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  • Design Strategies of Stimuli-Responsive Supramolecular Hydrogels Relying on Structural Analyses and Cell-Mimicking Approaches Published as part of the Accounts of Chemical Research special issue “Stimuli-Responsive Hydrogels”.

    Hajime Shigemitsu† and Itaru Hamachi*,†,‡

    †Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura, Kyoto 615-8510, Japan ‡Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, 5 Sanbancho, Chiyoda-ku, Tokyo 102-0075, Japan

    CONSPECTUS: Stimuli-responsive hydrogels are intriguing biomaterials useful for spatiotemporal controlled release of drugs, cells, and biological cues, cell engineering for various applications, and medical diagnosis. To date, many physical and chemical stimuli-responsive polymer hydrogels have been developed by chemical modification of polymer chains and cross-linking points. In particular, conjugation with biomole- cules to polymers produced promising biomolecule-responsive hydrogels. These examples clearly indicate high potentials of stimuli-responsive hydrogels as promising biomaterials. In addition to polymer hydrogels, supramolecular hydrogels formed by the assembly of small molecules (hydrogelators) via noncovalent interactions have also been regarded as unique and promising soft materials due to their flexible programmability in rendering them stimuli-responsive with the larger macroscopic change (i.e., gel−sol transition). This Account describes our strategies for the rational design of stimuli-responsive supramolecular hydrogels and their biological applications. Following the detailed structural analysis of a lead hydrogelator that clearly indicates the appropriate sites for incorporation of stimuli-responsive modules, we designed supramolecular hydrogels capable of responding to simple physical (thermal and light) and chemical (pH and metal ions) stimuli. More importantly, biomolecule-responsive hydrogels were successfully developed by supramolecularly mimicking the complex yet well-ordered structures and functions of live cells containing multiple components (a cell-mimicking approach). Development of biomolecule-responsive supramolecular hydrogels has been difficult as the conventional strategy relies on the chemical incorporation of stimuli-responsive modules, owing to the lack of modules that can effectively respond to structurally diverse and complicated biomolecules. Inspired by natural systems where functional compartments (e.g., cell organelles) sophisticatedly interact with each other, we sought to integrate the two distinct microenvironments of supramolecular hydrogels (the aqueous cavity surrounded by fibers and the fluidic hydrophobic fiber domain) with other functional materials (e.g., enzymes, peptides or proteins, fluorescent chemosensors, or inorganic porous or layered nanomaterials) for biomolecule responses. In situ fluorescence microscopy imaging clearly demonstrated that chemical isolation and crosstalk are highly successful between the integrated microenvironments in supramolecular hydrogels, similar to organelles in living cells, which allow for the construction of unique optical response and sensing systems for biomolecules. Furthermore, programmed hybridization of our chemically reactive hydrogels with appropriate enzymes can provide an unprecedented universal platform for biomolecule-degradable supramolecular hydrogels. Such biomolecule-responsive hydrogels are a potentially promising tool for user-friendly early diagnostics and on-demand drug-releasing soft materials. We expect that our rational design strategies for stimuli-responsive supramolecular hydrogels by modification of chemical structures and hybridization with functional materials will inspire scientists in various fields and lead to development of novel soft materials for biological applications.

    1. INTRODUCTION Stimuli-responsive hydrogels have attracted much attention not only owing to interests in fundamental science but because of their potential for a wide range of biological and biomedical applications, such as drug delivery systems, regenerative medicines, cancer therapy, and diagnosis.1−4 Selective and

    efficient stimuli response of hydrogels to a particular condition or molecule is anticipated to allow for the selective release of a drug or biological cue under biological crude conditions (i.e., in

    Received: February 3, 2017 Published: March 2, 2017


    © 2017 American Chemical Society 740 DOI: 10.1021/acs.accounts.7b00070 Acc. Chem. Res. 2017, 50, 740−750

  • cells, in culture media, in vivo) and the naked-eye detection of disease biomarkers without expensive analytical instruments. Additionally, a new strategy for cancer therapy by hydrogelation has recently emerged.5,6 Many stimuli-responsive polymer hydrogels have been developed for biological applications.7

