title: Functionalized nanogels carrying an anticancer microRNA for glioblastoma therapy.
abstract: Glioblastoma Multiforme (GBM) is one of the most aggressive forms of all cancers. The median survival with current standard-of-care radiation and chemotherapy is about 14months. GBM is difficult to treat due to heterogeneity in cancer cell population. MicroRNA-based drugs have rapidly become a vast and burgeoning field due to the ability of a microRNA (miRNA) to target many genes involved in key cellular pathways. However, in vivo delivery of miRNA remains a crucial challenge for its therapeutic success. To bypass this shortcoming, we designed polymeric nanogels (NGs), which are based on a polyglycerol-scaffold, as a new strategy of miRNA delivery for GBM therapy. We focused on miR-34a, which is known for its key role in important oncogenic pathways and its tumor suppression ability in GBM and other cancers. We evaluated the capability of six NG derivatives to complex with miR-34a, neutralize its negative charge and deliver active miRNA to the cell cytoplasm. Human U-87 MG GBM cells treated with our NG-miR-34a nano-polyplexes showed remarkable downregulation of miR-34a target genes, which play key roles in the regulation of apoptosis and cell cycle arrest, and induce inhibition of cells proliferation and migration. Administration of NG-miR-34a nano-polyplexes to human U-87 MG GBM-bearing SCID mice significantly inhibited tumor growth as opposed to treatment with NG-negative control miR polyplex or saline. The comparison between different polyplexes highlighted the key features for the rational design of polymeric delivery systems for oligonucleotides. Taken together, we expect that this new therapeutic approach will pave the way for safe and efficient therapies for GBM.
authors: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Zohar
authors: Z
authors: Shatsberg
authors: Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; Key Laboratory of Pollution Ecology and Environmental Engineering, Institute of Applied Ecology, Chinese Academy of Sciences, Shenyang 110016, China.
authors: Xuejiao
authors: X
authors: Zhang
authors: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Paula
authors: P
authors: Ofek
authors: Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors: Shashwat
authors: S
authors: Malhotra
authors: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Adva
authors: A
authors: Krivitsky
authors: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Anna
authors: A
authors: Scomparin
authors: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Galia
authors: G
authors: Tiram
authors: Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany.
authors: Marcelo
authors: M
authors: Calderón
authors: Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany. Electronic address: haag@chemie.fu-berlin.de.
authors: Rainer
authors: R
authors: Haag
authors: Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: ronitsf@post.tau.ac.il.
authors: Ronit
authors: R
authors: Satchi-Fainaro
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage* / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D000080385:Nanogels; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000378:metabolism; D011094:Polyethyleneimine / Q000008:administration & dosage* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D004337:Drug Carriers; C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D000080385:Nanogels; C413692:polyethylene glycol polyethyleneimine nanogel; D011092:Polyethylene Glycols; D011094:Polyethyleneimine
keywords: Glioblastoma; Nanogels; Nanomedicine; Polycations; Polyglycerol; Polymer therapeutics; Polyplex; miR-34a; microRNAs