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Glioblastoma multiforme(GBM)is a lethal,therapy-resistant brain cancer consisting of numerous tumor cell subpopulations,including stem-like glioma-initiating cells(GICs),which contribute to tumor recurrence following initial response to therapy.Here,we identified miR-182 as a regulator of apoptosis,growth,and differentiation programs whose expression level is correlated with GBM patient survival.Repression of Bcl2-like12(Bcl2L12),c-Met,and hypoxia-inducible factor 2α(HIF2A)is of central importance to miR-182 anti-tumor activity,as it results in enhanced therapy susceptibility,decreased GIC sphere size,expansion,and stemness in vitro.To evaluate the tumor-suppressive function of miR-182 in vivo,we synthesized miR-182-based spherical nucleic acids(182-SNAs);i.e.,gold nanoparticles covalently functionalized with mature miR-182 duplexes.Intravenously administered 182-SNAs penetrated the bloodbrain/blood-tumor barriers(BBB/BTB)in orthotopic GBM xenografts and selectively disseminated throughout extravascular glioma parenchyma,causing reduced tumor burden and increased animal survival.Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.
Glioblastoma multiforme (GBM) is a lethal, therapy-resistant brain cancer consisting of numerous tumor cell subpopulations, including stem-like glioma-initiating cells (GICs), which contribute to the tumor recurrence following initial response to therapy. Here, we identified miR- 182 as a regulator of apoptosis, growth, and differentiation programs whose expression level is correlated with GBM patient survival. Retression of Bcl2-like12 (Bcl2L12), c-Met, and hypoxia- inducible factor 2a (HIF2A) is of central importance to miR -182 anti-tumor activity, as it results in enhanced therapy susceptibility, decreased GIC sphere size, expansion, and stemness in vitro. To evaluate the tumor-suppressive function of miR-182 in vivo, we formed miR- 182-based spherical nucleic (182-SNAs); ie, gold nanoparticles covalently functionalized with mature miR-182 duplexes. Intravenously administered 182-SNAs penetrated the bloodbrain / blood-tumor barriers (BBB / BTB) in orthotopic GBM xenografts and selectively disseminated throu ghout extravascular glioma parenchyma, causing reduced tumor burden and increased animal survival. Our results indicate that harnessing the anti-tumor activities of miR-182 via safe and robust delivery of 182-SNAs represents a novel strategy for therapeutic intervention in GBM.