Developing a Self‐Healing Supramolecular Nucleoside Hydrogel Based on Guanosine and Isoguanosine

Recently, supramolecular hydrogels have attracted increasing interest owing to their tunable stability and inherent biocompatibility. However, only few studies have been reported in the literature on self‐healing supramolecular nucleoside hydrogels, compared to self‐healing polymer hydrogels. In this work, we successfully developed a self‐healing supramolecular nucleoside hydrogel obtained by simply mixing equimolar amounts of guanosine (G) and isoguanosine (isoG) in the presence of K⁺. The gelation properties have been studied systematically by comparing different alkali metal ions as well as mixtures with different ratios of G and isoG. To this end, rheological and phase diagram experiments demonstrated that the co‐gel not only possessed good self‐healing properties and short recovery time (only 20 seconds) but also could be formed at very low concentrations of K⁺. Furthermore, nuclear magnetic resonance (NMR), powder X‐ray diffraction (PXRD), and circular dichroism (CD) spectroscopy suggested that possible G₂isoG₂‐quartet structures occurred in this self‐healing supramolecular nucleoside hydrogel. This co‐gel, to some extent, addressed the problem of isoguanosine gels for the applications in vivo, which showed the potential to be a new type of drug delivery system for biomedical applications in the future.     

Introduction of Ferrocene as a Facilitator for the Construction of Supramolecular Polymers

Proper monomer design is the key to enhancing the strength of noncovalent interactions between the molecules toward the efficient formation of supramolecular polymers (SPs). We have designed and synthesized 1,n′-disubstituted ferrocene-azobenzene-long alkyl chains, Fc(CONH-Azo-TDP)₂, to afford SPs with a high probability. The design exploits the ‘‘molecular ball-bearing’’ property of the ferrocene core, which allows two azobenzene arms to rotate in the planes of cyclopentadienyl rings, generating the most suitable molecular conformation required for SP formation. This ferrocene monomer formed a supergel consisting of SPs supported by strong intermolecular (H-bonding and π-π stacking) interactions and higher enthalpy gain than the reference molecules, where the central ferrocene core was replaced by flexible aliphatic as well as rigid benzene linkers. The molecular conformation involved in SPs, the strength of noncovalent interactions, and the process of supramolecular polymerization were investigated through NMR, UV-Vis, XRD and TEM studies. The results demonstrate that ferrocene may act as a good modulator for constructing efficient SPs.     

Gel formation and photopolymerization during supramolecular self-assemblies of α-CDs with LA-PEG-LA copolymer end-capped with methacryloyl groups

A novel gelation occurs in water during supramolecular self-assemblies of α-cyclodextrins being threaded onto amphiphilic LA-PEG-LA copolymer end-capped with methacryloyl groups. The rheologic studies show that the gels are thixotropic and reversible. While exposed to UV irradiation with a photoinitiator added in advance, they can be photopolymerized in situ to give rise to chemically cross-linked biodegradable hydrogels with the markedly improved mechanical strength. The gels formed prior to and after UV irradiation are characterized using FTIR, ¹H NMR, WAXD and TGA techniques. The swelling ratio and in vitro degradation of the photocured hydrogels are also investigated. It appears that both physical and chemical gels have the potential to be used as injectable biomaterials.     

The Power of Confocal Laser Scanning Microscopy in Supramolecular Chemistry: In situ Real-time Imaging of Stimuli-Responsive Multicomponent Supramolecular Hydrogels

Multicomponent supramolecular hydrogels are promising scaffolds for applications in biosensors and controlled drug release due to their designer stimulus responsiveness. To achieve rational construction of multicomponent supramolecular hydrogel systems, their in-depth structural analysis is essential but still challenging. Confocal laser scanning microscopy (CLSM) has emerged as a powerful tool for structural analysis of multicomponent supramolecular hydrogels. CLSM imaging enables real-time observation of the hydrogels without the need of drying and/or freezing to elucidate their static and dynamic properties. Through multiple, selective fluorescent staining of materials of interest, multiple domains formed in supramolecular hydrogels (e. g. inorganic materials and self-sorting nanofibers) can also be visualized. CLSM and the related microscopic techniques will be indispensable to investigate complex life-inspired supramolecular chemical systems.     

