A Natural Glycyrrhizic Acid‐Tailored Light‐Responsive Gelator

The construction of stimuli‐responsive materials by using naturally occurring molecules as building blocks has received increasing attention owing to their bioavailability, biocompatibility, and biodegradability. Herein, a symmetrical azobenzene‐functionalized natural glycyrrhizic acid (trans‐ GAG ) was synthesized and could form stable supramolecular gels in DMSO/H₂O and MeOH/H₂O. Owing to trans–cis isomerization, this gel exhibited typical light‐responsive behavior that led to a reversible gel–sol transition accompanied by a variation in morphology and rheology. Additionally, this trans‐ GAG gel displayed a distinct injectable self‐healing property and outstanding biocompatibility. This work provides a simple yet rational strategy to fabricate stimuli‐responsive materials from naturally occurring, eco‐friendly molecules.     

Fibrous Networks with Incorporated Macrocycles: A Chiral Stimuli‐Responsive Supramolecular Supergelator and Its Application to Biocatalysis in Organic Media

A new and versatile, crown ether appended, chiral supergelator has been designed and synthesized based on the bis‐urea motif. The introduction of a stereogenic center improved its gelation ability significantly relative to its achiral analogue. This low‐molecular‐weight gelator forms supramolecular gels in a variety of organic solvents. It is sensitive to multiple chemical stimuli and the sol–gel phase transitions can be reversibly triggered by host–guest interactions. The gel can be used to trap enzymes and release them on demand by chemical stimuli. It stabilizes the microparticles in Pickering emulsions so that enzyme‐catalyzed organic reactions can take place in the polar phase inside the microparticles, the organic reactants diffusing through the biphasic interface from the surrounding organic phase. Because of the higher interface area between the organic and polar phases, enzyme activity is enhanced in comparison with simple biphasic systems.     

Multistimuli‐Responsive Supramolecular Organogels Formed by Low‐Molecular‐Weight Peptides Bearing Side‐Chain Azobenzene Moieties

This work demonstrates that the incorporation of azobenzene residues into the side chain of low‐molecular‐weight peptides can modulate their self‐assembly process in organic solvents leading to the formation of stimuli responsive physical organogels. The major driving forces for the gelation process are hydrogen bonding and π–π interactions, which can be triggered either by thermal or ultrasound external stimuli, affording materials having virtually the same properties. In addition, a predictive model for gelation of polar protic solvent was developed by using Kamlet–Taft solvent parameters and experimental data. The obtained viscoelastic materials exhibited interconnected multistimuli responsive behaviors including thermal‐, photo‐, chemo‐ and mechanical responses. All of them displayed thermoreversability with gel‐to‐sol transition temperatures established between 33–80 °C and gelation times from minutes to several hours. Structure–property relationship studies of a designed peptide library have demonstrated that the presence and position of the azobenzene residue can be operated as a versatile regulator to reduce the critical gelation concentration and enhance both the thermal stability and mechanical strength of the gels, as demonstrated by comparative dynamic rheology. The presence of N‐Boc protecting group in the peptides showed also a remarkable effect on the formation and properties of the gels. Despite numerous examples of peptide‐based gelators known in the literature, this is the first time in which low‐molecular‐weight peptides bearing side chain azobenzene units are used for the synthesis of “intelligent” supramolecular organogels. Compared with other approaches, this strategy is advantageous in terms of structural flexibility since it is compatible with a free, unprotected amino terminus and allows placement of the chromophore at any position of the peptide sequence.     

