Alkyl chain length dependent hydrogelation of L-tryptophan-based amphiphile

The search for low molecular weight hydrogelators (LMWHs) with varying structural motif is getting intense because of its potential application in biomedicines as well as the diversified area of nanobiotechnology. Hydrophobic interaction is one of the most crucial parameters in the design and development of such LMWHs. To this notion, a methodical investigation was carried out to find the influence of varying alkyl chain length of amphiphile on water gelation efficacy, which has been only marginally addressed in the literature to date. We have synthesized a series of low molecular weight L-tryptophan-based gelators, some of which are excellent gelator for plain water, an essential criterion for biological use. The alkyl chain induced hydrophobicity at the molecular level has remarkable influence in modulating water immobilization. Water gelation efficiency was improved more than 100 times on moving from 10 to 18 carbon atoms. The self-aggregation behavior of these thermoreversible hydrogelators investigated through different spectroscopic and microscopic techniques showed that an optimum balance between hydrophilicity and hydrophobicity is indeed essential, which can be largely regulated by varying the alkyl chain length. Thus, the study offers better understanding toward tailoring the properties of gel in plain water and thereby paving the way for potential applications.     

l-Lysine-based supramolecular hydrogels containing various inorganic ions

The preparation of supramolecular hydrogels containing various inorganic acids and salts using L-lysine-based hydrogelators is conducted and their thermal stabilities, gel strengths, FT-IR spectra, and electron micrographs are measured. These hydrogelators can form supramolecular hydrogels over a wide pH range and contain inorganic acids and salts. The supramolecular hydrogels based on ester-type hydrogelators have good thermal stabilities (high Tgel), while the hydrogelator with a carboxyl group forms a thermally sensitive gel with high mechanical strength. Furthermore, the gelation mechanism is discussed using FT-IR spectroscopy and TEM observations.     

Co‐assembly of Polyoxometalates and Zwitterionic Amphiphiles into Supramolecular Hydrogels: From Crystalline Fibrillar to Amorphous Micellar Networks

Gelation mechanism is of utmost importance to the rational design of supramolecular hydrogelators. Although both kinetic and thermodynamic controlled self‐assembly processes have been widely studied in hydrogels, the formation relationship between crystalline and amorphous gel networks still remains ambiguous. Herein, a gelation transformation from a kinetic to a thermodynamic process was achieved by balancing the rigidity and flexibility of the inorganic–organic co‐assemblies. By using polyoxometalates and zwitterionic amphiphiles, the transition morphologies between crystalline and amorphous hydrogel networks were evidenced for the first time, as ordered wormlike micelles. Given the versatile applications of hydrogels in biological systems and materials science, these findings may highlight the potential of inorganic–organic binary supramolecular hydrogelators and fill in the blank between kinetic and thermodynamic controlled gelation processes.     

Supramolecular Self-organization of Potential Hydrogelators on Attracting Surfaces

This article highlights the aggregation behaviour of potential low molecular weight hydrogelators on attracting surfaces. Our goal was the development of a method, which enables the finding of new hydrogelators that are not easily recognizable as such because they only form instable or no hydrogels in aqueous solution. To this end, a series of negatively charges azo-dyes was synthesized and positive charged glass slides were immersed into their aqueous solutions. All dyes showed supramolecular organization and significant concentration on the attracting glass surface. Microscopic investigations mostly revealed the formation of crystals. However, one compound, (1-(2-n-octylphenylazo)-2-hydroxy-6-naphthalenesulphonate, selectively formed a hydrogel on the surface whereas it does not gel in aqueous solution. This reveals the hydrogel as the stable form of this compound under equilibrium conditions. This method of surface-induced hydrogelation might facilitate the identification of new hydrogelators. Further more, it might also allow the mimicking of surface gelation as a process of biological relevance.     

A family of low-molecular-weight hydrogelators based on L-lysine derivatives with a positively charged terminal group

