Identification of Dormancy-Associated MicroRNAs for the Design of Osteosarcoma-Targeted Dendritic Polyglycerol Nanopolyplexes

Galia Tiram, Ehud Segal, Adva Krivitsky, Rony Shreberk-Hassidim, Shiran Ferber, Paula Ofek, Taturo Udagawa, Liat Edry, Noam Shomron, Maayan Roniger, Batsheva Kerem, Yuval Shaked, Sarit Aviel-Ronen, Iris Barshack, Marcelo Calderón, Rainer Haag, Ronit Satchi-Fainaro*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


The presence of dormant, microscopic cancerous lesions poses a major obstacle for the treatment of metastatic and recurrent cancers. While it is well-established that microRNAs play a major role in tumorigenesis, their involvement in tumor dormancy has yet to be fully elucidated. We established and comprehensively characterized pairs of dormant and fast-growing human osteosarcoma models. Using these pairs of mouse tumor models, we identified three novel regulators of osteosarcoma dormancy: MiR-34a, miR-93, and miR-200c. This report shows that loss of these microRNAs occurs during the switch from dormant avascular into fast-growing angiogenic phenotype. We validated their downregulation in patients̈ tumor samples compared to normal bone, making them attractive candidates for osteosarcoma therapy. Successful delivery of miRNAs is a challenge; hence, we synthesized an aminated polyglycerol dendritic nanocarrier, dPG-NH2, and designed dPG-NH2-microRNA polyplexes to target cancer. Reconstitution of these microRNAs using dPG-NH2 polyplexes into Saos-2 and MG-63 cells, which generate fast-growing osteosarcomas, reduced the levels of their target genes, MET proto-oncogene, hypoxia-inducible factor 1α, and moesin, critical to cancer angiogenesis and cancer cells̈ migration. We further demonstrate that these microRNAs attenuate the angiogenic capabilities of fast-growing osteosarcomas in vitro and in vivo. Treatment with each of these microRNAs using dPG-NH2 significantly prolonged the dormancy period of fast-growing osteosarcomas in vivo. Taken together, these findings suggest that nanocarrier-mediated delivery of microRNAs involved in osteosarcoma tumor-host interactions can induce a dormant-like state.

Original languageAmerican English
Pages (from-to)2028-2045
Number of pages18
JournalACS Nano
Issue number2
StatePublished - 23 Feb 2016

Bibliographical note

Funding Information:
The Satchi-Fainaro laboratory''s research leading to these results has received partial funding from the European Research Council under the European Union''s Seventh Framework Programme (FP/2007-2013)/ERC Consolidator Grant Agreement n. [617445], the Israel Science Foundation (Grant No. 1309/10, 918/14), Swiss Bridge Award, Israel Cancer Research Foundation (ICRF). We thank Cathleen Schlesener for the preparation of polyglycerolamine and Dr. Camila Avivi for her professional assistance with the histology analysis.

Publisher Copyright:
© 2016 American Chemical Society.


  • dendrimer
  • hyperbranched polymer
  • microRNA
  • osteosarcoma
  • polymeric nanomedicine
  • polyplex
  • tumor dormancy


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