胶质母细胞瘤（GBM）是一种高度侵袭性的脑癌，预后不良，治疗选择有限。 ALK 和 c-MET 抑制剂 Crizotinib 已显示出对新诊断 GBM 的临床前治疗潜力，尽管其疗效因血脑屏障穿透性差而受到限制。在此，我们将 Crizotinib 确定为核因子 κB (NF-κB) 诱导激酶的新型抑制剂，该激酶是 GBM 生长和增殖的关键调节因子。我们进一步表明，与未缀合的克唑替尼相比，克唑替尼与七次甲基花青染料或近红外染料（IR-克唑替尼）的缀合在体外更大程度地减弱了神经胶质瘤细胞的增殖和存活。此外，我们观察到 IR-Crizotinib 在原位小鼠异种移植 GBM 肿瘤中的定位增加，导致体内肿瘤生长受损。总体而言，IR-Crizotinib 表现出改善的颅内化疗递送和肿瘤定位，同时抑制 NIK 和非经典 NF-κB 信号传导，从而减少体外和体内神经胶质瘤的生长，并提高临床前啮齿动物模型的存活率。

Glioblastoma (GBM) is a highly aggressive form of brain cancer with a poor prognosis and limited treatment options. The ALK and c-MET inhibitor Crizotinib has demonstrated preclinical therapeutic potential for newly diagnosed GBM, although its efficacy is limited by poor penetration of the blood brain barrier. Here, we identify Crizotinib as a novel inhibitor of nuclear factor-κB (NF-κB)-inducing kinase, which is a key regulator of GBM growth and proliferation. We further show that the conjugation of Crizotinib to a heptamethine cyanine dye, or a near-infrared dye (IR-Crizotinib), attenuated glioma cell proliferation and survival in vitro to a greater extent than unconjugated Crizotinib. Moreover, we observed increased IR-Crizotinib localization to orthotopic mouse xenograft GBM tumors, which resulted in impaired tumor growth in vivo. Overall, IR-Crizotinib exhibited improved intracranial chemotherapeutic delivery and tumor localization with concurrent inhibition of NIK and noncanonical NF-κB signaling, thereby reducing glioma growth in vitro, as well as in vivo, and increasing survival in a preclinical rodent model.