Restoring the oncosuppressor activity of microRNA-34a in glioblastoma using a polyglycerol-based polyplex.
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-NH2carrying 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.
Department of Physiology and Pharmacology, Tel Aviv University, Tel Aviv, Israel.
Paula
P
Ofek
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
Marcelo
M
Calderón
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
Fatemeh Sheikhi
FS
Mehrabadi
Department of Physiology and Pharmacology, Tel Aviv University, Tel Aviv, Israel.
Adva
A
Krivitsky
Department of Physiology and Pharmacology, Tel Aviv University, Tel Aviv, Israel.
Shiran
S
Ferber
Department of Physiology and Pharmacology, Tel Aviv University, Tel Aviv, Israel.
Galia
G
Tiram
Rosetta Genomics, Rehovot, Israel.
Noga
N
Yerushalmi
Rosetta Genomics, Rehovot, Israel.
Sharon
S
Kredo-Russo
Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Rachel
R
Grossman
Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Zvi
Z
Ram
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany.
Rainer
R
Haag
Department of Physiology and Pharmacology, Tel Aviv University, Tel Aviv, Israel. Electronic address: ronitsf@post.tau.ac.il.
Ronit
R
Satchi-Fainaro
D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004337:Drug Carriers; D005909:Glioblastoma; D005990:Glycerol; D006801:Humans; D035683:MicroRNAs / Q000494:pharmacology*; D011108:Polymers
D004337:Drug Carriers; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D011108:Polymers; C043941:polyglycerol; D005990:Glycerol
Glioblastoma; MicroRNA-34a; Polyglycerol-based polyplex