A family of L-lysine-based low-molecular-weight compounds with various positively charged terminals (pyridinium and imidazolium derivatives) was synthesized and its gelation behavior in water was investigated. Most of the compounds can be very easily synthesized in high yields (total yields >90 %), and they function as excellent hydrogelators that form hydrogels below 1 wt %; particularly, N(epsilon)-lauroyl-N(alpha)-[11-(4-tert-butylpyridinium)undecanoyl]-L-lysine ethyl ester (2 c) and N(epsilon)-lauroyl-N(alpha)-[11-(4-phenylpyridinium)undecanoyl]-L-lysine ethyl ester (2 d), which are able to gel water at concentration of only 0.2 wt %. This corresponds to a gelator molecule that entraps more than 20 000 water molecules. All hydrogels are very stable and maintain the gel state for at least 9 months. TEM observations demonstrated that these hydrogelators self-assemble into a nanoscaled fibrous structure; a three-dimensional network is then formed by the entanglement of the nanofibers. An FTIR study in [D(6)]DMSO/D(2)O and in CHCl(3) revealed the existence of intermolecular hydrogen bonding between the amide groups. This was further supported by a (1)H NMR study in [D(6)]DMSO/H(2)O. A luminescence study, in which ANS (1-anilino-8-naphtharenesulfonic acid) was used as a probe, indicated that the hydrogelators self-assemble into nanostructures possessing hydrophobic pockets at a very low concentration. Consequently, it was found that the driving forces for self-assembly into a nanofiber are hydrogel bonding and hydrophobic interactions.     

In Situ Synthesis of a Supramolecular Hydrogelator at an Oil/Water Interface for Stabilization and Stimuli‐Induced Fusion of Microdroplets

Supramolecular hydrogels are expected to have applications as novel soft materials in various fields owing to their designable functional properties. Herein, we developed an in situ synthesis of supramolecular hydrogelators, which can trigger gelation of an aqueous solution without the need for temperature change. This was achieved by mixing two precursors, which induced the synthesis of a supramolecular gelator and its instantaneous self‐assembly into nanofibers. We then performed the in situ synthesis of this supramolecular gelator at an oil/water interface to produce nanofibers that covered the surfaces of the oil droplets (nanofiber‐stabilized oil droplets). External stimuli induced fusion of the droplets owing to disassembly of the gelator molecules. Finally, we demonstrated that this stimuli‐induced droplet fusion triggered a synthetic reaction within the droplets. This means that the confined nanofiber‐stabilized droplets can be utilized as stimuli‐responsive microreactors.     

Recent progress in exploiting small molecule peptides as supramolecular hydrogelators

Small molecule peptides and their derivatives are an emerging class of supramolecular hydrogelators that have attracted rapidly growing interest in the fields of drug delivery and regenerative medicine due to their inherent biodegradability and biocompatibility, as well as versatility in molecular design and ease of synthesis. Built upon the directional, intermolecular interactions such as hydrogen bonding and π-π stacking, peptide-based molecular units can associate in aqueous solution into filamentous assemblies of various sizes and shapes. Under appropriate conditions, these filamentous assemblies can percolate into a 3D network with materials properties tailorable for specific biomedical applications. In this review, we survey the literature published over the past three years in the development of peptide-based hydrogelators for biomedical applications. We highlight several representative examples and center our discussion on the fundamentals of molecular design, assembly, and gelation conditions.     

Biotin-amino acid conjugates: an approach toward self-assembled hydrogelation

[structure: see text] Amino acid-appended biotin hydrogelators are a new class of low-molecular-weight gelators that display remarkable gelation properties in aqueous media, including buffer solutions with variable pH.     

Structure and properties of an exceptional low molecular weight hydrogelator

Research for low molecular weight (LMW) hydrogelators has become an area of increasing interest due to many possible new applications for such compounds. They might serve as templates for nanostructures or in biomedical applications and even in drug discovery. In this investigation, we explored the structure-gelling relations of a LMW hydrogelator that can form a hydrogel in water at room temperature. To this end, various analytical techniques such as nuclear magnetic resonance, rheology, X-ray scattering, birefringence, and microscopy were applied to gain better insight on the structure of the gel and to provide an explanation for this unique gelation behavior.     

Organogel-hydrogel transformation by simple removal or inclusion of N-Boc-protection

Development of organo- and hydrogelators is on the rise because of their extensive applications, from advanced materials to biomedicine. However, designing both types of gelator from a common structural scaffold is challenging, and becomes more significant if transformation between them can be achieved by a simple method. The present work reports the design and synthesis of both organo- and hydrogelators from amino acid/peptide-based amphiphilic precursors with a naphthyl group at the N terminus and a primary amine-containing hydrophilic ethyleneoxy unit at the C terminus. In alkaline medium, tert-butyloxycarbonyl (Boc) protection at the primary amine of the amphiphiles resulted in efficient organogelators (minimum-gelation concentration (MGC)=0.075-1.5% w/v). Interestingly, removal of the Boc protection from the ethyleneoxy unit, under acidic conditions, yielded amphiphiles capable of gelating water (MGC=0.9-3.0% w/v). Simple protection and deprotection chemistry was used to achieve transformation between the organogel and hydrogel by alteration of the pH. Combinations of different aliphatic and aromatic amino acids were investigated to discover their cumulative effect on the gelation properties. Field-emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM) were employed to investigate the supramolecular morphology of the thermoreversible gels. Spectroscopic investigations (FTIR, photoluminescence, XRD) revealed that noncovalent interactions, such as hydrogen bonding, π-π stacking, and van der Waals interactions play a decisive role in self-assembled gelation.     

