Restoring the Oncosuppressor Activity of MicroRNA-34a in Glioblastoma Using a Polyglycerol-based Polyplex.
Paula Ofek, Marcelo Calderón, Fatemeh Sheikhi Mehrabadi, Adva Krivitsky, Shiran Ferber, Galia Tiram, Noga Yerushalmi, Sharon Kredo-Russo, Rachel Grossm, Zvi Ram, Rainer Haag, Ronit Satchi-Fainaro – 2016
Glioblastoma multiforme (GBM) is the most common and aggressive primary neoplasm of the brain. Poor prognosis is mainly attributed to tumor heterogeneity, invasiveness, and drug resistance. microRNA-based therapeutics represent a promising approach due to their ability to inhibit multiple targets. In this work, we aim to restore the oncosuppressor activity of microRNA-34a (miR-34a) in GBM. We developed a cationic carrier system, dendritic polyglycerolamine (dPG-NH2), which remarkably improves miRNA stability, intracellular trafficking, and activity. dPG-NH2 carrying mature miR-34a targets C-MET, CDK6, Notch1 and BCL-2, consequently inhibiting cell cycle progression, proliferation and migration of GBM cells. Following complexation with dPG-NH2, miRNA is stable in plasma and able to cross the blood–brain barrier. We further show inhibition of tumor growth following treatment with dPG-NH2–miR-34a in a human glioblastoma mouse model. We hereby present a promising technology using dPG-NH2–miR-34a polyplex for brain-tumor treatment, with enhanced efficacy and no apparent signs of toxicity.