Living polymerization of α‐amino acid‐N‐carboxyanhydrides

This article reviews recent developments in the polymerization of α‐amino acid‐ N‐carboxyanhydrides (NCAs) to form polypeptides. Traditional methods used to polymerize these monomers are described, and limitations in the utility of these systems for the preparation of polypeptides with controlled molecular weights and narrow molecular weight distributions are discussed. The development of transition‐metal‐based initiators, which activate the monomers to form covalent active species, permits the formation of polypeptides via the living polymerization of NCAs. In these systems, polymer molecular weights are controlled by monomer‐to‐initiator stoichiometry, polydispersities are low, and block copolypeptides can be prepared. The scope and limitations of these initiators and their key features and mode of operation are described in detail in this highlight. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 3011–3018, 2000     

Stimuli‐Responsive Supramolecular Hydrogels and Their Applications in Regenerative Medicine

Supramolecular hydrogels are a class of self‐assembled network structures formed via non‐covalent interactions of the hydrogelators. These hydrogels capable of responding to external stimuli are considered to be smart materials due to their ability to undergo sol–gel and/or gel–sol transition upon subtle changes in their surroundings. Such stimuli‐responsive hydrogels are intriguing biomaterials with applications in tissue engineering, delivery of cells and drugs, modulating tissue environment to promote innate tissue repair, and imaging for medical diagnostics among others. This review summarizes the recent developments in stimuli‐responsive supramolecular hydrogels and their potential applications in regenerative medicine. Specifically, various structural aspects of supramolecular hydrogelators involved in self‐assembly, the role of external stimuli in tuning/controlling their phase transitions, and how these functions could be harnessed to advance applications in regenerative medicine are focused on. Finally, the key challenges and future prospects for these versatile materials are briefly described.     

Phase‐transition characteristics of amphiphilic poly(2‐ethyl‐2‐oxazoline)/poly(ε‐caprolactone) block copolymers in aqueous solutions

Amphiphilic diblock and triblock copolymers of various block compositions based on hydrophilic poly(2‐ethyl‐2‐oxazoline) (PEtOz) and hydrophobic poly(ε‐caprolactone) were synthesized. The micelle formation of these block copolymers in aqueous media was confirmed by a fluorescence technique and dynamic light scattering. The critical micelle concentrations ranged from 35.5 to 4.6 mg/L for diblock copolymers and 4.7 to 9.0 mg/L for triblock copolymers, depending on the block composition. The phase‐transition behaviors of the block copolymers in concentrated aqueous solutions were investigated. When the temperature was increased, aqueous solutions of diblock and triblock copolymers exhibited gel–sol transition and precipitation, both of which were thermally reversible. The gel–sol transition‐ and precipitation temperatures were manipulated by adjustment of the block composition. As the hydrophobic portion of block copolymers became higher, a larger gel region was generated. In the presence of sodium chloride, the phase transitions were shifted to a lower temperature level. Sodium thiocyanate displaced the gel region and precipitation temperatures to a higher temperature level. The low molecular weight saccharides, such as glucose and maltose, contributed to the shift of phase‐transition temperatures to a lower temperature level, where glucose was more effective than maltose in lowering the gel–sol transition temperatures. The malonic acid that formed hydrogen bonds with the PEtOz shell of micelles was effective in lowering phase‐transition temperatures to 1.0M, above which concentration the block copolymer solutions formed complex precipitates. © 2000 John Wiley & Sons, Inc. J Polym Sci B: Polym Phys 38: 2400–2408, 2000     

A Designed 5‐Fluorouracil‐Based Bridged Silsesquioxane as an Autonomous Acid‐Triggered Drug‐Delivery System

Two new prodrugs, bearing two and three 5‐fluorouracil (5‐FU) units, respectively, have been synthesized and were shown to efficiently treat human breast cancer cells. In addition to 5‐FU, they were intended to form complexes through H‐bonds to an organo‐bridged silane prior to hydrolysis‐condensation through sol–gel processes to construct acid‐responsive bridged silsesquioxanes (BS). Whereas 5‐FU itself and the prodrug bearing two 5‐FU units completely leached out from the corresponding materials, the prodrug bearing three 5‐FU units was successfully maintained in the resulting BS. Solid‐state NMR (²⁹Si and ¹³C) spectroscopy show that the organic fragments of the organo‐bridged silane are retained in the hybrid through covalent bonding and the ¹H NMR spectroscopic analysis provides evidence for the hydrogen‐bonding interactions between the prodrug bearing three 5‐FU units and the triazine‐based hybrid matrix. The complex in the BS is not affected under neutral medium and operates under acidic conditions even under pH as high as 5 to deliver the drug as demonstrated by HPLC analysis and confirmed by FTIR and ¹³C NMR spectroscopic studies. Such functional BS are promising materials as carriers to avoid the side effects of the anticancer drug 5‐FU thanks to a controlled and targeted drug delivery.     

