Self-Assembled Supramolecular Hybrid Hydrogel Beads Loaded with Silver Nanoparticles for Antimicrobial Applications

This Full Paper reports the formation of silver (Ag) NPs within spatially resolved two-component hydrogel beads, which combine a low-molecular-weight gelator (LMWG) DBS-CONHNH₂ and a polymer gelator (PG) calcium alginate. The AgNPs are formed through in situ reduction of Ag^I, with the resulting nanoparticle-loaded gels being characterised in detail. The antibacterial activity of the nanocomposite gel beads was tested against two drug-resistant bacterial strains, often associated with hospital-acquired infections: vancomycin-resistant Enterococcus faecium (VRE) and Pseudomonas aeruginosa (PA14), and the AgNP-loaded gels showed good antimicrobial properties against both types of bacteria. It is suggested that the gel bead format of these AgNP-loaded hybrid hydrogels makes them promising versatile materials for potential applications in orthopaedics or wound healing.     

Self-Propelling Hybrid Gels Incorporating an Active Self-Assembled,Low-Molecular-Weight Gelator

Hybrid gel beads based on combining a low-molecular-weight gelator (LMWG) with a polymer gelator (PG) demonstrate an enhanced ability to self-propel in water, with the LMWG playing an active role. Hybrid gel beads were loaded with ethanol and shown to move in water owing to the Marangoni effect changes in surface tension caused by the expulsion of ethanol – smaller beads move farther and faster than larger beads. Flat shapes of the hybrid gel were cut using a “stamp” – circles moved the furthest, whereas stars showed more rotation on their own axes. Comparing hybrid LMWG/PG gel beads with PG-only beads demonstrated that the LMWG speeds up the beads, enhancing the rate of self-propulsion. Self-assembly of the LMWG into a “solid-like” network prevents its leaching from the gel. The LMWG also retains its own unique function – specifically, remediating methylene blue pollutant dye from basic water as a result of noncovalent interactions. The mobile hybrid beads accumulate this dye more effectively than PG-only beads. Self-propelling gel beads have potential applications in removal/delivery of active agents in environmental or biological settings. The ability of self-assembling LMWGs to enhance mobility and control removal/delivery suggests that adding them to self-propelling systems can add significant value.     

Steric‐Structure‐Dependent Gel Formation,Hierarchical Structures,Rheological Behavior,and Surface Wettability

A series of bicholesteryl‐based gelators with different central linker atoms C, N, and O (abbreviated to GC , GN , and GO , respectively) have been designed and synthesized. The self‐assembly processes of these gelators were investigated by using gelation tests, field‐emission scanning electron microscopy, field‐emission transmission electron microscopy, UV/Vis absorption, IR spectroscopy, X‐ray diffraction, rheology, and contact‐angle experiments. The gelation ability, self‐assembly morphology, rheological, and surface‐wettability properties of these gelators strongly depend on the central linker atom of the gelator molecule. Specifically, GC and GN can form gels in three different solvents, whereas GO can only form a gel in N,N‐dimethylformamide (DMF). Morphologies from nanofibers and nanosheets to nanospheres and nanotubes can be obtained with different central atoms. Gels of GC , GN , and GO formed in the same solvent (DMF) have different tolerances to external forces. All xerogels gave a hydrophobic surface with contact angles that ranged from 121 to 152°. Quantum‐chemical calculations indicate that the GC , GN , and GO molecules have very different steric structures. The results demonstrate that the central linker atom can efficiently modulate the molecular steric structure and thus regulate the supramolecular self‐assembly process and properties of gelators.     

