Effects of Glycon and Temperature on Self-Assembly Behaviors of α-Galactosyl Ceramide in Water.

α-Galactosyl ceramide (GalCer) is an anticancer glycolipid consisting of d-galactose and phytosphingosine-based ceramide. Although the amphiphilic structure of GalCer is expected to form self-associates in water, the self-assembly behaviors of GalCer and its derivatives have not been systematically investigated at this moment in spite of its great importance. The evaluation of morphologies and properties of the associates should open new insights into glycolipid chemistry such as the application of GalCer derivatives to a nanocarrier and the elucidation of the detailed pharmacological mechanism of GalCer. Herein, we show the synthesis of the aglycon fragment (Aglycon) of GalCer and the self-assembly behaviors of both GalCer and Aglycon in water. The critical aggregation concentrations of Aglycon and GalCer were determined using UV-vis spectral measurements at various concentrations. The transmission electron microscopy observations of the aqueous sample solutions indicated that the solution of GalCer includes vesicles, while that of Aglycon comprises giant micelles in the absence of vesicles. The vesicle formation in the solution of GalCer was also confirmed by Triton X-100-triggered dye-release experiments. To reveal the effects of glycon on the self-assembly behaviors in detail, we performed the measurements of dynamic light scattering, temperature-dependence of turbidity, differential scanning calorimetry, and wide-angle X-ray diffraction. The results clarify that the glycon moiety of GalCer has a significant role in the formation inhibition of second associates and the plasticization of the hydrophobe. This work will shed light on the other natural glycosides to evaluate the self-assembly behaviors for supramolecular and pharmacological applications in the near future.

Shear-Induced Adhesion of Alternating Peptides Prepared by Ugi Four-Center Three-Component Reaction.

The development of new peptide-based glues has been strongly urged from the viewpoints of industrial applications and biomedical engineering. However, the large-scale synthesis of polypeptides with an ordered sequence is highly challenging, which strictly restricts materials resources for the research and development of polypeptides. In this work, the framework of adhesive alternating peptides has been designed to be glycine (Gly)-N-substituted valine (Val) as the dipeptide repeating sequence, considering the peptapeptide repeating sequence of viscoelastic natural elastin as a motif. The alternating peptides are prepared via three-component polymerization exploiting Ugi four-center three-component reaction as the elemental polymerization reaction. The adhesive strength (SAdh ) values of the polymers are evaluated by a shear adhesive test method using two glass plates. Alternating peptides with Gly-N-benzylated Val dipeptide repeating units exhibit the optimal adhesive properties such as much higher SAdh than that of conventional fibrin glue and a unique readhesion capability. It is indicated that the remarkably high SAdh would be attributed to the shear-induced structural change of single polymer chain, the slow relaxation of extended structure, and the weak interchain interactions. Due to the favorable adhesive properties of alternating peptides, these adhesives may be highly suitable for real-world applications.

Thermoresponsive Structure and Dye Encapsulation of Micelles Comprising Bolaamphiphilic Quercetin Polyglycoside.

A bolaamphiphile is a special member of amphiphilic molecules, which contains a hydrophobic skeleton and two water-soluble groups on both ends. Bolaamphiphiles form thermally stable associates in water under lower concentration than those of typical monoheaded amphiphiles, indicating the potential usefulness of bolaamphiphiles as the component of nanomaterials. However, the structural diversity of bolaamphiphiles is limited at this moment. We recently developed the synthesis of quercetin-3-O-polyglycoside (QP) as a new entry of bolaamphiphiles via a one-pot polymerization using sugar-based cyclic sulfite initiated by quercetin skeleton. Herein, we show the bolaamphiphilic properties of QP in detail. The micellization behaviors of QP are systematically investigated through comparison with those of quercetin (Que) and isoquercitrin (IQ) to evaluate the roles of glycone on the micellization of quercetin derivatives. The morphology of the micelles bearing QP is observed by cryo-transmission electron microscopy (cryo-TEM), suggesting the formation of bolaamphiphile-specific giant ribbon-like micelles in addition to spherical micelles. The thermoresponsive micellization behaviors are also discussed through the critical micelle concentration (CMC) values, the dynamic light scattering analyses at various temperatures, and thermal hysteresis of the micellizations. It is indicated that the polysaccharide chains integrated on the surface of micelles would serve as a steric protecting group to endow the micelles with kinetic stability. These results will shed light on natural glycoside skeletons to design a new class of micelles for advanced health applications in near future.

