Preclinical evaluation of binimetinib (MEK162) delivered via polymeric nanocarriers in combination with radiation and temozolomide in glioma

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 binim...

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Bibliographic Details
Published in:Journal of neuro-oncology 2020-01, Vol.146 (2), p.239-246
Main Authors: Bikhezar, Fatima, de Kruijff, Robin M., van der Meer, Astrid J. G. M., Torrelo Villa, Guzman, van der Pol, Susanne M. A., Becerril Aragon, Gabriel, Gasol Garcia, Ana, Narayan, Ravi S., de Vries, Helga E., Slotman, Ben J., Denkova, Antonia G., Sminia, Peter
Format: Article
Language:English
Subjects:
Allosteric properties
Blood-brain barrier
Brain cancer
Brain tumors
Cell proliferation
Endothelial cells
Glioblastoma
Glioblastoma multiforme
Glioma
Laboratory Investigation
MAP kinase
Medicine
Medicine & Public Health
Metabolic pathways
Microvasculature
Neurology
Oncology
Radiation therapy
Spheroids
Temozolomide
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Summary: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.
ISSN:0167-594X
1573-7373
DOI:10.1007/s11060-019-03365-y