Multidrug‐Containing,Salt‐Based,Injectable Supramolecular Gels for Self‐Delivery,Cell Imaging and Other Materials Applications

Both molecular and crystal‐engineering approaches were exploited to synthesize a new class of multidrug‐containing supramolecular gelators. A well‐known nonsteroidal anti‐inflammatory drug, namely, indomethacin, was conjugated with six different l ‐amino acids to generate the corresponding peptides having free carboxylic acid functionality, which reacted further with an antiviral drug, namely, amantadine, a primary amine, in 1:1 ratio to yield six primary ammonium monocarboxylate salts. Half of the synthesized salts showed gelation ability that included hydrogelation, organogelation and ambidextrous gelation. The gels were characterized by table‐top and dynamic rheology and different microscopic techniques. Further insights into the gelation mechanism were obtained by temperature‐dependent ¹H NMR spectroscopy, FTIR spectroscopy, photoluminescence and dynamic light scattering. Single‐crystal X‐ray diffraction studies on two gelator salts revealed the presence of 2D hydrogen‐bonded networks. One such ambidextrous gelator (capable of gelling both pure water and methyl salicylate, which are important solvents for biological applications) was promising in both mechanical (rheoreversible and injectable) and biological (self‐delivery) applications for future multidrug‐containing injectable delivery vehicles.     

Stimuli-Sensitive Self-Assembled Tubules Based on Lysine-Derived Surfactants for Delivery of Antimicrobial Proteins

Drug delivery vectors based on amphiphiles have important features such as versatile physicochemical properties and stimuli-responsiveness. Amino acid-based surfactants are especially promising amphiphiles due to their enhanced biocompatibility compared to conventional surfactants. They can self-organize into micelles, vesicles and complex hierarchical structures, such as fibers, twisted and coiled ribbons, and tubules. In this work, we investigated the self-assembly and drug loading properties of a family of novel anionic double-tailed lysine-derived surfactants, with variable degree of tail length mismatch, designated as mLys10 and 10Lysn, where m and n are the number of carbon atoms in the tails. These surfactants form tubular aggregates with assorted morphologies in water that undergo gelation due to dense entanglement, as evidenced by light and electron microscopy. Lysozyme (LZM), an enzyme with antimicrobial properties, was selected as model protein for loading. After the characterization of the interfacial properties and phase behavior of the amphiphiles, the LZM-loading ability of the tubules was investigated, under varying experimental conditions, to assess the efficiency of the aggregates as pH- and temperature-sensitive nanocarriers. Further, the toxicological profile of the surfactants per se and surfactant/LZM hydrogels was obtained, using human skin fibroblasts (BJ-5ta cell line). Overall, the results show that the tubule-based hydrogels exhibit very interesting properties for the transport and controlled release of molecules of therapeutic interest.     

Sequential Assembly of Mutually Interactive Supramolecular Hydrogels and Fabrication of Multi-Domain Materials

A two-component self-sorting hydrogel based on acylhydrazide and carboxylic acid derivatives of 1,3:2,4-dibenzylidene-d -sorbitol (DBS-CONHNH₂ and DBS-COOH) is reported. A heating–cooling cycle induces the self-assembly of DBS-CONHNH₂, followed by the self-assembly of DBS-COOH induced by decreasing pH. Although the networks are formed sequentially, there is spectroscopic evidence of interactions between them, which impact on the mechanical properties and significantly enhance the ability of these low-molecular-weight gelators (LMWGs) to form gels when mixed. The DBS-COOH network can be switched “off” and “on” within the two-component gel through a pH change. By using a photo-acid generator, the two-component gel can be prepared combining the thermal trigger with photo-irradiation. Photo-patterned self-assembly of DBS-COOH within a pre-formed DBS-CONHNH₂ gel under a mask yields spatially controlled multi-domain gels. Different gel domains can have different functions, for example, controlling the rate of release of heparin incorporated into the gel, or directing gold nanoparticle assembly. Such photo-patterned multi-component hydrogels have potential applications in regenerative medicine or bio-nano-electronics.     