Substituent Optimization of (1 → 2)-Glucopyranan for Tough, Strong, and Highly Stretchable Film with Dynamic Interchain Interactions.

Polysaccharide is a naturally abundant material, which is regarded as an indispensable scaffold for a structural material. The properties of polysaccharides are dependent not only on the structure of repeating sugar unit but also the glycosidic position between the repeating units. Herein, we report the development of polysaccharide-based self-standing film consisting of naturally occurring (1 → 2)-glucopyranan skeleton. The self-standing film of (1 → 2)-glucopyranan derivative with hexyl carbamate groups Uret-Glcp(1,2) is found to be highly stretchable and tough, which exhibits maximum stress of σmax = 1.4 MPa, fracture strain of ε ∼ 800%, and the work of extension at fracture Wext ∼ 4 MJ m-3. It is indicated that the interchain hydrogen bonds in Uret-Glcp(1,2) film would serve as energy dissipative bonds for strengthening the film, where the application of mechanical stress to Uret-Glcp(1,2) film induces not only the rapture of physical interchain interactions, but also the formation of intrachain hydrogen bonds along the stretching direction. The effects of substituent and glycosidic position of polysaccharide on the properties are discussed in detail.

Effects of the Hydrophilic-Lipophilic Balance of Alternating Peptides on Self-Assembly and Thermo-Responsive Behaviors.

A series of N-substituted poly(Gly-alter-Val) peptides were successfully synthesized for the systematic evaluation of the micellization behavior of alternating peptides. Three-component polymerization employing an aldehyde, a primary ammonium chloride, and potassium isocyanoacetate afforded four alternating peptides in excellent yields. We investigated the dependence of the hydrophilic-lipophilic balance of alternating peptides on the micellization behavior. All the aqueous solutions of alternating peptides exhibited upper critical solution temperature (UCST) behaviors, strongly indicating that the alternating binary pattern would mainly contribute to the UCST behaviors. The cloud points of alternating peptides shifted to higher temperatures as the side chains became more hydrophilic, which is opposite to the trend of typical surfactants. Such unusual micellization behaviors appeared to be dependent on the quasi-stable structure of single polymer chains formed in water.

Bolaamphiphilic properties and pH-dependent micellization of quercetin polyglycoside.

Quercetin polyglycoside as a new bolaamphiphile is prepared via a one-pot grafting polymerization technique using sugar-based cyclic sulfite. Micelles comprising quercetin polyglycoside exhibit special pH-effects, in which the polyglycoside moieties on the surface of the micelle serve as a steric protecting group to endow chemical stabilization.

Structural factors of benzylated glucopyranans for shear-induced adhesion.

We have prepared benzylated glucopyranans and evaluated the structural effects on the adhesion capacity. It was found that 97%-benzylated (1→2)-glucopyranan exhibited a unique shear-induced adhesion. The effects of structural factors on the adhesion behaviors are discussed through systematic adhesion tests, differential scanning calorimetry, theoretical models, and IR spectroscopy.

Strong, tough, and repeatable adhesion of an alternating peptide comprising phenyl glycine as a repeating unit.

A new strategy for preparing peptide-based adhesive materials is provided. An exactly alternating peptide with glycine-N-butylphenyl glycine dipeptide repeating units exhibits excellent repeatable adhesion capacity. The adhesive properties are attributed to the viscoelastic properties and microfibril formation, which are tunable by simple manipulation of the reaction component on polymerization.

Self-Adjustable Adhesion of Polyampholyte Hydrogels.

