Research Center for Translational Medicine at East Hospital, School of Life Science and Technology, Tongji University, Shanghai, People's Republic of China.
Nanoscale. 2018 Jul 13;10(27):13106-13121. doi: 10.1039/c8nr02708k.
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.
胶质母细胞瘤（GBM）是人类脑肿瘤中最恶性和最致命的神经胶质瘤，包含自我更新、致瘤性的神经胶质瘤干细胞（GSCs），这些细胞有助于肿瘤的起始、治疗耐药性和进一步复发。在这项研究中，我们将体外细胞功效与体内抗肿瘤性能相结合，评估依托泊苷（VP16）负载层状双氢氧化物（LDH）纳米复合材料（L-V）对人 GSCs 的治疗效果。对 GSC 增殖和凋亡的影响表明，负载 LDH 可以显著提高 GSCs 对 VP16 的敏感性，并增强 GSC 的消除。进一步的 qPCR 和 Western blot 分析表明，L-V 可以有效抑制 GSC 相关多能性基因表达，并降低癌症干性。体内 GSC 异种移植小鼠模型表明，L-V 可以克服耐药性，根除 GSCs，显著降低干性并逆转上皮-间充质转化（EMT）。RNA-seq 分析表明，L-V 通过下调 PI3K/AKt/mTOR 表达和激活 Wnt/GSK3β/β-catenin 信号通路发挥重要作用，从而导致 GSC 干性丧失，并大大增强 GSC 靶向作用。总之，这项研究表明，L-V 逆转了 GSCs 的耐药性，为恶性神经胶质瘤化疗中纳米医学的临床转化应用提供了新策略。
