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

Research output: Contribution to journalArticlepeer-review

Abstract

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 languageEnglish
Pages (from-to)2028-2045
Number of pages18
JournalACS Nano
Volume10
Issue number2
DOIs
StatePublished - 23 Feb 2016

Keywords

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

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