title: Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma.
abstract: Tumor-angiogenesis is the multi-factorial process of sprouting of endothelial cells (EC) into micro-vessels to provide tumor cells with nutrients and oxygen. To explore miRNAs as therapeutic angiogenesis-inhibitors, we performed a functional screen to identify miRNAs that are able to decrease EC viability. We identified miRNA-7 (miR-7) as a potent negative regulator of angiogenesis. Introduction of miR-7 in EC resulted in strongly reduced cell viability, tube formation, sprouting and migration. Application of miR-7 in the chick chorioallantoic membrane assay led to a profound reduction of vascularization, similar to anti-angiogenic drug sunitinib. Local administration of miR-7 in an in vivo murine neuroblastoma tumor model significantly inhibited angiogenesis and tumor growth. Finally, systemic administration of miR-7 using a novel integrin-targeted biodegradable polymeric nanoparticles that targets both EC and tumor cells, strongly reduced angiogenesis and tumor proliferation in mice with human glioblastoma xenografts. Transcriptome analysis of miR-7 transfected EC in combination with in silico target prediction resulted in the identification of OGT as novel target gene of miR-7. Our study provides a comprehensive validation of miR-7 as novel anti-angiogenic therapeutic miRNA that can be systemically delivered to both EC and tumor cells and offers promise for miR-7 as novel anti-tumor therapeutic.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, University Utrecht, Utrecht, the Netherlands. These authors contributed equally to this work.
authors.forename: Negar
authors.initials: N
authors.lastname: Babae
authors.affiliation: InteRNA Technologies B.V., Utrecht, the Netherlands. These authors contributed equally to this work.
authors.forename: Meriem
authors.initials: M
authors.lastname: Bourajjaj
authors.affiliation: Aparna Biosciences Corporation, Rockville MD, USA. These authors contributed equally to this work.
authors.forename: Yijia
authors.initials: Y
authors.lastname: Liu
authors.affiliation: VU University Medical Center, MB Amsterdam, the Netherlands.
authors.forename: Judy R
authors.initials: JR
authors.lastname: Van Beijnum
authors.affiliation: InteRNA Technologies B.V., Utrecht, the Netherlands.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cerisoli
authors.affiliation: Aparna Biosciences Corporation, Rockville MD, USA.
authors.forename: Puthupparampil V
authors.initials: PV
authors.lastname: Scaria
authors.affiliation: InteRNA Technologies B.V., Utrecht, the Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Verheul
authors.affiliation: VU University Medical Center, MB Amsterdam, the Netherlands.
authors.forename: Maaike P
authors.initials: MP
authors.lastname: Van Berkel
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, University Utrecht, Utrecht, the Netherlands. .
authors.forename: Ebel H E
authors.initials: EH
authors.lastname: Pieters
authors.affiliation: InteRNA Technologies B.V., Utrecht, the Netherlands.
authors.forename: Rick J
authors.initials: RJ
authors.lastname: Van Haastert
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, University Utrecht, Utrecht, the Netherlands. .
authors.forename: Afrouz
authors.initials: A
authors.lastname: Yousefi
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences, University Utrecht, Utrecht, the Netherlands. .
authors.forename: Enrico
authors.initials: E
authors.lastname: Mastrobattista
authors.affiliation: MIRA Institute for Biomedical Technology & Technical Medicine, Faculty of Science & Technology, University of Twente, AE Enschede, the Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Hubrecht Institute, Cancer Genomics Center and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Eugene
authors.initials: E
authors.lastname: Berezikov
authors.affiliation: Hubrecht Institute, Cancer Genomics Center and University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Aparna Biosciences Corporation, Rockville MD, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Woodle
authors.affiliation: InteRNA Technologies B.V., Utrecht, the Netherlands.
authors.forename: Roel Q J
authors.initials: RQ
authors.lastname: Schaapveld
authors.affiliation: InteRNA Technologies B.V., Utrecht, the Netherlands.
authors.forename: Gregoire P
authors.initials: GP
authors.lastname: Prevost
authors.affiliation: VU University Medical Center, MB Amsterdam, the Netherlands.
authors.forename: Arjan W
authors.initials: AW
authors.lastname: Griffioen
authors.affiliation: InteRNA Technologies B.V., Utrecht, the Netherlands.
authors.forename: Paula I
authors.initials: PI
authors.lastname: Van Noort
authors.affiliation: Laboratory Clinical Chemistry & Haematology, University Medical Center Utrecht (UMCU), Utrecht, the Netherlands.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Schiffelers
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002642:Chick Embryo; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005909:Glioblastoma / Q000098:blood supply / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008819:Mice, Nude; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy; D011897:Random Allocation; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; C549242:MIRN7-1 microRNA, human