Layered double hydroxide eliminate embryotoxicity of chemotherapeutic drug through BMP-SMAD signaling pathway
Layered double hydroxide eliminate embryotoxicity of chemotherapeutic drug through BMP-SMAD signaling pathway
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层状双氢氧化物通过BMP-SMAD信号通路消除化疗药物的胚胎毒性
DOI：
10.1016/j.biomaterials.2019.119602
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发表时间：
2020
期刊：
影响因子：
14
通讯作者：
Rongrong Zhu
中科院分区：
文献类型：
--
作者：
Zhaojie Wang;Ziping Xu;Guoxin Jing;Qingxiu Wang;Li Yang;Xiaolie He;Lijuan Lin;Jintong Niu;Linnan Yang;Kun Li;Zhongmin Liu;Yechang Qian;Shilong Wang;Rongrong Zhu
近年来的研究表明，外源性化疗药物可以穿过胎盘屏障，引起胎儿毒性，而对妊娠癌症患者的替代治疗几乎没有。在这里，我们展示了层状双氢氧化物（LDH）对依托泊苷（VP16）诱导的离体小鼠胚胎干细胞（mESCs）毒性和体内胚胎发育障碍的强大保护作用。纳米复合系统（L-V）完全消除了原始VP16产生的线粒体介导的mESCs毒性，令人惊讶地保持了不含白血病抑制因子（LIF）的多能性，并阻止了自发性胚状体分化过程中外胚层标记物表达的下调。当妊娠小鼠暴露于VP16时，会产生胎儿生长迟缓，相关的胎盘和骨骼结构异常以及后代的长期毒性，而当用L-V代替时，这些有害影响被消除。VP16和L-V在子宫内的药物蓄积不同是导致功能变化的部分原因。进一步的转录组分析证实了发育相关的BMP4-SMAD6信号通路至关重要。我们的研究揭示了VP16对胚胎发育的破坏性作用以及利用纳米载体系统的毒性缓解方法，将为LDH作为一种副作用最小的替代治疗系统在诊断为癌症的孕妇中的临床应用提供重要指导。
Recent studies indicate that exogenous chemotherapy agents can cross the placenta barrier and cause fetal toxicity, while there exists barely alternative therapy for pregnant cancer patients. Here, we show a robust protective effect of layered double hydroxide (LDH) against etoposide (VP16) inducedin vitromouse embryonic stem cells (mESCs) toxicity andin vivoembryo developmental disorders. The nano-composite system (L-V) abrogated the original VP16 generated mitochondrial mediated mESCs toxicity totally, surprisingly maintained the pluripotency without leukemia inhibitory factor (LIF) and prevented the down-regulation of ectoderm marker expression during spontaneous embryoid bodies differentiation. Fetal growth retardation, the related placenta and skeletal structural abnormalities and long-term toxicity in the offspring were generated when pregnant mice exposed to VP16, while these detrimental effects were abolished when substituted with L-V. The different uterine drug accumulation of VP16 and L-V contributed to partly cause for the functional variation. And further transcriptome analysis confirmed developmental related BMP4-SMAD6 signaling pathway is of crucial importance. Our study revealed the devastating effects of VP16 on embryonic development and the toxicity-relieve method using nano-carrier system, which will provide important guidance for clinical application of LDH as alternative therapeutic system with minimal side effects for pregnant women diagnosed with cancer.