Fluorescent Dendritic Organogels Based on 2‐(2′‐Hydroxyphenyl)benzoxazole: Emission Enhancement and Multiple Stimuli‐Responsive Properties

A new highly efficient and versatile poly(benzyl ether) dendritic organogelator HPB‐G₁ with 2‐(2′‐hydroxyphenyl)benzoxazole (HPB) at the focal point has been designed and synthesized. HPB‐G₁ can form stable organogels toward various apolar and polar organic solvents. Further studies revealed that intermolecular multiple π–π stacking interactions are the main driving forces for the formation of the organogels. Notably, dendron HPB‐G₁ exhibited a significantly enhanced emission in the gel state in contrast to weak emission in solution. Most interestingly, these dendritic organogels exhibited multiple stimuli‐responsive behaviors upon exposure to environmental stimuli, including temperature, sonication, shear stress, and the presence of anions, metal cations, acids/bases, thus leading to reversible sol–gel phase transitions.     

Cucurbit[8]uril (CB[8])‐Based Supramolecular Switches

The use of cucurbit[8]uril as a molecular host has emerged in the chemical literature as a reliable strategy for the creation of dynamic chemical systems, owing to its ability to form homo‐ and heteroternary complexes in aqueous media with appropriate molecular switches as guests. In this manner, CB[8]‐based supramolecular switches can be designed in a predictable and modular fashion, through the selection of appropriate guests able to condition the redox, photochemical, or pH‐triggered behavior of tailored multicomponent systems. Furthermore, CB[8] allows the implementation of dual/triple and linear/orthogonal stimuli‐dependent properties into these molecular devices by a careful selection of the guests. This versatility in their design gives these supramolecular switches great potential for the rational development of new materials, in which their function is not only determined by the custom‐made stimuli‐responsiveness, but also by the transient aggregation/disaggregation of homo‐ or heteromeric building blocks.     

Triblock Copolymer Based on Poly(propylene oxide) and Poly(1‐[11‐acryloylundecyl]‐3‐methyl‐imidazolium bromide)

The controlled atom transfer radical polymerization of an ionic liquid, 1‐(11‐acryloylundecyl)‐3‐methyl imidazolium bromide (ILBr), from both ends of a telechelic poly(propylene oxide) (PPO) macroinitiator, end‐functionalized with bromoisobutyryloyl is reported. The resulting highly water‐soluble triblock, poly(ILBr‐b‐PO‐b‐ILBr) is multistimuli responsive. This new class of triblocks exhibits classical surface activity in lowering surface tension at the air–water interface and in modifying wetting in waterborne coatings. It also immunizes model colloids against coagulation induced by Debye–Hückel (indifferent electrolyte) electrostatic screening. Further, sol–gel thermoreversibility is unexpectedly found as an additional form of stimuli responsiveness.     

Sol‐gel technique for the preparation of β‐cyclodextrin gold nanoparticles as chiral stationary phase in open‐tubular capillary electrochromatography

A novel open‐tubular capillary electrochromatography column coated with β‐cyclodextrin was prepared using the sol‐gel technique. In the sol‐gel approach, owing to the three‐dimensional network of sol‐gel and the strong chemical bond between the stationary phase and the surface of capillary columns, good chromatographic characteristics and unique selectivity in separating enantiomers were shown. The influences of capillary inner diameter, coating time, organic modifier, buffer pH, and buffer concentration on separation were investigated. The sol‐gel‐coated β‐cyclodextrin column has shown improved enantioseparation efficiency of chlorphenamine, brompheniramine, pheniramine, zopiclone in comparison with the sol‐gel matrix capillary column. The migration time relative standard deviation of the separation of the enantiomers was less than 0.89% over five runs and 2.9% from column to column. This work confirmed that gold nanoparticles are promising electrochromatographic support to enhance the phase ratio of open‐tubular capillary electrochromatography column in capillary electrochromatography.     