Hydrogelators of cyclotriveratrylene derivatives

Developing cavity-based supramolecular hydrogels is in its infancy because not many such hydrogelators are available. Reported herein is our creation of rigid cavitand cyclotriveratrylene (CTV) based hydrogelators from the molecular backbones of CTVs that were in limited cases shown to form organogels. For doing so deprotonable -COOH or protonable -NH(2) was introduced as terminal group into the rigid and hydrophobic CTV backbones. We thus successfully obtained optically anisotropic supramolecular hydrogels from these new CTVs hydrogelators with excellent thermostability and high tolerance towards strong electrolytes. The obtained CTV-1 and CTV-2 hydrogels are luminescent and exhibit reversible gel-to-sol and sol-to-gel transitions upon pH variations. The success in creating CTV-1 and CTV-2 hydrogelators on the basis of the skeleton of a CTV-organogelator suggests that balancing the hydrophilic and hydrophobic characters of the ionic and hydrophobic moieties well in the gelator molecule is important for designing a promising hydrogelator.     

Gelation of Covalently Cross-Linked PEG-Heparin Hydrogels

We study PEG-heparin hydrogels to identify compositions that lead to gel formation and measure the corresponding gelation kinetics. The material consists of a maleimide-functionalized high molecular weight heparin (HMWH) backbone covalently cross-linked with bis-thiol poly(ethylene glycol) (PEG). Using multiple particle tracking microrheology, we investigate a broad composition space, defined by the number of maleimide functional sites per HMWH (f = 3.9-11.8), the molecular weight of the PEG cross-linker (M(n) = 2000, 5000, and 10 000), and the concentrations of the heparin and PEG polymers. Gelation kinetics are characterized by time-cure superposition, yielding the gel time, t(c), and the critical relaxation exponent, n. Gelation times range from 5 < t(c) ≤ 45 min, with the fastest kinetics occurring for the highest HMWH maleimide functionalities. t(c) depends nonmonotonically on the PEG cross-linker molecular weight, suggesting that gelation is affected by the length of the cross-linker relative to intermolecular interactions between heparin molecules. The critical relaxation exponent decreases from n = 0.52 for PEG 2000 to n = 0.39 for PEG 10 000. Finally, 219 equilibrated samples taken over the entire composition space are identified as liquid or solid, defining the "gelation envelope". The boundaries of this empirical gelation envelope are in good agreement with Flory-Stockmayer theory. In all, microrheological measurements enable characterization over a large parameter space and provide crucial insight into the gelation of complex, multifunctional hydrogelators used in therapeutic applications.     

Enzymatic Hydrolysis-Responsive Supramolecular Hydrogels Composed of Maltose-Coupled Amphiphilic Ureas

Maltose is a ubiquitous disaccharide produced by the hydrolysis of starch. Amphiphilic ureas bearing hydrophilic maltose moiety were synthesized via the following three steps: I) construction of urea derivatives by the condensation of 4-nitrophenyl isocyanate and alkylamines, II) reduction of the nitro group by hydrogenation, and III) an aminoglycosylation reaction of the amino group and the unprotected maltose. These amphiphilic ureas functioned as low molecular weight hydrogelators, and the mixtures of the amphipathic ureas and water formed supramolecular hydrogels. The gelation ability largely depended on the chain length of the alkyl group of the amphiphilic urea; amphipathic urea having a decyl group had the highest gelation ability (minimum gelation concentration=0.4 mM). The physical properties of the supramolecular hydrogels were evaluated by measuring their thermal stability and dynamic viscoelasticity. These supramolecular hydrogels underwent gel-to-sol phase transition upon the addition of α-glucosidase as a result of the α-glucosidase-catalyzed hydrolysis of the maltose moiety of the amphipathic urea.     