Developing nonspecific, fast, and strong adhesives that can glue hydrogels and biotissues substantially promotes the application of hydrogels as biomaterials. Inspired by the ubiquitous adhesiveness of bacteria, it is reported that neutral polyampholyte hydrogels, through their self-adjustable surface, can show rapid, strong, and reversible adhesion to charged hydrogels and biological tissues through the Coulombic interaction.

Oppositely charged polyelectrolytes form tough, self-healing, and rebuildable hydrogels.

A series of tough polyion complex hydrogels is synthesized by sequential homopolymerization of cationic and anionic monomers. Owing to the reversible interpolymer ionic bonding, the materials are self-healable under ambient conditions with the aid of saline solution. Furthermore, self-glued bulk hydrogels can be built from their microgels, which is promising for 3D/4D printing and the additive manufacturing of hydrogels.

Free Reprocessability of Tough and Self-Healing Hydrogels Based on Polyion Complex.

Tough hydrogels with facile processability to reform into various shapes are required in many practical applications. In this work, we reported that a novel, tough, and self-healing physical hydrogel based on polyion complex (PIC) can be dissolved in 4 M NaCl solution to form a PIC solution. The PIC solution can be easily reprocessed into various shapes, such as thin films, sheets, fibers, and capsules, by using simple methods, such as casting and injection, while maintaining excellent mechanical properties comparable to, or even better than, the original hydrogel. The reprocessability and robust mechanical properties of PIC hydrogels are promising for practical applications in soft materials, especially in 3D/4D printing technology.

Physical hydrogels composed of polyampholytes demonstrate high toughness and viscoelasticity.

Hydrogels attract great attention as biomaterials as a result of their soft and wet nature, similar to that of biological tissues. Recent inventions of several tough hydrogels show their potential as structural biomaterials, such as cartilage. Any given application, however, requires a combination of mechanical properties including stiffness, strength, toughness, damping, fatigue resistance and self-healing, along with biocompatibility. This combination is rarely realized. Here, we report that polyampholytes, polymers bearing randomly dispersed cationic and anionic repeat groups, form tough and viscoelastic hydrogels with multiple mechanical properties. The randomness makes ionic bonds of a wide distribution of strength. The strong bonds serve as permanent crosslinks, imparting elasticity, whereas the weak bonds reversibly break and re-form, dissipating energy. These physical hydrogels of supramolecular structure can be tuned to change multiple mechanical properties over wide ranges by using diverse ionic combinations. This polyampholyte approach is synthetically simple and dramatically increases the choice of tough hydrogels for applications.

A phase diagram of neutral polyampholyte - from solution to tough hydrogel.

Our recent study has revealed that neutral polyampholytes form tough physical hydrogels above a critical concentration Cm,c by forming ionic bonds of wide strength distribution. In this work, we systematically investigate the behavior of a polyampholyte system, poly(NaSS-co-DMAEA-Q), randomly copolymerized from oppositely charged monomers, sodium p-styrenesulfonate (NaSS) and acryloyloxethyltrimethylammonium chloride (DMAEA-Q) without and with a slight chemical cross-linking. A phase diagram of formulation has been constructed in the space of monomer concentration Cm and cross-linker density CMBAA. Three phases are observed for the as-synthesized samples: homogeneous solution at dilute Cm, phase separation at semi-dilute Cm, and homogenous gel at concentrated Cm. Above a critical Cm,c, the polyampholyte forms a supramolecular hydrogel with high toughness by dialysis of the mobile counter-ions, which substantially stabilizes both the intra- and inter chain ionic bonds. The presence of the chemical cross-linker (CMBAA > 0) brings about a shift of the tough gel phase to lower Cm,c. The tough polyampholyte gel, containing ∼50 wt% water, is highly stretchable and tough, exhibits fracture stress of σb∼ 0.4 MPa, fracture strain of εb∼ 30, and the work of extension at fracture Wext∼ 4 MJ m-3. These values are at the level of most tough soft materials. Owing to the reversible ion bonds, the poly(NaSS-co-DMAEA-Q) gels also exhibit complete self-recovery (100%) and high fatigue resistance upon repeated large deformation.