Pyrene‐Based Fluorescent Ambidextrous Gelators: Scaffolds for Mechanically Robust SWNT–Gel Nanocomposites

With the rapid progress in the development of supramolecular soft materials, examples of low‐molecular‐weight gelators (LMWGs) with the ability to immobilise both water and organic solvents by the same structural scaffold are very limited. In this paper, we report the development of pyrene‐containing peptide‐based ambidextrous gelators (AGs) with the ability to efficiently gelate both organic and aqueous solvents. The organo‐ and hydrogelation efficiencies of these gelators are in the range 0.7–1.1 % w/v in various organic solvents and 0.5–5 % w/v in water at certain acidic pH values (pH 2.0–4.0). Moreover, for the first time, AGs have been utilised to prepare single‐walled carbon‐nanotube (SWNT)‐included soft nanocomposites in both hydro‐ and organogel matrices. The influence of different non‐covalent interactions such as hydrogen bonding, hydrophobic, π–π and van der Waals interactions in self‐assembled gelation has been studied in detail by circular dichroism, FTIR, variable‐temperature NMR, 2D NOESY and luminescence spectroscopy. Interestingly, the presence of the pyrene moiety in the structure rendered these AGs intrinsically fluorescent, which was quenched upon successful integration of the SWNTs within the gel. The prepared hydro‐ and organogels along with their SWNT‐integrated nanocomposites are thermoreversible in nature. The supramolecular morphologies of the dried gels and SWNT–gel nanocomposites have been studied by transmission electron microscopy, fluorescence microscopy and polarising optical microscopy, which confirmed the presence of three‐dimensional self‐assembled fibrillar networks (SAFINs) as well as the integrated SWNTs. Importantly, rheological studies revealed that the inclusion of SWNTs within the ambidextrous gels improved the mechanical rigidity of the resulting soft nanocomposites up to 3.8‐fold relative to the native gels.     

A Dual Threat: Redox‐Activity and Electronic Structures of Well‐Defined Donor–Acceptor Fulleretic Covalent‐Organic Materials

The effect of donor (D)–acceptor (A) alignment on the materials electronic structure was probed for the first time using novel purely organic porous crystalline materials with covalently bound two‐ and three‐dimensional acceptors. The first studies towards estimation of charge transfer rates as a function of acceptor stacking are in line with the experimentally observed drastic, eight‐fold conductivity enhancement. The first evaluation of redox behavior of buckyball‐ or tetracyanoquinodimethane‐integrated crystalline was conducted. In parallel with tailoring the D‐A alignment responsible for “static” changes in materials properties, an external stimulus was applied for “dynamic” control of the electronic profiles. Overall, the presented D–A strategic design, with stimuli‐controlled electronic behavior, redox activity, and modularity could be used as a blueprint for the development of electroactive and conductive multidimensional and multifunctional crystalline porous materials.     

Nanocomposite Made of an Oligo(p‐phenylenevinylene)‐Based Trihybrid Thixotropic Metallo(organo)gel Comprising Nanoscale Metal–Organic Particles,Carbon Nanohorns,and Silver Nanoparticles

A silver ion (Ag⁺)‐triggered thixotropic metallo(organo)gel of p‐pyridyl‐appended oligo(p‐phenylenevinylene) derivatives (OPVs) is reported for the first time. Solubilization of single‐walled carbon nanohorns (SWCNHs) in solutions of the pure OPVs as well as in the metallogels mediated by π–π interactions has also been achieved. In situ fabrication of silver nanoparticles (AgNPs) in the SWCNH‐doped dihybrid gel leads to the formation of a trihybrid metallogel. The mechanical strength of the metallogels could be increased stepwise in the order: freshly prepared gel<dihybrid gel<trihybrid gel. Microscopic studies of the trihybrid gel indicate the formation of three distinct morphologies, that is, nanoscale metal–organic particles (NMOPs), flowerlike aggregates of SWCNHs and AgNPs, and also their integration with each other. Detailed studies suggest lamellar organizations of the linear metal–ligand complexes in the NMOPs, which upon association create a three‐dimensional network that eventually immobilizes the solvent molecules.     