Effect of C-terminal modification on the self-assembly and hydrogelation of fluorinated Fmoc-Phe derivatives

The development of hydrogels resulting from the self-assembly of low molecular weight (LMW) hydrogelators is a rapidly expanding area of study. Fluorenylmethoxycarbonyl (Fmoc) protected aromatic amino acids derived from phenylalanine (Phe) have been shown to be highly effective LMW hydrogelators. It has been found that side chain functionalization of Fmoc-Phe exerts a significant effect on the self-assembly and hydrogelation behavior of these molecules; fluorinated derivatives, including pentafluorophenylalanine (F(5)-Phe) and 3-F-phenylalanine (3-F-Phe), spontaneously self-assemble into fibrils that form a hydrogel network upon dissolution into water. In this study, Fmoc-F(5)-Phe-OH and Fmoc-3-F-Phe-OH were used to characterize the role of the C-terminal carboxylic acid on the self-assembly and hydrogelation of these derivatives. The C-terminal carboxylic acid moieties of Fmoc-F(5)-Phe-OH and Fmoc-3-F-Phe-OH were converted to C-terminal amide and methyl ester groups in order to perturb the hydrophobicity and hydrogen bond capacity of the C-terminus. Self-assembly and hydrogelation of these derivatives was investigated in comparison to the parent carboxylic acid compounds at neutral and acidic pH. It was found that hydrogelation of the C-terminal acids was highly sensitive to solvent pH, which influences the charge state of the terminal group. Rigid hydrogels form at pH 3.5, but at pH 7 hydrogel rigidity is dramatically weakened. C-terminal esters self-assembled into fibrils only slowly and failed to form hydrogels due to the higher hydrophobicity of these derivatives. C-terminal amide derivatives assembled much more rapidly than the parent carboxylic acids at both acidic and neutral pH, but the resultant hydrogels were unstable to shear stress as a function of the lower water solubility of the amide functionality. Co-assembly of acid and amide functionalized monomers was also explored in order to characterize the properties of hybrid hydrogels; these gels were rigid in unbuffered water but significantly weaker in phosphate buffered saline. These results highlight the complex nature of monomer/solvent interactions and their ultimate influence on self-assembly and hydrogelation, and provide insight that will facilitate the development of optimal amino acid LMW hydrogelators for gelation of complex buffered media.     

(S)-(+)-Ibuprofen-based hydrogelators: an approach toward anti-inflammatory drug delivery

We have synthesized (S)-(+)-ibuprofen-based hydrogelators that feature dipeptide linkages. In aqueous media, one of these hydrogelators formed robust gels that were stable for several months. Enzyme-mediated hydrolysis offers a route toward the sustained release of this anti-inflammatory agent.     

Cyclohexane bis-urea compounds for the gelation of water and aqueous solutions

A new class of efficient hydrogelators has been developed by a simple modification of the peripheral substituents of cyclohexane bis-urea organogelators with hydrophilic hydroxy or amino functionalities. These bis-urea hydrogelators were synthesised in two or three steps using an alternative procedure to the common isocyanate method. Gelation was obtained with organic solvents, water and strongly basic aqueous solutions like 25% ammonia. Hydrogelation was found to depend on a delicate balance between the hydrophobicity of the alkyl chains, hydrophilicity of the terminal substituents and the enantiomeric purity of the compound. The hydrogels consisted of a network of fibers, in which all urea groups are involved in intermolecular hydrogen bonding. Most likely, gelation is driven by hydrophobic interactions of the methylene units, whereas hydrogen bond formation between the urea groups provides the necessary anisotropy of the aggregation and the high thermal stability of the gels.     

Counterion-induced modulation in the antimicrobial activity and biocompatibility of amphiphilic hydrogelators: influence of in-situ-synthesized Ag-nanoparticle on the bactericidal property

The necessity for the development of new antimicrobial agents due to the ever increasing threat from microbes is causing a rapid surge in research. In the present work, we have shown the efficient antimicrobial activity of a series of amino acid-based hydrogelating amphiphiles through alteration in their counterion. The subtle variation in the counterion from chloride to various organic carboxylates had a significant impact on the antimicrobial properties with notable improvement in biocompatibility toward mammalian cells. Incorporation of a hydrophobic moiety in the counterion augmented the antibacterial property of the amphiphilic hydrogelator as minimum inhibitory concentration (MIC) against the Gram-positive bacterial strain, Bacillus subtilis decreased up to 5-fold (with respect to the chloride) in the case of n-hexanoate. These counterion-varied amphiphilic hydrogelators were also found to be effective against fungal strains (Candida albicans and Saccharomyces cerevisiae) where they exhibited MICs in the range of 1.0-12.5 μg/mL. To widen the spectrum of antibacterial activity, particularly against Gram-negative bacteria, silver nanoparticles (AgNPs) were synthesized in situ within the supramolecular assemblies of the carboxylate hydrogelators. These AgNP-amphiphile soft-nanocomposites showed bactericidal property against both Gram-positive and Gram-negative bacteria. Encouragingly, these carboxylate hydrogelators showed superior biocompatibility toward mammalian cells, HepG2 and NIH3T3, as compared to the chloride analogue at a concentration range of 10-200 μg/mL. Importantly, the AgNP composites also showed sufficient viability to mammalian cells. Because of the intrinsic hydrogelation ability of these counterion-varied amphiphiles, the resulting soft materials and the nanocomposites could find applications in biomedicine and tissue engineering.     