Pillararene-Based Supramolecular Vesicles for Stimuli-Responsive Drug Delivery

Supramolecular vesicles (SMVs) self-assembled from the supra-amphiphiles, consisting of two scaffolds linked together through noncovalent interactions, can realize stimuli-responsive controlled release of encapsulated drugs for enhanced therapeutic efficacy and minimized side effect of drugs. Pillararenes (PAs), an emerging kind of macrocyclic hosts in 2008, are easy to modify with a variety of functionalities. SMVs from PAs and specific guests mainly based on the host–guest interactions have attracted increasing attention because of their drug delivery and controlled drug release. A great progress in the construction and stimuli-responsive drug delivery of the PA-based SMVs has been made since the first work was reported in 2012. This review summarizes the major achievements of the PA-based SMVs for stimuli-responsive drug delivery over the past 5 years, including the microstructures of SMVs, multiple stimuli-responsive SMVs, prodrug SMVs from prodrug PAs and guests, bola-type SMVs, multifunctional SMVs, glucose-responsive SMVs for insulin delivery, novel SMVs from responsive PAs, thermo-responsive SMVs, and ternary SMVs, for chemotherapy, photothermal therapy, photodynamic therapy, and other biological applications. The future challenges and research directions of PA-based SMVs are also outlined from the points of views of the fundamental research, biological applications, and clinical applications of PA-based SMVs.     

Self‐Assembling Supramolecular Hybrid Hydrogel Beads

With the goal of imposing shape and structure on supramolecular gels, we combine a low‐molecular‐weight gelator (LMWG) with the polymer gelator (PG) calcium alginate in a hybrid hydrogel. By imposing thermal and temporal control of the orthogonal gelation methods, the system either forms an extended interpenetrating network or core–shell‐structured gel beads—a rare example of a supramolecular gel formulated inside discrete gel spheres. The self‐assembled LMWG retains its unique properties within the beads, such as remediating Pd^II and reducing it in situ to yield catalytically active Pd⁰ nanoparticles. A single PdNP‐loaded gel bead can catalyse the Suzuki–Miyaura reaction, constituting a simple and easy‐to‐use reaction‐dosing form. These uniquely shaped and structured LMWG‐filled gel beads are a versatile platform technology with great potential in a range of applications.     

Nanostructured Micelle Nanotubes Self-Assembled from Dinucleobase Monomers in Water

Despite the central importance of aqueous amphiphile assemblies in science and industry, the size and shape of these nano-objects is often difficult to control with accuracy owing to the non-directional nature of the hydrophobic interactions that sustain them. Here, using a bioinspired strategy that consists of programming an amphiphile with shielded directional Watson–Crick hydrogen-bonding functions, its self-assembly in water was guided toward a novel family of chiral micelle nanotubes with partially filled lipophilic pores of about 2 nm in diameter. Moreover, these tailored nanotubes are successfully demonstrated to extract and host molecules that are complementary in size and chemical affinity.     

基于脲基氢键组装的功能超分子凝胶

有机小分子化合物在分子间氢键、π-π堆积、亲疏水作用、范德华力等非共价键弱相互作用力驱动下,自组装形成三维网络结构的物理凝胶称为超分子凝胶。含有脲基的凝胶因子由于其强氢键缔合能力以及与阴离子、金属离子、卤素化合物等作用的可调变多样性,成为组装超分子凝胶中特别有效的氢键组装单元。本文分别从单脲基、双脲基和多脲基的凝胶因子分类综述了基于脲基氢键组装的功能超分子凝胶的研究工作,特别是近几年来的重要进展。对一些成功例子,从分子设计及成胶操作条件控制等方面的精细调谐如何解决聚集-溶解这对主要矛盾,从而实现溶胶-凝胶的转化及其可能的应用前景进行了评述。本文展望了该领域的发展方向与趋势,指出超分子凝胶研究经过多年的快速发展,深化对其蕴含机制以及动力学过程的认识与调控以实现具有多种刺激响应、多重信号输出的多组分复合功能凝胶体系的加工制备是发展趋势与必然要求,展现出广泛的应用前景也极富挑战性。     

Supramolecular Gels by Design: Towards the Development of Topical Gels for Self‐Delivery Application