Converting drugs into gelators: supramolecular hydrogels from N-acetyl-L-cysteine and coinage-metal salts

Here we present the concept of metallophilic hydrogels, supramolecular systems in which the gelator species are metal-thiolates that self-assemble through metallophilic attractions. The principle is applied for a small drug, the mucolytic agent N-acetyl-l-cysteine (NAC), which readily forms hydrogels in the presence of Au(iii), Ag(i) and Cu(ii) salts. The resulting transparent hydrogels present pH induced sol/gel transition. Scanning electron microscopy (SEM) measurements reveal a microporous structure in form of flakes for the three of them. The low pH at which these hydrogels are formed (pH < 4) limits their direct use as drug-delivery systems, but still this system constitutes a novel method for easy and fast conversion of small drugs into potent hydrogelators. Future developments will help to fully develop the idea in order to create a new class of supramolecular drug-delivery systems.     

Facile Construction of Bio-Based Supramolecular Hydrogels from Dehydroabietic Acid with a Tricyclic Hydrophenanthrene Skeleton and Stabilized Gel Emulsions

Supramolecular hydrogels have attracted great attention due to their special properties. In this research, bio-based supramolecular hydrogels were conveniently constructed by heating and ultrasounding two components of dehydroabietic acid with a rigid tricyclic hydrophenanthrene skeleton and morpholine. The microstructures and properties of hydrogels were investigated by DSC, rheology, SAXS, CD spectroscopy, and cryo-TEM, respectively. The critical gel concentration (CGC) of the hydrogel was 0.3 mol·L⁻¹ and the gel temperature was 115 °C. In addition, the hydrogel showed good stability and mechanical properties according to rheology results. Cryo-TEM images reveal that the microstructure of hydrogel is fibrous meshes; its corresponding mechanism has been studied using FT-IR spectra. Additionally, oil-in-water gel emulsions were prepared by the hydrogel at a concentration above its CGC, and the oil mass fraction of the oil-in-water gel emulsions could be freely adjusted between 5% and 70%. This work provides a convenient way to prepare bio-based supramolecular hydrogels and provides a new method for the application of rosin.     

An Accurate Assay for Simultaneous Determination of Irinotecan and Its Active Metabolite SN-38 in Rat Plasma by LC with Fluorescence Detection

An accurate LC method was developed and validated for simultaneous determination of irinotecan (CPT-11) and its active metabolite SN-38 in rat plasma. Plasma samples were pretreated with 0.4 g mL^?1 sodium dodecyl sulfate to inactive the carboxylesterase and avoid the conversion of CPT-11 to SN-38. Chromatographic separation was achieved on a Diamaonsil C₁₈ column using acetonitrile–50 mM phosphate buffered solution (30:70, v/v) at pH 4.0 as the mobile phase with the flow rate of 1 mL min^?1. The linear quantitation ranges for CPT-11 and SN-38 were 5.05–3,030 and 3.15–315 ng mL^?1 with r ² > 0.99, respectively. The lower limit of quantification (LLOQ) was 2.33 ng mL^?1 for CPT-11 and 0.26 ng mL^?1 for SN-38 with intra- and inter-day relative standard deviation of <12% and the accuracy values of >90%. The method was proved to be accurate and sensitive enough and was successfully applied to a pharmacokinetic study of CPT-11 in rats.     