Pristine Carbon‐Nanotube‐Included Supramolecular Hydrogels with Tunable Viscoelastic Properties

Research investigations involving pristine carbon nanotubes (CNTs) and their applications in diversified fields have been gathering enormous impetus in recent times. One such emerging domain deals with the hybridization of CNTs within hydrogels to form soft nanocomposites with superior properties. However, till now, reports on the inclusion of pristine CNTs within low‐molecular‐weight hydrogels are very scarce due to their intrinsic feature of remaining in the bundled state and strong repulsive behavior to the aqueous milieu. Herein, the synthesis of a series of amino acid/dipeptide‐based amphiphilic hydrogelators having a quaternary ammonium/imidazolium moiety at the polar head and a C16 hydrocarbon chain as the hydrophobic segment is reported. The synthesized amphiphiles exhibited excellent hydrogelation (minimum gelation concentration (MGC) ≈0.7–5 % w/v) as well as single‐walled carbon nanotube (SWNT) dispersion ability in aqueous medium. Interestingly, the dispersed SWNTs were incorporated into the supramolecular hydrogel formed by amphiphiles with an imidazolium moiety at the polar end through complementary cation–π and π–π interactions. More importantly, the newly synthesized hydrogelators were able to accommodate a significantly high amount of pristine SWNTs (2–3.5 % w/v) at their MGCs without affecting the gelating properties. This is the first time that such a huge amount of SWNTs has been successfully incorporated within hydrogels. The efficient inclusion of SWNTs to develop soft nanocomposites was thoroughly investigated by spectroscopic and microscopic methods. Remarkably, the developed nanocomposites showed manifold enhancement (≈85‐fold) in their mechanical strength compared with native hydrogel without SWNTs. The viscoelastic properties of these nanocomposites were readily tuned by varying the amount of incorporated CNTs.     

Supramolecular gels formed by amphiphilic low-molecular-weight gelators of N alpha,N epsilon-diacyl-L-lysine derivatives

Simple L-lysine derivatives, N(alpha)-hexanoyl-N(epsilon)-lauroyl-L-lysine (1), its alkali metal salts (2-4), and two-component compounds that consist of 1 with 2 to 4, were synthesized and their hydrogelation and organogelation properties were studied. Addition of hydrochloric acid to an aqueous solution of the alkali metal salt at room temperature produced a translucent hydrogel. This hydrogelation occurred as a result of a change in nanostructure from micelle-like aggregates to nanofibers, which was induced by partial protonation of the carboxylate to form a carboxylic acid. On the other hand, two-component low-molecular-weight gelators exhibited amphiphilic gelation behavior and functioned as not only hydrogelators, but also as organogelators. FTIR studies revealed that lateral ionic interactions between the carboxylate, alkali metal cation, carboxylic acid, and protons, in addition to hydrogen-bonding and van der Waals interactions play a very important role in hydrogelation. Furthermore, it was found that the water-insoluble carboxylic acid compound underwent a precipitation-dissolution transition with a thermally reversible sol-gel transition in the two-component gelator systems.     

Synthesis and characterization of d-glucosamine-derived low molecular weight gelators

Carbohydrate-based low molecular weight gelators are an interesting class of molecules with many potential applications. Previously, we have found that certain esters and carbamates of 4,6-O-benzylidene-α-d-methyl-glucopyranoside are low molecular weight gelators for a variety of solvents, including water. In order to obtain effective and robust sugar-based organogelators and understand the structure and gelation relationship, we extended our studies using 4,6-O-benzylidene-α-d-methyl-2-deoxy-2-amino-glucopyranoside as the headgroup. A series of amides and ureas were prepared from the protected d-glucosamine and the corresponding isocyanates or acid chlorides, in good yields. The self-assembling properties of these compounds were studied in several solvents, including water and aqueous solutions. Comparing to the ester and carbamate derivatives previously prepared from d-glucose, the amides and urea derivatives afforded more robust gels at lower concentrations typically. Most of these compounds were found to be efficient low molecular weight hydrogelators (LMHGs) for aqueous solutions at concentrations lower than 0.5 wt %. The preparation and characterization of these compounds are reported here.