Targeted delivery of miR-200c/DOC to inhibit cancer stem cells and cancer cells by the gelatinases-stimuli nanoparticles
Targeted delivery of miR-200c/DOC to inhibit cancer stem cells and cancer cells by the gelatinases-stimuli nanoparticles
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通过明胶酶刺激纳米颗粒靶向递送 miR-200c/DOC 以抑制癌症干细胞和癌细胞。
DOI：
10.1016/j.biomaterials.2013.06.004
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发表时间：
2013-09-01
期刊：
影响因子：
14
通讯作者：
Liu, Bao-Rui
中科院分区：
文献类型：
--
作者：
Lin, Qin;Li, Ru-Tian;Liu, Bao-Rui
最近发现癌症干细胞（CSC）是成功癌症治疗的重要障碍。新的证据表明 miR-200c 作为一种有效的 CSC 抑制剂，可以恢复对微管靶向药物的敏感性。在目前的工作中，建立了智能明胶酶刺激纳米颗粒（NP）来共同递送miR-200c和多西紫杉醇（DOC），以验证它们对抑制CSC和非CSC癌细胞的协同作用。用 miR-200c NP 处理肿瘤细胞后，评估 miR-200c 及其靶基因 III 类 β-微管蛋白 (TUBB3)TUBB3 的表达。研究了 miR-200c/DOC NPs 对肿瘤细胞活力、迁移和侵袭以及 E-cadherin 和 CD44 表达的影响。在异种移植胃癌小鼠中比较了 miR-200c/DOC NP 与 DOC NP 的抗肿瘤作用。此外，将治疗后残留的肿瘤皮下接种到裸鼠体内，以进一步研究NPs的有效维持。我们发现明胶酶刺激的纳米粒子促进 miR-200c 进入细胞，在 9 天内在肿瘤细胞中实现 miR-200c 的持续表达。 miR-200c/DOC NP 可能通过降低 TUBB3 水平和逆转 EMT 显着增强 DOC 的细胞毒性。 miR-200c NPs 在静脉注射后在胃癌异种移植物中实现了高水平的体内积累和长期保留。 miR-200c/DOC NPs 显着抑制体内肿瘤生长，提高 miR-200c 和 E-钙粘蛋白水平，并下调 TUBB3 和 CD44 表达。当miR-200c/DOC NPs处理后残留的肿瘤重新移植到裸鼠体内时，肿瘤的生长速度最慢。 miR-200c/DOC NPs 可能提供一种有前途的核酸和药物共同递送方式，以同时抑制 CSC 和非 CSC 癌细胞。 (C) 2013 Elsevier Ltd. 保留所有权利。
Cancer stem cells (CSCs) are recently discovered as vital obstacles for the successful cancer therapy. Emerging evidences suggest that miR-200c functions as an effective CSCs inhibitor and can restore sensitivity to microtubule-targeting drugs. In the present work, the intelligent gelatinases-stimuli nanoparticles (NPs) was set up to co-deliver miR-200c and docetaxel (DOC) to verify their synergetic effects on inhibition of CSCs and non-CSC cancer cells. After tumor cells were treated with miR-200c NPs, miR-200c and its targeted gene class III beta-tubulin (TUBB3)TUBB3 expression were evaluated. The effects of miR-200c/DOC NPs on tumor cell viability, migration and invasion as well as the expression of E-cadherin and CD44 were studied. The antitumor effects of miR-200c/DOC NPs were compared with DOC NPs in xenograft gastric cancer mice. Moreover, the residual tumors after treatment were subcutaneously seeded into nude mice to further investigate the effective maintenance of NPs. We found that the gelatinases-stimuli NPs facilitated miR-200c into cells, achieving sustained miR-200c expression in tumor cells during 9 days. The miR-200c/DOC NPs significantly enhanced cytotoxicity of DOC, possibly by decreasing TUBB3 level, and reversing EMT. The miR-200c NPs achieved high levels of in vivo accumulation and long retention in gastric cancer xenografts after intravenous administration. The miR-200c/DOC NPs prominently suppressed in vivo tumor growth with elevated miR-200c and E-cadherin levels and down-regulated TUBB3 and CD44 expressions. When the residual tumors after miR-200c/DOC NPs treatment were re-transplanted into nude mice, the tumors demonstrated the slowest growth speed. The miR-200c/DOC NPs may provide a promising modality for co-delivery of nucleic acid and drugs to simultaneously inhibit CSCs and non-CSC cancer cells. (C) 2013 Elsevier Ltd. All rights reserved.