Injectable supramolecular hybrid hydrogels formed by MWNT‐grafted‐poly(ethylene glycol) and α‐cyclodextrin

Poly(ethylene glycol)‐grafted‐multiwalled carbon nanotube (MWNT‐g‐PEG) was synthesized by a coupling reaction and formed inclusion complexes (ICs) after selective threading of the PEG segment of the MWNT‐g‐PEG through the cavities of α‐cyclodextrins (α‐CDs) units. The polypseudorotaxane structures of the as‐obtained hydrogels were confirmed by ¹H NMR, X‐ray diffraction and DSC analyses. The complexation of the PEG segments with α‐CDs and the hydrophobic interaction between the MWNT resulted in the formation of supramolecular hybrid hydrogels with a strong network. Thermal analysis showed that the thermal stability of the hydrogel was substantially improved by up to 100 °C higher than that of native hydrogel. The resultant hybrid hydrogels were found to be thixotropic and reversible, and could be applied as a promising injectable drug delivery system. The mechanical strength of the hybrid hydrogels was greatly improved in comparison with that of the corresponding native hydrogels. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 48: 3145–3151, 2010     

Enzymatic Dissolution of Biocomposite Solids Consisting of Phosphopeptides to Form Supramolecular Hydrogels

Enzyme‐catalyzed dephosphorylation is essential for biomineralization and bone metabolism. Here we report the exploration of using enzymatic reaction to transform biocomposites of phosphopeptides and calcium (or strontium) ions to supramolecular hydrogels as a mimic of enzymatic dissolution of biominerals. ³¹P NMR shows that strong affinity between the phosphopeptides and alkaline metal ions (e.g., Ca²⁺ or Sr²⁺) induces the formation of biocomposites as precipitates. Electron microscopy reveals that the enzymatic reaction regulates the morphological transition from particles to nanofibers. Rheology confirms the formation of a rigid hydrogel. As the first example of enzyme‐instructed dissolution of a solid to form supramolecular nanofibers/hydrogels, this work provides an approach to generate soft materials with desired properties, expands the application of supramolecular hydrogelators, and offers insights to control the demineralization of calcified soft tissues.     

DNA-based supramolecular hydrogels: From construction strategies to biomedical applications

DNA-based supramolecular hydrogels are important and promising biomaterials for various applications due to their inherent biocompatibility and tunable physicochemical properties. The three-dimensional supramolecular matrix of DNA formed by non-covalently dynamic cross-linking provides exceptional adaptability, self-healing, injectable and responsive properties for hydrogels. In addition, DNA hydrogels are also ideal bio-scaffold materials owing to their tissue-like mechanics and intrinsic biological functions. Technically, DNA can assemble into supramolecular networks by pure complementary base pairing; it can also be combined with other building blocks to construct hybrid hydrogels. This review focuses on the development and construction strategies of DNA hydrogels. Assembly and synthesis methods, diverse responsiveness and biomedical applications are summarized. Finally, the challenges and prospects of DNA-based supramolecular hydrogels are discussed.     

Peptide dendrimer-crosslinked inorganic-organic hybrid supramolecular hydrogel for efficient anti-biofouling

A novel kind of inorganic-organic hybrid supramolecular hydrogel with excellent anti-biofouling capability was developed. The hydrogel was formed via ionic interaction between the negative-charged sodium polyacrylate (SPA) entwined clay nanosheets (CNS) and positive-charged polyhedral oligomeric silsesquioxane (POSS) core-based generation one (L-Arginine) dendrimer (POSS-R).     

