Systemic Delivery of Tumor-Targeting siRNA Nanoparticles against an Oncogenic LncRNA Facilitates Effective Triple-Negative Breast Cancer Therapy

Abstract

Long non-coding RNAs (lncRs), by virtue of their versatility and multilevel gene regulation, have emerged as attractive pharmacological targets for treating heterogenous and complex malignancies like triple-negative breast cancer (TNBC). Despite multiple studies on lncRNA functions in tumor pathology, systemic targeting of these "undruggable" macromolecules with conventional approaches remains a challenge. Here, we demonstrate effective TNBC therapy by nanoparticlemediated RNAi of the oncogenic lncRNA DANCR, which is significantly overexpressed in TNBC. Tumor-targeting RGD-PEG-ECO/siDANCR nanoparticles were formulated via selfassembly of multifunctional amino lipid ECO, cyclic RGD peptide-PEG, and siDANCR for systemic delivery. MDA-MB-231 and BT549 cells treated with the therapeutic RGD-PEG-ECO/ siDANCR nanoparticles exhibited 80-90% knockdown in the expression of DANCR for up to 7 days, indicating efficient intracellular siRNA delivery and sustained target silencing. The RGD-PEG-ECO/siDANCR nanoparticles mediated excellent in vitro therapeutic efficacy, reflected by the significant reduction in the invasion, migration, survival, tumor spheroid formation, and proliferation of the TNBC cell lines. At the molecular level, functional ablation of DANCR

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

“…Vaidya et al describe an effective TNBC therapy that uses nanoparticle-mediated transfer of RNAi molecules targeting the TNBC/CSC enriched lncRNA DANCR [132]. This therapy led to reduced tumor progression and was associated with no side effects in a murine xenograft model of TNBC.…”

Extradomain-B Fibronectin is a molecular marker of invasive breast cancer cells

“…Total cellular protein was extracted as previously described (Vaidya et al, 2019). Protein extracts (40 µg) were run on SDS-PAGE, transferred onto nitrocellulose membrane and immunoblotted with primary antibodies overnight.…”

Role of eIF4E on epithelial‐mesenchymal transition, invasion, and chemoresistance of prostate cancer cells

“…ECO/siRNA nanoparticles have been shown to mediate effective RNAi of various oncogenic targets in vitro and in vivo [8‐10]. To further confirm the role of eIF4E in PCa cells, the effects of down‐regulation of eIF4E were assessed using RNAi based on ECO/siRNA nanoparticles.…”

“…The precise role of eIF4E in EMT, invasion, and chemoresistance in PCa is still to be established with consideration of different subpopulations in order to develop precision medicine for PCa. In this work, we aimed to explore the role of eIF4E in EMT, invasion, and chemoresistance in PCa for establishing a promising new therapeutic strategy by regulating eIF4E expression using (1-aminoethyl)iminobis[Noleicylcysteinyl-1-aminoethyl) propionamide] (ECO)/small interfering RNA (siRNA) nanoparticles previously developed in our lab [8][9][10] for PCa therapy in the context of tumor heterogeneity.Two PCa cell lines (PC3 and DU145) and their corresponding paclitaxel (PTX)-resistant cell lines (PC3-DR and DU145-DR) were investigated to assess the role of eIF4E Abbreviations: ECO, (1-aminFoethyl)iminobis[N-oleicylcysteinyl-1-aminoethyl) propionamide]; eIF4E, eukaryotic translation initiation factor 4E; EMT, epithelial-mesenchymal transition; MET, mesenchymal-epithelial transition; MMP3, matrix metalloproteinase 3; PCa, prostate cancer; PTX, paclitaxel; siRNA, small interfering RNA.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.…”

“…The expression of eIF4E followed the same trend with the expression of mesenchymal markers in all four cell lines, regardless of drug resistance. Considering the results of morphology, EMT, and invasiveness of all four cell lines, it was found that eIF4E ECO/siRNA nanoparticles have been shown to mediate effective RNAi of various oncogenic targets in vitro and in vivo [8][9][10]. To further confirm the role of eIF4E in PCa cells, the effects of down-regulation of eIF4E were assessed using RNAi based on ECO/siRNA nanoparticles.…”