Department of Biomedical Engineering, University of Delaware, 161 Colburn Lab, 150 Academy Street, Newark, DE, 19716, USA.
Department of Materials Science and Engineering, University of Delaware, Newark, DE, 19716, USA.
Small. 2017 Jul;13(26). doi: 10.1002/smll.201700544. Epub 2017 May 22.
Antibodies that antagonize cell signaling pathways specific to their targeted receptor are invaluable tools to study and treat malignancies, but their utility is limited by high production costs and treatment dosages. Researchers have shown that antibodies conjugated to nanoparticles display increased affinity for their target relative to freely delivered antibodies due to multivalency, and this study investigates how this multivalency can enable antibody-nanoparticle conjugates to inhibit oncogenic cell signaling more effectively than freely delivered antibodies. This effect was evaluated using triple negative breast cancer (TNBC) cells that are characterized by hyperactive Wnt signaling mediated through overexpressed Frizzled7 (FZD7) transmembrane receptors. Through analysis of the expression of β-catenin and Axin2, two downstream targets in the Wnt pathway, the results demonstrate that FZD7 antibody-nanoshell conjugates (FZD7-NS) are drastically more effective at inhibiting Wnt signaling in TNBC cells than freely delivered FZD7 antibodies. Additionally, cells treated with FZD7-NS, but not cells treated with freely delivered FZD7 antibodies, have decreased viability, indicating the therapeutic potential of this technology. The results demonstrate that antibody-functionalized nanoparticles can exploit multivalency for improved signal cascade interference over free antibodies, and this may ultimately permit lower antibody dosages to be administered to study signaling pathways or to manage diseases.
拮抗特定于其靶受体的细胞信号通路的抗体是研究和治疗恶性肿瘤的宝贵工具,但由于高生产成本和治疗剂量,其用途受到限制。研究人员已经表明,与自由递呈的抗体相比,连接到纳米颗粒上的抗体由于多价性而显示出对其靶标的更高亲和力,本研究调查了这种多价性如何使抗体-纳米颗粒缀合物比自由递呈的抗体更有效地抑制致癌细胞信号。使用三阴性乳腺癌 (TNBC) 细胞评估了这种效应,这些细胞的特征是通过过度表达的 Frizzled7 (FZD7) 跨膜受体介导的 Wnt 信号过度活跃。通过分析 Wnt 通路的两个下游靶标 β-连环蛋白和 Axin2 的表达,结果表明,FZD7 抗体-纳米壳缀合物 (FZD7-NS) 比自由递呈的 FZD7 抗体更有效地抑制 TNBC 细胞中的 Wnt 信号。此外,用 FZD7-NS 处理的细胞而非用自由递呈的 FZD7 抗体处理的细胞活力降低,表明该技术具有治疗潜力。结果表明,抗体功能化的纳米颗粒可以利用多价性来改善信号级联干扰,而这最终可能允许降低抗体剂量以研究信号通路或管理疾病。
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