    Chemical modification of polymer chains and cross-linkers produced various physical and chemical stimuli-responsive polymer-based hydrogels.8 Also, biomolecule-responsive poly- mer hydrogels have been developed by conjugation with polymers and biomolecules.9−12 These successful examples of stimuli-responsive hydrogels clearly indicate their potential as promising biomaterials. Besides polymer hydrogels, supramolecular hydrogels con-

    sisting of small molecules (hydrogelators) have been actively developed and are now recognized as unique and promising soft materials, owing to their high and flexible programmability in lending them stimuli responsiveness.13−16 It is generally accepted that hydrogelators assemble to form nanofibers, which is critical for supramolecular hydrogelation. This fiber formation is driven by a variety of noncovalent interactions such as hydrogen- bonding (H-bonding), hydrophobic, van der Waals, and π/π interactions. The delicate balance between these noncovalent interactions can readily modulate the resultant self-assembled structures, which sensitively affects the hydrogelation. The close connection between the gelator structure and macroscopic properties of the resultant hydrogel should enable one to rationally design and tune the properties of stimuli-responsive hydrogels at the small molecule level. In addition, the preparation protocol of supramolecular hydrogels is largely different from that of conventional polymer-based hydrogels that often require polymerization in the presence of adducts such as initiators and

    cross-linkers. In the case of supramolecular hydrogels, no adducts are required and the operations (e.g., heating and cooling, simple injection of hydrogelator to aqueous solution, or ultrasound treatment) are quite easy for gelation. This is regarded as an important advantage of supramolecular hydrogelators for biological applications. To date, many supramolecular hydrogels have been reported

    to exhibit response to stimuli such as heat, pH, metal ions, and light, and these have been applied to cell cultures, control of drug release, and so on. These are usually designed through the insertion of an appropriate stimuli-responsive group into the hydrogelator scaffold. Given the relationship between the gelator structure and the gelation properties, it was reasonably expected that a structural perturbation of the gelator given by a stimulus may cause macroscopic gel−sol or sol−gel changes. However, the employed stimuli have been rather simple so far. The more sophisticated supramolecular hydrogels able to respond to complex biomolecules (i.e., bioactive vitamin, saccharides, DNA, RNA, and noncatalytic proteins) are still limited and difficult to construct,13 while a few enzyme-responsive hydro- gels have been reported by several research groups.17−21

    A major obstacle for the development of biomolecule- responsive hydrogels may be the poor molecular recognition capability of synthetic molecules as stimuli-responsive groups, and thus it is difficult to find a suitable module capable of discriminating a target molecule among diverse nontargets in the context of hydrogelator design. Moreover, time-consum- ing efforts are required for incorporating the modules into the supramolecular hydrogelator, even if stimuli-responsive (molecular recognition) modules with high affinity and selectivity are developed. Therefore, an alternative and more

    Figure 1. A combinatorial screening for the development of supramolecular hydrogelators based on solid-phase synthesis.

    Accounts of Chemical Research Article

    DOI: 10.1021/acs.accounts.7b00070 Acc. Chem. Res. 2017, 50, 740−750


  • general approach is required for the creation of biomolecule- responsive supramolecular hydrogels. Based on our successful examples, we herein describe a few

    strategies for the rational design of stimuli-responsive supra- molecular hydrogels composed of lipid mimetic or short peptide- based gelators. One of the strategies substantially relies on the detailed structural analyses of the supramolecular fibers, a fundamental element of supramolecular hydrogels, and the clear characterization of the two different microenvironments inside of the hydrogels. We initially discovered a few supra- molecular hydrogelators comprising lipid-like molecules using a combinatorial screening approach.22−26 The molecular packing resolved by X-ray analysis led to rationally modifying the hydrogelators in order to exhibit stimuli-responsiveness for metal ions, pH, and light.27−30 In situ confocal fluorescence microscopy observation also revealed that two distinct microenvir

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