Supramolecular Polymer Hydrogels from Bolaamphiphilic L‐Histidine and Benzene Dicarboxylic Acids: Thixotropy and Significant Enhancement of EuIII Fluorescence

Supramolecular polymers from the bolaamphiphilic L ‐histidine ( BolaHis ) and benzene dicarboxylic acids (o‐phthalic acid, OPA ; isophthalic acid, IPA and terephthalic acid, TPA ) were found to form hydrogels although neither of the single components could gel water. It was suggested that the hydrogen bond and ionic interactions among different imidazole and carboxylic acid groups are responsible for the formation of the supramolecular polymer as well as the hydrogel formation. Depending on the structures of the dicarboxylic acids, different behaviors of the gels were observed. The hydrogels from OPA / BolaHis and IPA / BolaHis showed thixotropic properties, that is, the hydrogel was destroyed by hand shaking and then slowly gelated again at room temperature. However, the hydrogels of TPA / BolaHis could not. Interestingly, when Eu^III was doped into IPA / BolaHis supramolecular polymers, very strong luminescence enhancement was observed. FT‐IR spectroscopies and XRD analysis revealed that the strong luminescence enhancement could be attributed to the matched supramolecular nanostructures, which render the correct binding and a good dispersion of Eu^III ions. The work offers a new approach for fabricating functional hydrogels through the supramolecular polymers.     

Cation‐Tuned Stimuli‐Responsive and Optical Properties of Supramolecular Hydrogels

Hierarchical self‐assembly of an amphiphilic tris‐urea in aqueous media is shown. A mixture of the amphiphilic tris‐urea and an alkaline solution gave a viscous solution composed of fibrous aggregates. This viscous solution transformed into supramolecular hydrogels, which are capable of hierarchically organizing into higher‐order aggregates in response to several cationic triggers. The resulting supramolecular hydrogels were relatively stiff and their storage moduli attained over 10³ Pa. The stimuli‐responsive and optical properties of the resulting hydrogels were influenced by the cationic trigger. Proton and calcium ion triggers gave pH‐ and chemical stimuli‐responsive hydrogels, respectively. A terbium ion trigger also provided a highly luminescent hydrogel through energy transfer from the tris‐urea to terbium.     

Determination of the Camptothecin Derivatives CPT-11 and SN-38 in Urine and Saliva by Micellar Electrokinectic Chromatography

The anti-cancer synthetic drug irinotecan (CPT-11) and its active metabolite SN-38 have been determined by micellar electrokinetic capillary chromatography (MEKC). The detection of the analytes was made at 368 nm and their separation took less than 7 min using a borate buffer (pH 8.8 at 25 mmol L^?1) solution containing sodium dodecyl sulfate (45 mmol L^?1) and acetonitrile (13.5% v/v). On-line analyte concentration (normal stacking mode) and the use of a highly sensitive cell (Z shaped cell) improved detection limits (at the 10^?8 mol L^?1 level). Recovery in fortified human saliva was 108 ± 5%, in agreement with the result achieved with the reference HPLC method. For the analysis of urine from rats submitted to a single dose of CPT-11 and SN-38, camptothecin was used as internal standard enabling recoveries close to 100% when compared to the results achieved using HPLC.     

An Easy Access to Organic Salt‐Based Stimuli‐Responsive and Multifunctional Supramolecular Hydrogels

By exploiting orthogonal hydrogen bonding involving supramolecular synthons and hydrophobic/hydrophilic interactions, a new series of simple organic salt based hydrogelators derived from pyrene butyric acid and its β‐alanine amide derivative, and various primary amines has been achieved. The hydrogels were characterised by microscopy, table‐top rheology and dynamic rheology. FTIR, variable‐temperature ¹H NMR and emission spectroscopy established the role of various supramolecular interactions such as hydrogen bonding and π–π stacking in hydrogelation. Single‐crystal X‐ray diffraction (SXRD) studies supported the conclusion that orthogonal hydrogen bonding involving amide–amide and primary ammonium monocarboxylate (PAM) synthons indeed played a crucial role in hydrogelation. The hydrogels were found to be stimuli‐responsive and were capable of sensing ammonia and adsorbing water‐soluble dye (methylene blue). All the hydrogelators were biocompatible (MTT assay in RAW 264.7 cells), indicating their suitability for use in drug delivery.     

