Etoposide loaded layered double hydroxide nanoparticles reversing chemoresistance and eradicating human glioma stem cells in vitro and in vivo.
Etoposide loaded layered double hydroxide nanoparticles reversing chemoresistance and eradicating human glioma stem cells in vitro and in vivo.
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DOI：
10.1039/c8nr02708k
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发表时间：
2018-07
期刊：
影响因子：
6.7
通讯作者：
Zhaojie Wang;Peng Liang;Xiaolie He;Bin Wu;Qiang Liu;Ziping Xu;Huijun Wu;Zhongmin Liu;Yechang Qian;Shilong Wang;Rongrong Zhu
中科院分区：
文献类型：
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作者：
Zhaojie Wang;Peng Liang;Xiaolie He;Bin Wu;Qiang Liu;Ziping Xu;Huijun Wu;Zhongmin Liu;Yechang Qian;Shilong Wang;Rongrong Zhu
胶质母细胞瘤（GBM）是人类脑肿瘤中最恶性和致命的胶质瘤，并且包含有助于肿瘤起始、治疗抗性和进一步复发的自我更新的致瘤性胶质瘤干细胞（GSC）。在这项研究中，我们结合体外细胞功效和体内抗肿瘤性能来评估负载依托泊苷（VP 16）的层状双氢氧化物（LDH）纳米复合物（L-V）对人GSC的结果。对GSC增殖和凋亡的影响显示，LDH负载可显著增强GSC对VP 16的敏感性，并促进GSC的清除。进一步的qPCR和western blot分析表明，L-V可以有效地减弱GSC相关的多能性基因的表达，并降低癌症的干性。体内GSC异种移植模型表明，L-V可以克服耐药性，清除GSC，显著降低干细胞，逆转上皮-间质转化（EMT）。RNA-seq分析表明，L-V通过下调PI 3 K/AKt/mTOR表达，激活Wnt/GSK 3 β/β-catenin信号通路，从而导致GSC干性丧失，大大增强GSC靶向效应。综上所述，本研究证明了L-V逆转GSCs耐药性的优异性能，从而为纳米药物在恶性胶质瘤化疗中的临床转化应用提供了新的策略。
Glioblastoma (GBM) is the most malignant and lethal glioma in human brain tumors and contains self-renewing, tumorigenic glioma stem cells (GSCs) that contribute to tumor initiation, therapeutic resistance and further recurrence. In this study, we combined in vitro cellular efficacy with in vivo antitumor performance to evaluate the outcome of an etoposide (VP16) loaded layered double hydroxide (LDH) nanocomposite (L-V) on human GSCs. The effects on GSC proliferation and apoptosis showed that loading with LDH could significantly sensitize GSCs to VP16 and enhance the GSC elimination. Further qPCR and western blot assays demonstrated that L-V could effectively attenuate GSC related pluripotency gene expression and reduce the cancer stemness. An in vivo GSC xenograft mice model showed that L-V can overcome drug resistance, eradicate GSCs, sharply decrease the stemness and reverse the epithelial-mesenchymal transition (EMT). RNA-seq analysis elucidated that L-V plays a vital role by down-regulating the PI3K/AKt/mTOR expression and activating the Wnt/GSK3β/β-catenin signaling pathway, hence leading to GSC stemness loss and greatly enhancing the GSC targeting effect. Taken together, this study demonstrated the outstanding performance of L-V reversing the drug resistance of GSCs, thus providing a novel strategy for clinical translation application of nanomedicine in malignant glioma chemotherapy.