Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and MET signaling pathways
Dual functionalized brain-targeting nanoinhibitors restrain temozolomide-resistant glioma via attenuating EGFR and MET signaling pathways
复制标题
双功能化脑靶向纳米抑制剂通过减弱 EGFR 和 MET 信号通路抑制替莫唑胺耐药神经胶质瘤
DOI：
10.1038/s41467-019-14036-x
复制
发表时间：
2020-01-30
影响因子：
16.6
通讯作者：
Cai, Jinquan
中科院分区：
文献类型：
--
作者：
Meng, Xiangqi;Zhao, Yu;Cai, Jinquan
受体酪氨酸激酶（RTK）蛋白的激活在胶质瘤的恶性进展中经常被观察到。在这项研究中，表皮生长因子受体（EGFR）和间充质-上皮转化因子（MET）信号通路的串扰激活被证明有助于替莫唑胺（TMZ）耐药，导致胶质母细胞瘤患者预后不良。为了同时减轻EGFR和MET活化，通过将Inherbin 3和cMBP缀合在NHS-PEG 8-Mal修饰的MPC-纳米颗粒的表面上来开发双重功能化的脑靶向纳米抑制剂BIP-MPC-NP。在BIP-MPC-NP存在下，DNA损伤修复减弱，TMZ敏感性通过TTP介导的TMZ耐药胶质瘤中E2 F1的下调而增强。体内磁共振成像（MRI）显示在注射BIP-MPC-NP和TMZ后肿瘤生长的显著抑制和小鼠的延长的存活。这些结果证明了这种纳米抑制剂作为克服胶质瘤中TMZ耐药性的可行策略的前景。
Activation of receptor tyrosine kinase (RTK) protein is frequently observed in malignant progression of gliomas. In this study, the crosstalk activation of epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling pathways is demonstrated to contribute to temozolomide (TMZ) resistance, resulting in an unfavorable prognosis for patients with glioblastoma. To simultaneously mitigate EGFR and MET activation, a dual functionalized brain-targeting nanoinhibitor, BIP-MPC-NP, is developed by conjugating Inherbin3 and cMBP on the surface of NHS-PEG8-Mal modified MPC-nanoparticles. In the presence of BIP-MPC-NP, DNA damage repair is attenuated and TMZ sensitivity is enhanced via the down-regulation of E2F1 mediated by TTP in TMZ resistant glioma. In vivo magnetic resonance imaging (MRI) shows a significant repression in tumor growth and a prolonged survival of mice after injection of the BIP-MPC-NP and TMZ. These results demonstrate the promise of this nanoinhibitor as a feasible strategy overcoming TMZ resistance in glioma.