title: Identification of Dormancy-Associated MicroRNAs for the Design of Osteosarcoma-Targeted Dendritic Polyglycerol Nanopolyplexes.
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 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.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Galia
authors.initials: G
authors.lastname: Tiram
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Ehud
authors.initials: E
authors.lastname: Segal
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Adva
authors.initials: A
authors.lastname: Krivitsky
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Rony
authors.initials: R
authors.lastname: Shreberk-Hassidim
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Ferber
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Paula
authors.initials: P
authors.lastname: Ofek
authors.affiliation: Vertex Pharmaceuticals , Cambridge, Massachusetts 02142, United States.
authors.forename: Taturo
authors.initials: T
authors.lastname: Udagawa
authors.affiliation: Department of Cell & Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Edry
authors.affiliation: Department of Cell & Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
authors.affiliation: Department of Genetics, The Life Sciences Institute, Edmond J. Safra Campus, The Hebrew University , Jerusalem 91905, Israel.
authors.forename: Maayan
authors.initials: M
authors.lastname: Roniger
authors.affiliation: Department of Genetics, The Life Sciences Institute, Edmond J. Safra Campus, The Hebrew University , Jerusalem 91905, Israel.
authors.forename: Batsheva
authors.initials: B
authors.lastname: Kerem
authors.affiliation: Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion, Israel Institute of Technology , Haifa 32000, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Shaked
authors.affiliation: Department of Pathology, Sheba Medical Center , Tel Hashomer 52621, Israel.|Talpiot Medical Leadership Program, Sheba Medical Center , Tel Hashomer 52621, Israel.
authors.forename: Sarit
authors.initials: S
authors.lastname: Aviel-Ronen
authors.affiliation: Department of Pathology, Sheba Medical Center , Tel Hashomer 52621, Israel.|Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin , Berlin 14195, Germany.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Calderón
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin , Berlin 14195, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv 69978, Israel.
authors.forename: Ronit
authors.initials: R
authors.lastname: Satchi-Fainaro
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D055808:Drug Discovery; D005990:Glycerol / Q000737:chemistry*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D050997:Nanomedicine; D049329:Nanostructures / Q000737:chemistry*; D012516:Osteosarcoma / Q000235:genetics* / Q000378:metabolism; D011108:Polymers / Q000737:chemistry*; D000090063:Proto-Oncogene Mas
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; C000715470:MAS1 protein, human; D035683:MicroRNAs; D011108:Polymers; D000090063:Proto-Oncogene Mas; C043941:polyglycerol; D005990:Glycerol
keywords: dendrimer; hyperbranched polymer; microRNA; osteosarcoma; polymeric nanomedicine; polyplex; tumor dormancy