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Targeting Tumorigenicity of Breast Cancer Stem Cells Using SAHA/Wnt-b Catenin Antagonist Loaded Onto Protein Corona of Gold Nanoparticles.
International Journal of Nanomedicine ( IF 8 ) Pub Date : 2020-06-11 , DOI: 10.2147/ijn.s234636
Azam Shamsian 1, 2 , Mohammad Reza Sepand 3 , Marziye Javaheri Kachousangi 1, 2 , Tahereh Dara 4 , Seyed Nasser Ostad 3 , Fatemeh Atyabi 1, 2 , Mohammad Hossein Ghahremani 1, 3
Affiliation  

Background: Among various theories for the origin of cancer, the “stemness phenotype model” suggests a dynamic feature for tumor cells in which non-cancer stem cells (non-CSCs) can inter-convert to CSCs. Differentiation with histone-deacetylase inhibitor, vorinostat (SAHA), can induce stem cells to differentiate as well as enforces non-CSCs to reprogram to CSCs. To avoid this undesirable effect, one can block the Wnt-βcatenin pathway. Thus, a dual delivery system of SAHA and a Wnt-βcatenin blocker will be beneficial in the induction of differentiation of CSCs. Protein corona (PC) formation in nanoparticle has a biologic milieu, and despite all problematic properties, it can be employed as a medium for dual loading of the drugs.
Materials and Methods: We prepared sphere gold nanoparticles (GNPs) with human plasma protein corona loaded with SAHA as differentiating agent and PKF118-310 (PKF) as a Wnt-βcatenin antagonist. The MCF7 breast cancer stem cells were treated with NPs and the viability and differentiation were evaluated by Western blotting and sphere formation assay.
Results: We found that both drugs loaded onto corona-capped GNPs had significant cytotoxicity in comparison to bare GNP-corona. Data demonstrated an increase in stem cell population and upregulation of mesenchymal marker, Snail by SAHA-loaded GNPs treatment; however, the combination of PKF loaded GNPs along with SAHA-loaded GNPs resulted in a reduction of stem cell populations and Snail marker. We have shown that in MCF7 and its CSCs simultaneous treatment with SAHA and PKF118-310 induced differentiation and inhibition of Snail induction.
Conclusion: Our study reveals the PC-coated GNPs as a biocompatible career for both hydrophilic (PKF) and hydrophobic (SAHA) agents which can decrease breast cancer stem cell populations along with reduced stemness state regression.



中文翻译:

使用负载在金纳米颗粒蛋白冠上的 SAHA/Wnt-b 连环蛋白拮抗剂靶向乳腺癌干细胞的致瘤性。

背景:在癌症起源的各种理论中,“干细胞表型模型”表明了肿瘤细胞的动态特征,其中非癌症干细胞(非 CSCs)可以相互转化为 CSCs。与组蛋白去乙酰化酶抑制剂伏立诺他 (SAHA) 的分化可以诱导干细胞分化并强制非 CSC 重新编程为 CSC。为了避免这种不良影响,可以阻断 Wnt-βcatenin 通路。因此,SAHA 和 Wnt-β 连环蛋白阻断剂的双重递送系统将有利于诱导 CSC 的分化。纳米颗粒中的蛋白质电晕 (PC) 形成具有生物环境,尽管存在所有问题,但它可以用作药物双重加载的介质。
材料和方法:我们制备了球形金纳米粒子 (GNP),其载有 SAHA 作为分化剂和 PKF118-310 (PKF) 作为 Wnt-βcatenin 拮抗剂的人血浆蛋白冠。用 NPs 处理 MCF7 乳腺癌干细胞,并通过蛋白质印迹和球形成测定评估其活力和分化。
结果:我们发现,与裸露的 GNP 冠状病毒相比,加载到冠状病毒覆盖的 GNP 上的两种药物都具有显着的细胞毒性。数据表明,负载 SAHA 的 GNP 处理可增加干细胞群和间充质标志物 Snail 的上调;然而,负载 PKF 的 GNP 与负载 SAHA 的 GNP 的组合导致干细胞群和 Snail 标记的减少。我们已经表明,在 MCF7 及其 CSCs 中,SAHA 和 PKF118-310 的同时处理诱导了 Snail 诱导的分化和抑制。
结论:我们的研究揭示了 PC 涂层 GNP 作为亲水性 (PKF) 和疏水性 (SAHA) 试剂的生物相容性事业,可以减少乳腺癌干细胞数量以及减少干性状态回归。

更新日期:2020-06-11
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