Following a supramolecular synthon approach, simple salt formation has been employed to gain access to a series of supramolecular gelators derived from the well‐known non‐steroidal anti‐inflammatory drug (NSAID) ibuprofen. A well‐studied gel‐inducing supramolecular synthon, namely primary ammonium monocarboxylate (PAM), has been exploited to generate a series of PAM salts by reacting ibuprofen with various primary amines. Remarkably, all of the salts ( S1 – S7 ) thus synthesized proved to be good to moderate gelators of various polar and nonpolar solvents. Single‐crystal and powder X‐ray diffraction studies established the existence of the PAM synthons in the gel network, confirming the efficacy of the supramolecular synthon approach employed. Most importantly, the majority of the salts ( S2 , S3 , S6 , and S7 ) were capable of gelling methyl salicylate (MS), an important ingredient found in many commercial topical gels. In vitro experiments (MTT and PGE₂ assays) revealed that all of the salts (except S3 and S7 ) were biocompatible (up to 0.5 mm concentration), and the most suited one, S6 , displayed anti‐inflammatory ability as good as that of the parent drug ibuprofen. A topical gel of S6 with methyl salicylate and menthol was found to be suitable for delivering the gelator drug in a self‐delivery fashion in treating skin inflammation in mice. Histological studies, including immunohistology, were performed to further probe the role of the gelator drug S6 in treating inflammation. Cell imaging studies supported cellular uptake of the gelator drug in such biomedical application.     

肽自组装水凝胶的制备及在生物医学中的应用

短肽自组装水凝胶作为一种新型的生物材料,具有生物相容性高、免疫原性低、含水量高、降解产物可被机体重吸收利用、结构与天然细胞外基质类似等优点,使其在材料科学、生物医药及临床医学等领域具有广阔的应用前景。在这篇综述中,我们主要介绍了常用的几种制备稳定的肽自组装水凝胶方法,包括酶催化的水凝胶化、化学/物理交联的水凝胶化以及光催化的水凝胶化。进一步,我们介绍一些关于肽自组装水凝胶在药物递送和抗肿瘤治疗、抗菌和伤口愈合以及3D生物打印和组织工程中的应用。我们希望通过本文的论述能引起更多的人对肽自组装水凝胶的关注,以推进其在生物医学领域应用的发展。     

Triazolyl‐Based Molecular Gels as Ligands for Autocatalytic ‘Click’ Reactions

The catalytic performance of triazolyl‐based molecular gels was investigated in the Huisgen 1,3‐dipolar cycloaddition of alkynes and azides. Low‐molecular‐weight gelators derived from l ‐valine were synthesized and functionalized with a triazole fragment. The resultant compounds formed gels either with or without copper, in a variety of solvents of different polarity. The gelators coordinated Cu^I and exhibited a high catalytic activity in the gel phase for the model reaction between phenylacetylene and benzylazide. Additionally, the gels were able to participate in autocatalytic synthesis and the influence of small structural changes on their performance was observed.     

Supramolecular Self‐Assembly of Histidine‐Capped‐Dialkoxy‐Anthracene: A Visible‐Light‐Triggered Platform for Facile siRNA Delivery

Supramolecular self‐assembly of histidine‐capped‐dialkoxy‐anthracene (HDA) results in the formation of light‐responsive nanostructures. Single‐crystal X‐ray diffraction analysis of HDA shows two types of hydrogen bonding. The first hydrogen bond is established between the imidazole moieties while the second involves the oxygen atom of one amide group and the hydrogen atom of a second amide group. When protonated in acidic aqueous media, HDA successfully complexes siRNA yielding spherical nanostructures. This biocompatible platform controllably delivers siRNA with high efficacy upon visible‐light irradiation leading up to 90 % of gene silencing in live cells.     