Rational Design of Heat‐Set and Specific‐Ion‐Responsive Supramolecular Hydrogels Based on the Hofmeister Effect

Smart supramolecular hydrogels have been prepared from a bolaamphiphilic L ‐valine derivative in aqueous solutions of different salts. The hydrogels respond selectively to different ions and are either reinforced or weakened. In one case, in contrast to conventional systems, the hydrogels are formed upon heating of the system. The use of the hydrogels in the controlled release of an entrapped dye is described as a proof of the potential applications of these systems. The responsive hydrogels were rationally designed by taking into account the noticeable effect of different ions from the Hofmeister series in the solubility of the hydrogelator, which was assessed by using NMR experiments. On the one hand, kosmotropic anions such as sulfate produce a remarkable solubility decrease in the gelator, which is associated with gel reinforcement, as measured by rheological experiments. On the other hand, chaotropic species such as perchlorate weaken the gel. A dramatic effect was observed in the presence of guanidinium chloride, which boosted the solubility of the gelator, in accordance with its chaotropic behaviour reported in protein science. In this case, a direct interaction of the guanidinium species with the carbonyl groups of the hydrogelator is detected by ¹³C NMR spectroscopy. The weakening of this interaction upon a temperature increase allows for the preparation of heat‐set hydrogelating systems.     

Fabrication of novel supramolecular hydrogels with high mechanical strength and adjustable thermosensitivity

An effective strategy was developed to fabricate the supramolecular hydrogels with high mechanical strength and adjustable thermosensitivity in aqueous systems, in which physical hydrogel precursors were first formed by the inclusion complexation of Pluronic F68/poly(epsilon-caprolactone) block copolymer end-capped with acryloyl groups with alpha-cyclodextrin (alpha-CD) and subsequently in situ UV photo-cross-linking was carried out. In this way, strong supramolecular hydrogels with elastic moduli greater than 100 000 Pa could be created, which is an order of magnitude higher than that previously achieved with related supramolecular hydrogels. Moreover, the stimuli-responsive property of these hydrogels could be tailored by changing the molar feed ratio of alpha-CD to the macromer. By X-ray diffraction and thermogravimetric analyses, the polypseudorotaxane structure of the inclusion complexes in as-obtained hydrogels was confirmed.     

Synthesis of a Bis‐Urea Dimer and Its Effects on the Physical Properties of an Amphiphilic Tris‐Urea Supramolecular Hydrogel

The successful development of stiff supramolecular gels is an important goal toward their practical application. One approach to stiffen supramolecular gels is to introduce covalent cross‐links. The bis‐urea dimer 2 , having a structure similar to that of the low‐molecular‐weight gelator 1 , was synthesized. Supramolecular hydrogels were formed from mixtures of 1 and 2 in appropriate ratios, with 2 acting as a covalent cross‐linker to connect the fibrous aggregates formed by the self‐assembly of 1 . The introduction of these covalent cross‐links greatly influenced the dynamic viscoelasticity of the supramolecular hydrogels. In the supramolecular hydrogel of 1 mixed with 5 % 2 , the storage modulus was 1.35 times higher than that of the supramolecular hydrogel of 1 alone, and the crossover strain was extended from 5 % to over 20 %. The supramolecular hydrogel of 1 and 2 was free‐standing and supported 13 times its own weight.     

Coinage Metal–Glutathione Thiolates as a New Class of Supramolecular Hydrogelators

Summary: Coinage metal salts (e.g. Au^III, Ag^I and Cu^II salts) readily react with thiols to give the corresponding metal(I) thiolates. These thiolate species are known to either self-assemble into insoluble polymeric species or to form soluble oligomers, depending on the nature of the thiol ligand. Here we demonstrate that this self-assembling ability can be applied to create supramolecular hydrogels. Glutathione (GSH), a naturally occurring tripeptide, has been used in combination with Au^III, Ag^I and Cu^II salts to obtain pH responsive hydrogels that are able to gelate 100 times their weight in water.