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

Autor: Peter Sminia, Robin M. de Kruijff, Helga E. de Vries, Gabriel Becerril Aragon, Ravi S. Narayan, Susanne M A van der Pol, Guzman Torrelo Villa, Ana Gasol Garcia, Fatima Bikhezar, Ben J. Slotman, Astrid J.G.M. van der Meer, Antonia G. Denkova
Přispěvatelé: Molecular cell biology and Immunology, Radiation Oncology, Amsterdam Neuroscience - Neurovascular Disorders, CCA - Cancer biology and immunology, ACS - Microcirculation
Jazyk: angličtina
Rok vydání: 2019
Předmět:
Zdroj: Journal of Neuro-Oncology
Bikhezar, F, de Kruijff, R M, van der Meer, A J G M, Torrelo Villa, G, van der Pol, S M A, Becerril Aragon, G, Gasol Garcia, A, Narayan, R S, de Vries, H E, Slotman, B J, Denkova, A G & Sminia, P 2020, ' Preclinical evaluation of binimetinib (MEK162) delivered via polymeric nanocarriers in combination with radiation and temozolomide in glioma ', Journal of Neuro-Oncology, vol. 146, no. 2, pp. 239-246 . https://doi.org/10.1007/s11060-019-03365-y, https://doi.org/10.1007/s11060-019-03365-y
Journal of Neuro-Oncology, 146(2), 239-246. Kluwer Academic Publishers
Journal of Neuro-Oncology, 146(2)
ISSN: 1573-7373
0167-594X
Popis: 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.
Databáze: OpenAIRE
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