Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma
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Negar Babae1,*, Meriem Bourajjaj2,*, Yijia Liu3,*, Judy R. Van Beijnum4, Francesco Cerisoli2, Puthupparampil V. Scaria3, Mark Verheul2, Maaike P. Van Berkel4, Ebel H. E. Pieters1, Rick J. Van Haastert2, Afrouz Yousefi1, Enrico Mastrobattista1, Gert Storm5, Eugene Berezikov6, Edwin Cuppen6, Martin Woodle3, Roel Q. J. Schaapveld2, Gregoire P. Prevost2, Arjan W. Griffioen4, Paula I. Van Noort2 and Raymond M. Schiffelers7
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
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
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.
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