Blocking ACAT-1 Activity for Tumor Therapy with Fluorescent Hyperstar Polymer-Encapsulated Avasimible.,Macromolecular Bioscience

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Blocking ACAT-1 Activity for Tumor Therapy with Fluorescent Hyperstar Polymer-Encapsulated Avasimible.
Macromolecular Bioscience ( IF 4.4 ) Pub Date : 2020-05-13 , DOI: 10.1002/mabi.201900438
Ting Bai ₁ , Bobo Zhu ₂ , Dongyan Shao ₂ , Ziyang Lian ₂ , Pei Liu ₁ , Junling Shi ₂ , Jie Kong ₁

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Targeting the distinct cholesterol metabolism of tumor cells is proposed as a novel way to treat tumors. Blocking acyl‐CoA cholesterol acyltransferase‐1 (ACAT‐1) by the inhibitor avasimible (Ava), which elevates intracellular free cholesterol levels, is shown to effectively induce apoptosis. However, Ava faces disadvantages of poor water solubility, a short half‐life, and no capability for fluorescence detection, which have greatly limited its application. Herein, a fluorescent hyperstar polymer (FHSP) is developed to encapsulate Ava to improve its ability to inhibit HeLa cells and K562 cells. The results of this study show that the obtained Ava–FHSP micelles possess a high drug loading capacity of 22.7% and bright green fluorescence. Ava and Ava–FHSP are cytotoxic to both HeLa and K562 cells and cause reductions in cell size, nuclear lysis, and chromatin condensation and hindered proliferation of both cell types by causing S phase cell cycle arrest. Further mechanistic analysis indicates that Ava–FHSP reduces the protein and messenger RNA expression of ACAT‐1 and significantly increases intracellular free cholesterol levels, which can increase endoplasmic reticulum stress and finally cause cell apoptosis. All these results suggest that this fluorescent hyperstar polymer represents a potential therapeutic tumor strategy by changing the cholesterol metabolism of tumor cells.

中文翻译：

用荧光超星聚合物封装的Avasimible阻断肿瘤治疗的ACAT-1活性。

针对肿瘤细胞独特的胆固醇代谢被提议作为治疗肿瘤的新方法。抑制可利用物（Ava）阻断酰基辅酶A胆固醇酰基转移酶-1（ACAT-1），可提高细胞内游离胆固醇水平，已显示可有效诱导细胞凋亡。但是，Ava的缺点是水溶性差，半衰期短，无法进行荧光检测，这极大地限制了其应用。在本文中，开发了荧光超巨星聚合物（FHSP）来封装Ava，以提高其抑制HeLa细胞和K562细胞的能力。这项研究的结果表明，所获得的Ava–FHSP胶束具有22.7％的高载药量和亮绿色荧光。Ava和Ava–FHSP对HeLa和K562细胞均具有细胞毒性，并导致细胞大小减少，核裂解，染色质凝集和通过导致S期细胞周期停滞而阻止两种细胞的增殖。进一步的机理分析表明，Ava–FHSP降低了ACAT-1的蛋白质和信使RNA的表达，并显着提高了细胞内游离胆固醇的水平，这可能会增加内质网应激并最终导致细胞凋亡。所有这些结果表明，这种荧光超级明星聚合物通过改变肿瘤细胞的胆固醇代谢，代表了一种潜在的治疗性肿瘤策略。会增加内质网应激，最终导致细胞凋亡。所有这些结果表明，这种荧光超级明星聚合物通过改变肿瘤细胞的胆固醇代谢，代表了一种潜在的治疗性肿瘤策略。会增加内质网应激，最终导致细胞凋亡。所有这些结果表明，这种荧光超级明星聚合物通过改变肿瘤细胞的胆固醇代谢，代表了一种潜在的治疗性肿瘤策略。

更新日期：2020-05-13

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