Kinetic Analysis of Nanostructures Formed by Enzyme-Instructed Intracellular Assemblies against Cancer Cells.
Kinetic Analysis of Nanostructures Formed by Enzyme-Instructed Intracellular Assemblies against Cancer Cells.
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DOI：
10.1021/acsnano.8b01016
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发表时间：
2018-04-24
期刊：
影响因子：
17.1
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Li J;Bullara D;Du X;He H;Sofou S;Kevrekidis IG;Epstein IR;Xu B
最近的研究表明，在细胞外或细胞内环境中的酶指导自组装（EISA）可以作为一个多步骤的过程来控制细胞的命运。然而，关于EISA在细胞内或细胞周围复杂环境中的动力学知识很少。本文设计并合成了三个二肽前体（LD-1-SO 3，DL-1-SO 3，DD-1-SO 3），它们分别以二苯丙氨酸（L-Phe-D-Phe，D-Phe-L-Phe，D-Phe-D-Phe）为骨架，N-端被2-（萘-2-基）乙酸封端，C-端被2-（4-（2-氨基乙氧基）-4-氧代丁酰胺基）乙烷-1-磺酸封端。在通过羧酸酯酶（CES）水解时，这些前体导致水凝胶因子，其以不同的速率在水中自组装。虽然所有三种前体都通过进行细胞内EISA选择性地杀死癌细胞，特别是高级别浆液性卵巢癌细胞（HGSC），但DL-1-SO 3和DD-1-SO 3分别表现出最低和最高的抗癌细胞活性。该趋势与PBS缓冲液中前体转化为水凝胶因子的速率负相关。由于CES存在于细胞外和细胞内，我们使用动力学模型来分析细胞内EISA的动力学，并计算每种前体杀死癌细胞的细胞毒性。我们的结果表明：（i）前体的立体化学影响由水凝胶因子形成的纳米结构的形态，以及酶转化的速率;（ii）前体的细胞外水解的减少有利于细胞内的细胞内EISA;（iii）固有特征（例如，EISA分子的自组装能力和形态）在很大程度上决定了细胞内EISA的细胞毒性。作为细胞内EISA的动力学分析，本工作阐明了立体化学如何在复杂的细胞外和/或细胞内环境中调节EISA，以开发抗癌分子过程。此外，它为理解细胞内外形成的异常蛋白质或肽聚集体的动力学和细胞毒性提供了见解。
Recent studies have demonstrated that enzyme-instructed self-assembly (EISA) in extra- or intracellular environments can serve as a multistep process for controlling cell fate. There is little knowledge, however, about the kinetics of EISA in the complex environments in or around cells. Here we design and synthesize three dipeptidic precursors (LD-1-SO3, DL-1-SO3, DD-1-SO3), consisting of diphenylalanine (L-Phe-D-Phe, D-Phe-L-Phe, D-Phe-D-Phe, respectively) as the backbone, which are capped by 2-(naphthalen-2-yl)acetic acid at the N-terminal and by 2-(4-(2-aminoethoxy)-4-oxobutanamido)ethane-1-sulfonic acid at the C-terminal. On hydrolysis by carboxylesterases (CES), these precursors result in hydrogelators, which self-assemble in water at different rates. While all three precursors selectively kill cancer cells, especially high-grade serous ovarian carcinoma cells (HGSC), by undergoing intracellular EISA, DL-1-SO3 and DD-1-SO3 exhibit the lowest and the highest activities, respectively, against the cancer cells. This trend inversely correlates with the rates of converting the precursors to the hydrogelators in PBS buffer. Because CES exists both extra- and intracellularly, we use kinetic modeling to analyze the kinetics of EISA inside cells and to calculate the cytotoxicity of each precursor for killing cancer cells. Our results indicate that (i) the stereochemistry of the precursors affects the morphology of the nanostructures formed by the hydrogelators, as well as the rate of enzymatic conversion; (ii) decreased extracellular hydrolysis of precursors favors intracellular EISA inside the cells; (iii) the inherent features (e.g., self-assembling ability and morphology) of the EISA molecules largely dictate the cytotoxicity of intracellular EISA. As the kinetic analysis of intracellular EISA, this work elucidates how the stereochemistry modulates EISA in the complex extra- and/or intracellular environment for developing anticancer molecular processes. Moreover, it provides insights for understanding the kinetics and cytotoxicity of aggregates of aberrant proteins or peptides formed inside and outside cells.
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影响因子：
16.6
作者：
Domcke, Silvia;Sinha, Rileen;Levine, Douglas A.;Sander, Chris;Schultz, Nikolaus
通讯作者：
Schultz, Nikolaus
影响因子：
15
作者：
Cai, Kaimin;He, Xi;Cheng, Jianjun
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Cheng, Jianjun
影响因子：
8
作者：
Baker, SJ;Reddy, EP
通讯作者：
Reddy, EP
影响因子：
9.9
作者：
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影响因子：
8.8
作者：
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通讯作者：
Canal, P