Evaluating Dual-Targeted ECO/siRNA Nanoparticles against an Oncogenic lncRNA for Triple Negative Breast Cancer Therapy with Magnetic Resonance Molecular Imaging

Abstract

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 down-regulation of DANCR and EDB-FN and suppressed invasion and 3D spheroid formation of the cells. Magnetic resonance molecular imaging (MRMI) with an EDB-FN-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 dual-targeted 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.

Assessment of the Efficacy of the Combination of RNAi of lncRNA DANCR with Chemotherapy to Treat Triple Negative Breast Cancer Using Magnetic Resonance Molecular Imaging

“…The results imply that the chemotherapy induced the transition of the cancer cells to a resistant phenotype. ZD2-siDANCR-ELNP were effective to down-regulate the expression of both DANCR and EDB-FN in naïve cancer cells and paclitaxel-treated cells, which was consistent with the previous observation using ZD2/RGD-PEG-ECO/siDANCR . ZD2-siDANCR-ELNP transfection sensitized the TNBC cells to paclitaxel and reduced the dose necessary to achieve the same reduction in cell viability as ZD2-siNS-ELNP transfection or no transfection in MDA-MB-231 cells.…”

“…MRMI is a high-resolution molecular imaging modality that can provide detailed molecular information about solid tumors during cancer therapies. MT218-MRMI noninvasively visualizes the expression of EDB-FN for the detection, characterization, and therapeutic response of multiple cancers, including TNBC. ,, In this study, MT218-MRMI revealed the dynamic and heterogeneous changes in EDB-FN expression in tumor ECM in correlation with therapeutic outcomes in response to various treatments. Although the three therapies showed similar inhibition of TNBC growth after treatments for 6 weeks, MT218-MRMI clearly differentiated tumor responses based on the molecular signature of EDB-FN, which was supported by histopathological and/or immunohistochemical analyses.…”

“…TNBC tumors in particular have high EDB-FN expression, and patients whose tumors overexpress EDB-FN have significantly poorer survival than those with low EDB-FN expression . Dual-targeted ZD2/RGD-siDANCR-ELNP were found to be more effective than using single-targeted RGD-siDANCR-ELNP for treating TNBC . Moreover, we also developed an EDB-FN-targeting gadolinium-based contrast agent using the same peptide-targeting strategy, called MT218, for magnetic resonance molecular imaging (MRMI) of cancer .…”

Construction of Targeting-Peptide-Based Imaging Reagents and Their Application in Bioimaging

“…Magnetic resonance imaging (MRI) has been widely used in clinical diagnostics . MRI is a noninvasive technique with the advantages of having extremely high spatial resolution and the absence of radiation exposure. − This feature allows early detection of even tumors as small as a few hundred cells and hundreds of micrometers in size . However, MRI has low sensitivity and usually requires a contrast agent to increase its sensitivity.…”

“…157−160 This feature allows early detection even tumors as small as a few hundred cells and hundreds of micrometers in size. 161 However, MRI has low sensitivity and usually requires a contrast agent to increase its sensitivity. Generally, MRI contrast agents are broadly classified into longitudinal relaxation contrast agents (T1 preparation) and transverse relaxation contrast agents (T2 preparation).…”