BACKGROUND AND PURPOSE Glioblastoma multiforme (GBM) is the most aggressive subtype of malignant gliomas, with an average survival rate of 15 months after diagnosis. More than 90% of all GBMs have activating mutations in the MAPK/ERK pathway. Recently, we showed the allosteric MEK1/2 inhibitor binimetinib (MEK162) to inhibit cell proliferation and to enhance the effect of radiation in preclinical human GBM models. Because the free drug cannot pass the blood-brain barrier (BBB), we investigated the use of nanocarriers for transport of the drug through the BBB and its efficacy when combined with radiotherapy and temozolomide (TMZ) in glioma spheroids. METHODS In vitro studies were performed using multicellular U87 human GBM spheroids. Polymeric nanocarriers (polymersomes) were loaded with MEK162. The interaction between nanocarrier delivered MEK162, irradiation and TMZ was studied on the kinetics of spheroid growth and on protein expression in the MAPK/ERK pathway. BBB passaging was evaluated in a transwell system with human cerebral microvascular endothelial (hCMEC/D3) cells. RESULTS MEK162 loaded polymersomes inhibited spheroid growth. A synergistic effect was found in combination with fractionated irradiation and an additive effect with TMZ on spheroid volume reduction. Fluorescent labeled polymersomes were taken up by human cerebral microvascular endothelial cells and passed the BBB in vitro. CONCLUSION MEK162 loaded polymersomes are taken up by multicellular spheroids. The nanocarrier delivered drug reduced spheroid growth and inhibited its molecular target. MEK162 delivered via polymersomes showed interaction with irradiation and TMZ. The polymersomes crossed the in vitro BBB model and therewith offer exciting challenges ahead for delivery of therapeutics agents to brain tumours.

中文翻译：

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胶质瘤中通过聚合物纳米载体与放射线和替莫唑胺联用的比尼替尼（MEK162）的临床前评价。

背景与目的多形性胶质母细胞瘤（GBM）是恶性神经胶质瘤中最具侵略性的亚型，诊断后的平均生存期为15个月。所有GBM中有90％以上在MAPK / ERK途径中具有激活性突变。最近，我们在临床前的人GBM模型中显示了变构MEK1 / 2抑制剂Binimetinib（MEK162）抑制细胞增殖并增强放射作用。因为游离药物不能通过血脑屏障（BBB），所以我们研究了使用纳米载体通过BBB转运药物及其与放疗和替莫唑胺（TMZ）联合治疗胶质瘤球体的功效。方法使用多细胞U87人GBM球体进行体外研究。聚合物纳米载体（聚合物小体）装有MEK162。纳米载体之间的相互作用传递了MEK162，辐射和TMZ研究了球体生长的动力学和MAPK / ERK途径中的蛋白质表达。在具有人脑微血管内皮（hCMEC / D3）细胞的Transwell系统中评估了BBB传代。结果载有MEK162的聚合物囊泡抑制了球状细胞的生长。结合分次照射发现协同作用，TMZ与球体体积减少产生相加作用。荧光标记的聚合物囊泡被人脑微血管内皮细胞吸收，并在体外通过了血脑屏障。结论负载MEK162的聚合物囊泡被多细胞球体吸收。纳米载体递送的药物减少了球状体的生长并抑制了其分子靶标。经由聚合物小体递送的MEK162显示出与辐射和TMZ的相互作用。