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

• Published in: ACS nano 2016-02, Vol.10 (2), p.2028-2045
• Main Authors: Tiram, Galia, Segal, Ehud, Krivitsky, Adva, Shreberk-Hassidim, Rony, Ferber, Shiran, Ofek, Paula, Udagawa, Taturo, Edry, Liat, Shomron, Noam, Roniger, Maayan, Kerem, Batsheva, Shaked, Yuval, Aviel-Ronen, Sarit, Barshack, Iris, Calderón, Marcelo, Haag, Rainer, Satchi-Fainaro, Ronit
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Cell Line, Tumor; Drug Carriers - chemistry; Drug Discovery; Glycerol - chemistry; Humans; Mice; Mice, SCID; MicroRNAs - chemistry; MicroRNAs - genetics; Nanomedicine; Nanostructures - chemistry; Osteosarcoma - genetics; Osteosarcoma - metabolism; Polymers - chemistry
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.5b06189

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 patients’ 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 cells’ 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.