Self‐assembly of star‐shaped polystyrene‐block‐polypeptide copolymers synthesized by the combination of atom transfer radical polymerization and ring‐opening living polymerization of α‐amino acid‐N‐carboxyanhydrides

The self‐assembling nature and phase‐transition behavior of a novel class of triarm, star‐shaped polymer–peptide block copolymers synthesized by the combination of atom transfer radical polymerization and living ring‐opening polymerization of α‐amino acid‐N‐carboxyanhydride are demonstrated. The two‐step synthesis strategy adopted here allows incorporating polypeptides into the usual synthetic polymers via an amido–amidate nickelacycle intermediate, which is used as the macroinitiator for the growth of poly(γ‐benzyl‐L ‐glutamate). The characterization data are reported from analyses using gel permeation chromatography and infrared, ¹H NMR, and ¹³C NMR spectroscopy. This synthetic scheme grants a facile way to prepare a wide range of polymer–peptide architectures with perfect microstructure control, preventing the formation of homopolypeptide contaminants. Studies regarding the supramolecular organization and phase‐transition behavior of this class of polymer‐block‐polypeptide copolymers have been accomplished with X‐ray diffraction, infrared spectroscopy, and thermal analyses. The conformational change of the peptide segment in the block copolymer has been investigated with variable‐temperature infrared spectroscopy. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 2774–2783, 2006     

Triple redox/temperature responsive diselenide‐containing homopolypeptide micelles and supramolecular hydrogels thereof

Stimuli‐responsive polypeptides are receiving much attention for drug delivery systems and tissue engineering scaffolds; however, it is challenging to construct multiple‐responsive polypeptides and one‐component polymeric hydrogels. Herein, a novel type of triple redox/temperature‐responsive diselenide‐containing poly(methoxydiethylene glycol‐l ‐glutamate) homopolypeptide was facilely synthesized by selenocystamine‐initiated ring‐opening polymerization in DMF at 30 °C, and their chemical structures and physical properties were fully characterized by means of ¹H NMR, GPC, FT‐IR, WAXD, and CD. They self‐assembled into spherical micelles in aqueous solution, which possess a lower critical solution temperature, redox‐responsiveness inherited from diselenide bond, and the triple stimuli‐sensitive self‐assembly behaviors, as characterized by means of turbidity, DLS, TEM, and zeta potential measurements. The diselenide‐containing homopolypeptides formed supramolecular hydrogels at room temperature, exhibiting a thermal gel–sol transition. The rheological tests evidence that the mechanical modulus of the hydrogel is independent of angular frequency within 100 rad/s and at 25 °C, in which the storage modulus of G′ is order of magnitude greater than the loss modulus of G″, displaying a solid‐like elastic behavior. Moreover, the mechanical modulus of the hydrogel can be tuned by changing the chain length of the homopolypeptide, the 10‐mM 1,4‐dithiothreitol (DTT) reduction, and 1 mM H₂O₂ oxidation, respectively. Consequently, this work provides a simple strategy to fabricate triple‐stimuli responsive polypeptide micelles and one‐component hydrogels. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 1067–1077     

Alkene–Azide 1,3‐Dipolar Cycloaddition as a Trigger for Ultrashort Peptide Hydrogel Dissolution

