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Versatile Low-Molecular-Weight Hydrogelators: Achieving Multiresponsiveness through a Modular Design

Authors

  • Dr. Lilia Milanesi,

    Corresponding author
    1. Institute of Structural and Molecular Biology
    2. Department of Biological Sciences, School of Science, Birkbeck University of London, London WC1E 7HX (UK), Fax: (+44) 20-7631-6246
    • Institute of Structural and Molecular Biology
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  • Prof. Christopher A. Hunter,

    1. Centre for Chemical Biology, Krebs Institute for Biomolecular Science, Department of Chemistry, The University of Sheffield, Sheffield S3 7HF (UK)
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  • Dr. Nadejda Tzokova,

    1. Centre for Chemical Biology, Krebs Institute for Biomolecular Science, Department of Chemistry, The University of Sheffield, Sheffield S3 7HF (UK)
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  • Prof. Jonathan P. Waltho,

    1. Department of Molecular Biology and Biotechnology, The University of Sheffield, Sheffield S10 2TN (UK)
    2. Faculty of Life Sciences
    3. Manchester Interdisciplinary Biocentre, The University of Manchester, Manchester M1 7DN (UK)
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  • Dr. Salvador Tomas

    Corresponding author
    1. Institute of Structural and Molecular Biology
    2. Department of Biological Sciences, School of Science, Birkbeck University of London, London WC1E 7HX (UK), Fax: (+44) 20-7631-6246
    • Institute of Structural and Molecular Biology
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Abstract

Multiresponsive low-molecular-weight hydrogelators (LMWHs) are ideal candidates for the development of smart, soft, nanotechnology materials. The synthesis is however very challenging. On the one hand, de novo design is hampered by our limited ability to predict the assembly of small molecules in water. On the other hand, modification of pre-existing LMWHs is limited by the number of different stimuli-sensitive chemical moieties that can be introduced into a small molecule without seriously disrupting the ability to gelate water. Herein we report the synthesis and characterization of multistimuli LMWHs, based on a modular design, composed of a hydrophobic, disulfide, aromatic moiety, a maleimide linker, and a hydrophilic section based on an amino acid, here N-acetyl-L-cysteine (NAC). As most LMWHs, these gelators experience reversible gel-to-sol transition following temperature changes. Additionally, the NAC moiety allows reversible control of the assembly of the gel by pH changes. The reduction of the aromatic disulfide triggers a gel-to-sol transition that, depending on the design of the particular LMWH, can be reverted by reoxidation of the resulting thiol. Finally, the hydrolysis of the cyclic imide moieties provides an additional trigger for the gel-to-sol transition with a timescale that is appropriate for use in drug-delivery applications. The efficient response to the multiple external stimuli, coupled to the modular design makes these LMWHs an excellent starting point for the development of smart nanomaterials with applications that include controlled drug release. These hydrogelators, which were discovered by serendipity rather than design, suggest nonetheless a general strategy for the introduction of multiple stimuli-sensitive chemical moieties, to offset the introduction of hydrophilic moieties with additional hydrophobic ones, in order to minimize the upsetting of the critical hydrophobic–hydrophilic balance of the LMWH.

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