@article{200236,
  keywords = {self-assembly, nanostructure assembly kinetics enzyme cancer drug delivery, anticancer, enzyme, nanostructure, stereochemistry},
  author = {Jie Li and Domenico Bullara and Xuewen Du and Hongjian He and Stavroula Sofou and IoannisG. Kevrekidis and Irving R. Epstein and Bing Xu},
  title = {Kinetic analysis of nanostructures formed by enzyme-instructed intracellular assemblies against cancer cells},
  abstract = { 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, resp.) 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. Whereas all three precursors selectively kill cancer cells, especially high-grade serous ovarian carcinoma cells, by undergoing intracellular EISA, DL-1-SO3 and DD-1-SO3 exhibit the lowest and the highest activities, resp., against the cancer cells. This trend inversely correlates with the rates of converting the precursors to the hydrogelators in phosphate-buffered saline. 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 stereochem. of the precursors affects the morphol. of the nanostructures formed by the hydrogelators, as well as the rate of enzymic conversion; (ii) decreased extracellular hydrolysis of precursors favors intracellular EISA inside the cells; (iii) the inherent features (e.g., self-assembling ability and morphol.) of the EISA mols. largely dictate the cytotoxicity of intracellular EISA. As the kinetic anal. of intracellular EISA, this work elucidates how the stereochem. modulates EISA in the complex extra- and/or intracellular environment for developing anticancer mol. processes. Moreover, it provides insights for understanding the kinetics and cytotoxicity of aggregates of aberrant proteins or peptides formed inside and outside cells. },
  year = {2018},
  journal = {ACS Nano},
  volume = {12},
  number = {4},
  pages = {3804-3815},
  publisher = {American Chemical Society},
  isbn = {1936-086X1936-0851},
  url = {https://doi.org/10.1021/acsnano.8b01016},
  language = {eng},
}