMC is fabricated through conjugating doxorubicin (DOX)-liposome (DL) to the surface of microbubbles (MBs) via the biotin-avidin linkage. The resulting drug-loaded complexes are then characterized and incubated with MCF-7/ADR human breast cancer cells and followed by US exposure. Our results show the more rapid cellular uptake, evident enhancement of nuclear accumulation and less drug efflux in the resistant cells treated by DLMC + US than those treated by DL, DL + verapamil under the same US treatment or DLMC without US. The enhanced drug delivery and cellular uptake also associated with the increase of cytotoxicity against MCF-7/ADR cells, lower MCF-7/ADR cell viability and higher apoptotic cells. Mechanism investigations further disclose a significant increase of reactive oxygen species (ROS) level, enhanced DNA damage and obvious reduction of P-glycoprotein expression in the resistant cells treated with DLMC + US compared with the control cases of cells treated by DLMC, DL + US or DL + verapamil + US. In conclusion, our study demonstrates that DLMC in combination with US may provide an effective delivery of drug to sensitize cells to circumvent MDR and to enhance the therapeutic index of the chemotherapy. (C) 2013 Elsevier B.V. All rights reserved.