Laboratory for Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Frauenklinikstrasse 26, 8091 Zurich, Switzerland.
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Vladimir-Prelog-Weg 1-5, 8093 Zurich, Switzerland.
J Control Release. 2019 Feb 10;295:130-139. doi: 10.1016/j.jconrel.2018.12.009. Epub 2018 Dec 8.
In glioblastoma, the benefit from temozolomide chemotherapy is largely limited to a subgroup of patients (30-35%) with tumors exhibiting methylation of the promoter region of the O-methylguanine-DNA methyltransferase (MGMT) gene. In order to allow more patients to benefit from this treatment, we explored magnetic resonance image-guided microbubble-enhanced low-intensity pulsed focused ultrasound (LIFU) to transiently open the blood-brain barrier and deliver a first-in-class liposome-loaded small molecule MGMT inactivator in mice bearing temozolomide-resistant gliomas. We demonstrate that a liposomal O-(4-bromothenyl)guanine (OBTG) derivative can efficiently target MGMT, thereby sensitizing murine and human glioma cells to temozolomide in vitro. Furthermore, we report that image-guided LIFU mediates the delivery of the stable liposomal MGMT inactivator in the tumor region resulting in potent MGMT depletion in vivo. Treatment with this new liposomal MGMT inactivator facilitated by LIFU-mediated blood-brain barrier opening reduced tumor growth and significantly prolonged survival of glioma-bearing mice, when combined with temozolomide chemotherapy. Exploring this novel combined approach in the clinic to treat glioblastoma patients with MGMT promoter-unmethylated tumors is warranted.
在胶质母细胞瘤中，替莫唑胺化疗的获益在很大程度上仅限于肿瘤启动子区域 O-甲基鸟嘌呤-DNA 甲基转移酶 (MGMT) 基因甲基化的亚组患者（30-35%）。为了让更多的患者从这种治疗中获益，我们探索了磁共振成像引导的微泡增强低强度脉冲聚焦超声（LIFU）来短暂打开血脑屏障，并在携带替莫唑胺耐药性胶质母细胞瘤的小鼠中递送一种首创的载小分子 MGMT 失活剂的脂质体。我们证明，一种载有 O-(4-溴苯基)鸟嘌呤（OBTG）衍生物的脂质体可以有效地靶向 MGMT，从而使鼠和人胶质母细胞瘤细胞对替莫唑胺在体外敏感。此外，我们报告说，图像引导的 LIFU 介导了稳定的脂质体 MGMT 失活剂在肿瘤区域的递送至体内有效地耗尽 MGMT。当与替莫唑胺化疗联合使用时，这种新的通过 LIFU 介导的血脑屏障开放的脂质体 MGMT 失活剂的治疗促进了肿瘤生长的减少，并显著延长了荷瘤小鼠的存活时间。在临床上探索这种新的联合方法来治疗 MGMT 启动子未甲基化肿瘤的胶质母细胞瘤患者是有必要的。
