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Micellar Stability in Biological Media Dictates Internalization in Living Cells

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Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Baldiri Reixac 15-21, 08028 Barcelona, Spain
Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel
§ Tel Aviv University Center for Nanoscience and Nanotechnology, Tel-Aviv University, Tel-Aviv 6997801, Israel
BLAVATNIK CENTER for Drug Discovery, Tel-Aviv University, Tel-Aviv 6997801, Israel
Cite this: J. Am. Chem. Soc. 2017, 139, 46, 16677–16687
Publication Date (Web):October 27, 2017
https://doi.org/10.1021/jacs.7b08351
Copyright © 2017 American Chemical Society

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    Abstract

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    The dynamic nature of polymeric assemblies makes their stability in biological media a crucial parameter for their potential use as drug delivery systems in vivo. Therefore, it is essential to study and understand the behavior of self-assembled nanocarriers under conditions that will be encountered in vivo such as extreme dilutions and interactions with blood proteins and cells. Herein, using a combination of fluorescence spectroscopy and microscopy, we studied four amphiphilic PEG–dendron hybrids and their self-assembled micelles in order to determine their structure–stability relations. The high molecular precision of the dendritic block enabled us to systematically tune the hydrophobicity and stability of the assembled micelles. Using micelles that change their fluorescent properties upon disassembly, we observed that serum proteins bind to and interact with the polymeric amphiphiles in both their assembled and monomeric states. These interactions strongly affected the stability and enzymatic degradation of the micelles. Finally, using spectrally resolved confocal imaging, we determined the relations between the stability of the polymeric assemblies in biological media and their cell entry. Our results highlight the important interplay between molecular structure, micellar stability, and cell internalization pathways, pinpointing the high sensitivity of stability–activity relations to minor structural changes and the crucial role that these relations play in designing effective polymeric nanostructures for biomedical applications.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b08351.

    • Detailed experimental information, characterization data, CMC measurements, UV and fluorescence spectra, HPLC degradation/stability data, cytotoxicity, and confocal imaging (PDF)

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