Gold nanoparticles loaded with cullin-5 DNA increase sensitivity to 17-AAG in cullin-5 deficient breast cancer cells
Gold nanoparticles loaded with cullin-5 DNA increase sensitivity to 17-AAG in cullin-5 deficient breast cancer cells
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DOI：
10.1016/j.ijpharm.2019.04.022
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发表时间：
2019-06-10
影响因子：
5.8
通讯作者：
Ehrlich, Elana S.
中科院分区：
文献类型：
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作者：
Talamantez-Lyburn, Sarah;Brown, Pierce;Ehrlich, Elana S.
由于肿瘤细胞的生长和增殖依赖于HSP90，HSP90抑制剂具有治疗多种类型癌症的潜力。HSP90抑制剂需要Cullin-5(Cul5)E3泛素连接酶来诱导客户蛋白降解和随后的细胞死亡。与患者匹配的对照组相比，Cul5在乳腺癌细胞中的表达水平较低。这种观察到的Cul5低表达可能在17-AAG和相关HSP90抑制剂作为单一疗法的疗效下降的报道中起到了作用。我们开发了一种通过金纳米颗粒(AuNPs)将17-AAG+Cul5 DNA输送到细胞的方法。携带Cul5 DNA的AuNPs增加了Cul5缺陷的AU565细胞对17-AAG的敏感性。通过紫外-可见光谱、透射电子显微镜、凝胶电泳法和H-1核磁共振对AuNPs进行了表征，表明17-AAG与DNA的结合以及AuNP的稳定性。对Cul5基因缺陷的AU565细胞的研究表明，联合应用Cul5和17-AAG可增加细胞毒作用。我们的结果提供了证据，即DNA与药物一起传递可能是一种使耐药肿瘤细胞增敏的方法。
HSP90 inhibitors have the potential to treat many types of cancer due to the dependence of tumor cells on HSP90 for cell growth and proliferation. The Cullin-5 (Cul5) E3 ubiquitin ligase is required for HSP90 inhibitors to induce client protein degradation and subsequent cell death. Cul5 is expressed at low levels in breast cancer cells compared to patient matched controls. This observed low Cul5 expression may play a role in the reported decreased efficacy of 17-AAG and related HSP90 inhibitors as a monotherapy. We have developed a method for delivery of 17-AAG plus Cul5 DNA to cells via gold nanoparticles (AuNPs). Delivery of AuNPs containing Cul5 DNA increases the sensitivity of Cul5 deficient AU565 cells to 17-AAG. Characterization of AuNPs by UV-vis spectrum, TEM, gel electrophoresis assay and H-1 NMR indicate attachment of both 17-AAG and DNA payload as well as AuNP stability. Studies in Cul5 deficient AU565 cells reveal that delivery of Cul5 and 17-AAG together increase cytotoxicity. Our results provide evidence that delivery of DNA with drug may serve as a method to sensitize drug resistant tumor cells.