Differentiation antagonizing noncoding RNA(DANCR)is recognized as an oncogenic long noncoding RNA(lncRNA)overexpressed in triple negative breast cancer(TNBC).We showed in a previous study that RNAi with targeted multi...Differentiation antagonizing noncoding RNA(DANCR)is recognized as an oncogenic long noncoding RNA(lncRNA)overexpressed in triple negative breast cancer(TNBC).We showed in a previous study that RNAi with targeted multifunctional ionizable lipid ECO/siRNA nanoparticles was effective to regulate this undruggable target for effective treatment of TNBC.In this study,we developed dual-targeted ECO/siDANCR nanoparticles by targeting a tumor extracellular matrix oncoprotein,extradomain B fibronectin(EDB-FN),and integrins overexpressed on cancer cells for enhanced delivery of siDANCR.The treatment of Hs578T TNBC cells and MCF-7 estrogen receptor-positive cells in vitro resulted in significant downregulation of DANCR and EDB-FN and suppressed invasion and 3D spheroid formation of the cells.Magnetic resonance molecular imaging(MRMI)with an EDBFN-targeted contrast agent,MT218,was used to noninvasively evaluate tumor response to treatment with the targeted ECO/siDANCR nanoparticles in female nude mice bearing orthotopic Hs578T and MCF-7 xenografts.MRMI with MT218 was effective to differentiate between aggressive TNBC with high DANCR and EDB-FN expression and ER+MCF-7 tumors with low expression of the targets.MRMI showed that the dualtargeted ECO/siDANCR nanoparticles resulted in more significant inhibition of tumor growth in both models than the controls and significantly reduced EDB-FN expression in the TNBC tumors.The combination of MRMI and dual-targeted ECO/siDANCR nanoparticles is a promising approach for image-guided treatment of TNBC by regulating the onco-lncRNA.展开更多
基金supported by the National Cancer Institute of the National Institutes of Health,grant R01 CA235152,and by the Tissue Resources Shared Resource of the Case Comprehensive Cancer Center(P30 CA043703).
文摘Differentiation antagonizing noncoding RNA(DANCR)is recognized as an oncogenic long noncoding RNA(lncRNA)overexpressed in triple negative breast cancer(TNBC).We showed in a previous study that RNAi with targeted multifunctional ionizable lipid ECO/siRNA nanoparticles was effective to regulate this undruggable target for effective treatment of TNBC.In this study,we developed dual-targeted ECO/siDANCR nanoparticles by targeting a tumor extracellular matrix oncoprotein,extradomain B fibronectin(EDB-FN),and integrins overexpressed on cancer cells for enhanced delivery of siDANCR.The treatment of Hs578T TNBC cells and MCF-7 estrogen receptor-positive cells in vitro resulted in significant downregulation of DANCR and EDB-FN and suppressed invasion and 3D spheroid formation of the cells.Magnetic resonance molecular imaging(MRMI)with an EDBFN-targeted contrast agent,MT218,was used to noninvasively evaluate tumor response to treatment with the targeted ECO/siDANCR nanoparticles in female nude mice bearing orthotopic Hs578T and MCF-7 xenografts.MRMI with MT218 was effective to differentiate between aggressive TNBC with high DANCR and EDB-FN expression and ER+MCF-7 tumors with low expression of the targets.MRMI showed that the dualtargeted ECO/siDANCR nanoparticles resulted in more significant inhibition of tumor growth in both models than the controls and significantly reduced EDB-FN expression in the TNBC tumors.The combination of MRMI and dual-targeted ECO/siDANCR nanoparticles is a promising approach for image-guided treatment of TNBC by regulating the onco-lncRNA.
