Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Neuroscience Institute, Heilongjiang Academy of Medical Sciences, 150086, Harbin, China.
State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials of Ministry of Education, College of Chemistry, Nankai University, 300071, Tianjin, China.
Nat Commun. 2020 Jan 30;11(1):594. doi: 10.1038/s41467-019-14036-x.
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-PEG-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.
受体酪氨酸激酶（RTK）蛋白的激活在神经胶质瘤的恶性进展中经常观察到。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 的激活，通过 NHS-PEG-Mal 修饰的 MPC-纳米颗粒表面上缀合 Inherbin3 和 cMBP，开发了一种双功能化的脑靶向纳米抑制剂 BIP-MPC-NP。在 BIP-MPC-NP 的存在下，通过 TTP 介导的 E2F1 的下调，减弱了 DNA 损伤修复，并且增强了 TMZ 耐药性神经胶质瘤中 TMZ 的敏感性。体内磁共振成像（MRI）显示，注射 BIP-MPC-NP 和 TMZ 后，肿瘤生长显著受到抑制，小鼠的存活时间延长。这些结果表明，这种纳米抑制剂作为一种可行的策略，克服了神经胶质瘤中 TMZ 耐药性具有很大的潜力。
