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Membrane Microdomain Structures of Liposomes and Their Contribution to the Cellular Uptake Efficiency into HeLa Cells
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    Membrane Microdomain Structures of Liposomes and Their Contribution to the Cellular Uptake Efficiency into HeLa Cells
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    Department of Pharmaceutical Technology, Graduate School of Medical and Pharmaceutical Science, Unversity of Toyama, Sugitani 2630, Toyama-shi, Toyama 930-0194, Japan
    Department of Pharmaceutics and §Department of Drug Delivery Research, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan
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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2016, 13, 2, 369–378
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    https://doi.org/10.1021/acs.molpharmaceut.5b00601
    Published December 28, 2015
    Copyright © 2015 American Chemical Society

    Abstract

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    The purpose of this study is to obtain a comprehensive relationship between membrane microdomain structures of liposomes and their cellular uptake efficiency. Model liposomes consisting of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/cholesterol (Ch) were prepared with various lipid compositions. To detect distinct membrane microdomains in the liposomes, fluorescence-quenching assays were performed at temperatures ranging from 25 to 60 °C using 1,6-diphenyl-1,3,5-hexatriene-labeled liposomes and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl. From the data analysis using the response surface method, we gained a better understanding of the conditions for forming distinct domains (Lo, Ld, and gel phase membranes) as a function of lipid composition. We further performed self-organizing maps (SOM) clustering to simplify the complicated behavior of the domain formation to obtain its essence. As a result, DPPC/DOPC/Ch liposomes in any lipid composition were integrated into five distinct clusters in terms of similarity of the domain structure. In addition, the findings from synchrotron small-angle X-ray scattering analysis offered further insight into the domain structures. As a last phase of this study, an in vitro cellular uptake study using HeLa cells was conducted using SOM clusters’ liposomes with/without PEGylation. As a consequence of this study, higher cellular uptake was observed from liposomes having Ch-rich ordered domains.

    Copyright © 2015 American Chemical Society

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.molpharmaceut.5b00601.

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    Molecular Pharmaceutics

    Cite this: Mol. Pharmaceutics 2016, 13, 2, 369–378
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.molpharmaceut.5b00601
    Published December 28, 2015
    Copyright © 2015 American Chemical Society

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