An alkene–azide 1,3‐dipolar cycloaddition between trans‐cyclooctene (TCO) and an azide‐capped hydrogel that promotes rapid gel dissolution is reported. Using an ultrashort aryl azide‐capped peptide hydrogel (PhePhe), we have demonstrated proof‐of‐concept where upon reaction with TCO, the hydrogel undergoes a gel–sol transition via 1,2,3‐triazoline degradation and 1,6‐self‐immolation of the generated aniline. The potential application of this as a general trigger in sustained drug delivery is demonstrated through release of encapsulated cargo (doxorubicin). Administration of TCO resulted in 87 % of the cargo being released in 10 h, compared to 13–14 % in the control gels. This is the first example of a potential bioorthogonal‐triggered hydrogel dissolution using a traditional click‐type reaction. This type of stimulus could be extended to other aryl azide‐capped hydrogels.     

Poly(ϵ‐caprolactone)‐b‐poly(ethylene glycol)‐b‐poly(ϵ‐caprolactone) triblock copolymers: Synthesis and self‐assembly in aqueous solutions

Nontoxic and biodegradable poly(?‐caprolactone)‐b‐poly(ethylene glycol)‐b‐poly(?‐caprolactone) triblock copolymers were synthesized by the solution polymerization of ?‐caprolactone in the presence of poly(ethylene glycol). The chemical structure of the resulting triblock copolymer was characterized with ¹H NMR and gel permeation chromatography. In aqueous solutions of the triblock copolymers, the micellization and sol–gel‐transition behaviors were investigated. The experimental results showed that the unimer‐to‐micelle transition did occur. In a sol–gel‐transition phase diagram obtained by the vial‐tilting method, the boundary curve shifted to the left, and the gel regions expanded with the increasing molecular weight of the poly(?‐caprolactone) block. In addition, the hydrodynamic diameters of the micelles were almost independent of the investigated temperature (25–55 °C). The atomic force microscopy results showed that spherical micelles formed at the copolymer concentration of 2.5 × 10^?4 g/mL, whereas necklace‐like and worm‐like shapes were adopted when the concentration was 0.25 g/mL, which was high enough to form a gel. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 45: 605–613, 2007     

Biological Glucose Metabolism Regulated Peptide Self‐Assembly as a Simple Visual Biosensor for Glucose Detection

A glucose oxidase (GOx)‐mediated glucose metabolism was in vitro mimicked and employed to regulate the self‐assembly of peptide‐based building blocks. In this new stimuli‐responsive self‐assembly system, two peptide‐based building blocks, respectively, having aspartic acid (gelator 1 ) and lysine (gelator 2 ) residues were designed and prepared. When adding glucose and GOx to the aqueous solution of gelator 1 or the self‐assembled fibrillar hydrogel of gelator 2 to construct glucose metabolism system, the metabolic product (gluconic acid) can trigger the protonation of the peptide molecules and induce the phase transitions of gelators 1 (sol‐gel) and 2 (gel‐sol). Because this glucose metabolism regulated peptide self‐assembly is built on the oxidation of glucose, it can be used as a simple visual biosensor for glucose detection.     

Self‐Assembly of Metal–Organic Frameworks into Monolithic Materials with Highly Controlled Trimodal Pore Structures

We present a two‐step template‐free approach toward monolithic materials with controlled trimodal porous structures with macro‐, meso‐, and micropores. Our method relies on two ordering processes in discrete length scales: 1) Spontaneous formation of macroporous structures in monolithic materials by the sol–gel process through the short‐range ordered self‐assembly of metal–organic frameworks (MOFs), and 2) reorganization of the framework structures in a mediator solution. The Zr‐terephthalate‐based MOF (UiO‐66‐NH₂) was adopted as a proof of concept. The self‐assembly‐induced phase separation process offered interconnected macropores with diameters ranging from 0.9 to 1.8 μm. The subsequent reorganization process converted the microporous structure from low crystalline framework to crystalline UiO‐66. The resultant mesopore size within the skeletons was controlled in the range from 9 to 21 nm. This approach provides a novel way of designing spaces from nano‐ to micrometer scale in network‐forming materials.