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

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• 作者：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
• 刊名：ACS Nano
• 出版年：2016
• 出版时间：February 23, 2016
• 年：2016
• 卷：10
• 期：2
• 页码：2028-2045
• 全文大小：986K
• ISSN：1936-086X

文摘

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.