Preclinical evaluation of binimetinib (MEK162) delivered via polymeric nanocarriers in combination with radiation and temozolomide in glioma
Preclinical evaluation of binimetinib (MEK162) delivered via polymeric nanocarriers in combination with radiation and temozolomide in glioma
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DOI：
10.1007/s11060-019-03365-y
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发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Sminia, Peter
中科院分区：
文献类型：
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作者：
Bikhezar, Fatima;de Kruijff, Robin M.;Sminia, Peter
背景与目的多形性胶质母细胞瘤是恶性胶质瘤中最具侵袭性的亚型，确诊后平均存活率为15个月。超过90%的基底膜在MAPK/ERK通路中存在激活突变。最近，我们展示了变构MEK1/2抑制剂比尼美替尼(MEK162)在临床前人类GBM模型中抑制细胞增殖和增强辐射效应的作用。由于游离药物不能通过血脑屏障(BBB)，我们研究了利用纳米载体转运药物通过血脑屏障，以及联合放射治疗和替莫唑胺(TMZ)对胶质瘤球体的疗效。方法采用多细胞U87人GBM球体进行体外研究。聚合物纳米载体(聚合体)负载MEK162。研究了MEK162纳米载体、辐射和TMZ之间的相互作用对球体生长动力学和MAPK/ERK途径蛋白表达的影响。人脑微血管内皮细胞(hCMEC/D3)在Transwell系统中进行血脑屏障传代。分次照射与TMZ联合作用对球体体积缩小有协同作用，与TMZ存在相加作用。人脑微血管内皮细胞可摄取荧光标记的多聚体，并在体外通过血脑屏障。结论MEK162多聚体被多细胞球体摄取。这种纳米载体输送的药物减少了球体的生长，并抑制了其分子靶点。通过聚合体传递的MEK162与辐射和TMZ有相互作用。聚合体跨越了体外血脑屏障模型，从而为脑肿瘤治疗药物的输送提供了令人兴奋的挑战。
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.