Hexanoate-Cucurbit[7]uril: Highly Soluble with Controlled Release Ability

Current drug delivery systems gain more functions with increased complexity. With the idea of less is more, we synthesized hexanoate-cucurbit[7]uril (CB[7]C₅COONa) with multiple promising features for drug delivery. The hexanoate group integrates multiple functions. It endows CB[7]C₅COONa extremely high solubility of over 600 mg mL⁻¹ and well-defined pH-controlled release ability without sacrificing on the high binding affinity of CB[7] cavity. Based on the pH-controlled release ability, CB[7]C₅COONa can be used for controlling the bioactivity of drug molecules. We anticipate that the strategy of function integration would be useful for the design of simple yet powerful drug delivery systems.     

Insulin Delivery from Glucose-Responsive,Self-Assembled,Polyamine Nanoparticles: Smart “Sense-and-Treat” Nanocarriers Made Easy

Polyamine–salt aggregates (PSA) are biomimetic soft materials that have attracted great attention due to their straightforward fabrication methods, high drug-loading efficiencies, and attractive properties for pH-triggered release. Herein, a simple and fast multicomponent self-assembly process was used to construct cross-linked poly(allylamine hydrochloride)/phosphate PSAs (hydrodynamic diameter of 360 nm) containing glucose oxidase enzyme, as a glucose-responsive element, and human recombinant insulin, as a therapeutic agent for the treatment of diabetes mellitus (GI-PSA). The addition of increasing glucose concentrations promotes the release of insulin due to the disassembly of the GI-PSAs triggered by the catalytic in situ formation of gluconic acid. Under normoglycemia, the GI-PSA integrity remained intact for at least 24 h, whereas hyperglycemic conditions resulted in 100 % cargo release after 4 h of glucose addition. This entirely supramolecular strategy presents great potential for the construction of smart glucose-responsive delivery nanocarriers.     

Alternating Magnetic Field Controlled Targeted Drug Delivery Based on Graphene Oxide-Grafted Nanosupramolecules

Graphene oxide (GO)-grafted nanosupramolecules have recently emerged as neoteric nano drug carriers in the therapy of refractory diseases. Herein, a multicomponent nanosupramolecular drug carrier based on a targeted peptide and magnetic GO is reported, the drug-release behavior of which can be regulated by an alternating magnetic field (AMF). This multicomponent nanosupramolecular carrier is composed of β-cyclodextrin (β-CD)/nickel nanoparticle-modified graphene oxide (GONiCD) and mitochondrial ion-targeting peptide (MitP)-grafted hyaluronic acid (HAMitP). Owing to the host–guest interaction between β-cyclodextrin and the cyclohexyl groups on MitP, GONiCD and HAMitP could form supramolecular assemblies during the doxorubicin (Dox) loading process, which not only remarkably enhances the drug-loading capacity, but also improves the drug-release efficiency under AMF stimulus. During co-incubation with tumor cells, the Dox-loaded assemblies could strongly target the tumor mitochondria and damage both the mitochondria and the nuclei, owing to Dox release from the assemblies induced by AMF. This study sheds light on the exploration of peptide caps for controlled drug loading/release of supramolecular nanocarriers for efficient drug delivery and anticancer therapy.     

Water‐Regulated Self‐Assembly Structure Transformation and Gelation Behavior Prediction Based on a Hydrazide Derivative

Herein, we report the water‐regulated supramolecular self‐assembly structure transformation and the predictability of the gelation ability based on an azobenzene derivative bearing a hydrazide group, namely, N‐(3,4,5‐tributoxyphenyl)‐N′‐4‐[(4‐hydroxyphenyl)azophenyl] benzohydrazide (BNB‐t4). The regulation effects are demonstrated in the morphological transformation from spherical to lamellar particles then back to spherical in different solvent ratios of n‐propanol/water. The self‐assembly behavior of BNB‐t4 was characterized by minimum gelation concentration, microstructure, thermal, and mechanical stabilities. From the spectroscopy studies, it is suggested that gel formation of BNB‐t4 is mainly driven by intermolecular hydrogen bonding, accompanied with the contribution from π–π stacking as well as hydrophobic interactions. The successfully established correlation between the self‐assembly behavior and solubility parameters yields a facile way to predict the gelation performance of other molecules in other single or mixed solvents.