Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma

// Negar Babae 1,* , Meriem Bourajjaj 2,* , Yijia Liu 3,* , Judy R. Van Beijnum 4 , Francesco Cerisoli 2 , Puthupparampil V. Scaria 3 , Mark Verheul 2 , Maaike P. Van Berkel 4 , Ebel H. E. Pieters 1 , Rick J. Van Haastert 2 , Afrouz Yousefi 1 , Enrico Mastrobattista 1 , Gert Storm 5 , Eugene Berezikov 6 , Edwin Cuppen 6 , Martin Woodle 3 , Roel Q. J. Schaapveld 2 , Gregoire P. Prevost 2 , Arjan W. Griffioen 4 , Paula I. Van Noort 2 and Raymond M. Schiffelers 7 1 Utrecht Institute for Pharmaceutical Sciences, University Utrecht, Utrecht, the Netherlands 2 InteRNA Technologies B.V., Utrecht, the Netherlands 3 Aparna Biosciences Corporation, Rockville MD, USA 4 VU University Medical Center, MB Amsterdam, the Netherlands 5 MIRA Institute for Biomedical Technology & Technical Medicine, Faculty of Science & Technology, University of Twente, AE Enschede, the Netherlands 6 Hubrecht Institute, Cancer Genomics Center and University Medical Center Utrecht, Utrecht, the Netherlands 7 Laboratory Clinical Chemistry & Haematology, University Medical Center Utrecht (UMCU), Utrecht, the Netherlands * These authors contributed equally to this work Correspondence: Negar Babae, email: // Raymond M. Schiffelers, email: // Keywords : microRNA; miR-7; angiogenesis; delivery; Therapy Received : March 20, 2014 Accepted : July 18, 2014 Published : July 18, 2014 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.