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Oncotarget. 2014 Aug 30;5(16):6687-700.

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

Author information

1
Utrecht Institute for Pharmaceutical Sciences, University Utrecht, Utrecht, the Netherlands. These authors contributed equally to this work.
2
InteRNA Technologies B.V., Utrecht, the Netherlands. These authors contributed equally to this work.
3
Aparna Biosciences Corporation, Rockville MD, USA. These authors contributed equally to this work.
4
VU University Medical Center, MB Amsterdam, the Netherlands.
5
InteRNA Technologies B.V., Utrecht, the Netherlands.
6
Aparna Biosciences Corporation, Rockville MD, USA.
7
Utrecht Institute for Pharmaceutical Sciences, University Utrecht, Utrecht, the Netherlands. .
8
MIRA Institute for Biomedical Technology & Technical Medicine, Faculty of Science & Technology, University of Twente, AE Enschede, the Netherlands.
9
Hubrecht Institute, Cancer Genomics Center and University Medical Center Utrecht, Utrecht, the Netherlands.
10
Laboratory Clinical Chemistry & Haematology, University Medical Center Utrecht (UMCU), Utrecht, the Netherlands.

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.

PMID:
25149532
PMCID:
PMC4196156
DOI:
10.18632/oncotarget.2235
[Indexed for MEDLINE]
Free PMC Article

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