Host-guest Inclusion Complexes Research Articles

Synthesis and characterization of self-healable supramolecular hydrogel based on carboxymethyl cellulose for biomedical applications

Hydrogels have been widely used in biomedical fields including tissue engineering, drug delivery and cell delivery and 3D cell delivery due to abundant water content in their hydrophilic three-dimensional networks and having soft tissue similar to the human body. In recent years, supramolecular hydrogels (SHG) formed by the inclusion complex between polyethylene glycol (PEG) and macrocycles such as cyclodextrin (CD) have attracted much interest due to their excellent biocompatibility and great potential in biomedical. In this research, a carboxymethyl cellulose (CMC)-based graft copolymer was prepared by using acrylic acid (AA) and maleic anhydride functionalized β-CD (β-CD-MA) as comonomers and ammonium persulfate (APS) as initiator. Then, a self-healable supramolecular hydrogel was synthesized by formation of a host-guest inclusion complex between CMC-g-poly (AA-co-β-CD-MA) as host molecule and cytosine- and guanine-modified PEG as guest molecules. The prepared hydrogel was characterized by Scanning Electron Microscope (SEM), X-Ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Nuclear magnetic resonance spectroscopy (1H NMR). The thermal stability of hydrogel was also determined by thermal gravimetric (TGA) and differential scanning calorimetry (DSC) methods. In addition, the loading and release profiles of metformin hydrochloride (MH) drug as a model on hydrogel was investigated. The results indicated that the drug release from the hydrogel peaks around 360 min and aligns with the Ritger-Peppas model. The hydrogel's self-healing property was examined at ambient temperature and 37 °C. It showed 70 % healing in 1.5 h and completed recovery after 9 h.

Crystal structure and supra-molecular features of a host-guest inclusion complex based on A1/A2-hetero-difunctionalized pillar[5]arene.

A host-guest supra-molecular inclusion complex was obtained from the co-crystallization of A1/A2-bromo-but-oxy-hy-droxy difunctionalized pillar[5]arene (PilButBrOH) with adipo-nitrile (ADN), C47H53.18Br0.82O10·C6H8N2. The adipo-nitrile guest is stabilized within the electron-rich cavity of the pillar[5]arene host via multiple C-H⋯O and C-H⋯π inter-actions. Both functional groups on the macrocyclic rim are engaged in supra-molecular inter-actions with an adjacent inclusion complex via hydrogen-bonding (O-H⋯N or C-H⋯Br) inter-actions, resulting in the formation of a supra-molecular dimer in the crystal structure.

Preparation, characterization and heat release behavior of inclusion complexes formed between carvone or limonene and acyclic cucurbit[n]urils.

Carvone and limonene are naturally occurring monoterpenoids with unique aromas, making them valuable substances in synthetic fragrance production. However, their application is limited due to low stability and rapid volatilization. To address this challenge, host-guest complexes offer a promising solution. In this study, two acyclic cucurbit[n]urils were synthesized to form inclusion complexes with carvone and limonene, aiming to enhance their thermal stability and achieve excellent heat release properties. The binding behavior of the complexes was investigated using NMR, X-ray diffraction (XRD), Fourier transform infrared (FTIR) and molecular bonding analyses, confirming the formation of host-guest inclusion complexes. Our study successfully prepared four inclusion complexes (M1/CA, M2/CA, M1/LI, M2/LI) and characterized them using NMR, XRD and FTIR techniques. These complexes exhibited a 1:1 stoichiometric ratio, and their binding constants were determined through fluorescence titration. The thermal controlled release experiment shows that the degree of carvone and limonene release is different with a change of temperature, indicating that the inclusion complexes have good thermally controlled release performance, and the thermal release retention rate has a certain correlation with KS value. The larger the KS value, the higher the thermal release retention rate of the inclusion complexes, the lower the volatilization of the inclusion complexes, the longer the retention time and the better the thermal stability. This study presents a novel approach for developing carvone- and limonene-based fragrances, expanding their application potential in various industries. © 2024 Society of Chemical Industry.

Viscoelastic behaviors for optimizing self-healing of gels with host–guest inclusion complexes

Viscoelastic behaviors for optimizing self-healing of gels with host–guest inclusion complexes

The Many Faces of Cyclodextrins within Self-Assembling Polymer Nanovehicles: From Inclusion Complexes to Valuable Structural and Functional Elements.

Most chemotherapeutic agents are poorly soluble in water, have low selectivity, and cannot reach the tumor in the desired therapeutic concentration. On the other hand, sensitive hydrophilic therapeutics like nucleic acids and proteins suffer from poor bioavailability and cell internalization. To solve this problem, new types of controlled release systems based on nano-sized self-assemblies of cyclodextrins able to control the speed, timing, and location of therapeutic release are being developed. Cyclodextrins are macrocyclic oligosaccharides characterized by a high synthetic plasticity and potential for derivatization. Introduction of new hydrophobic and/or hydrophilic domains and/or formation of nano-assemblies with therapeutic load extends the use of CDs beyond the tried-and-tested CD-drug host-guest inclusion complexes. The recent advances in nano drug delivery have indicated the benefits of the hybrid amphiphilic CD nanosystems over individual CD and polymer components. This review provides a comprehensive overview of the most recent advances in the design of CDs self-assemblies and their use for delivery of a wide range of therapeutic molecules. It aims to offer a valuable insight into the many roles of CDs within this class of drug nanocarriers as well as current challenges and future perspectives.

Photochromism, Thermochromism, and Electrochromism in Solid-State Host-Guest Inclusion Complexes of β-Cyclodextrin with Dialkylcarboxyl-Substituted Viologens.

Multi-stimuli-responsive chromic materials have immense potential for utilization. Herein, two supramolecular inclusion complexes were prepared by self-assembly of β-cyclodextrin (β-CD) with dialkylcarboxyl-substituted viologens, N,N'-di(3-carboxy-propyl)-4,4'-bipyridinium dichloride (CPV·Cl2) and N,N'-di(6-carboxy-hexyl)-4,4'-bipyridinium dibromide (CHV·Br2). The self-assembled inclusion complexes CPV2+@β-CD and CHV2+@β-CD2 in the solid-state exhibited naked-eye photochromism, thermochromism, and electrochromism in response to multiple external stimuli including light, temperature, and electric field, respectively. Solid-state UV-vis diffuse reflectance and electron spin resonance (ESR) spectroscopy revealed that the observed photochromism, thermochromism and electrochromism are attributed to the formation of viologen free radicals induced by electron transfer under external stimuli. The excellent stimuli-response chromic properties of the title inclusion complexes support their practical utility in visual display, multiple anticounterfeiting, and multilevel information encryption.

Investigation of Host-Guest Inclusion Complex of Mephenesin with α-Cyclodextrin for Innovative Application in Biological System.

The goal of this study was to use coevaporation to look into how polyether compounds like mephenesin (MEP) can be encapsulated into the host molecule α-cyclodextrin's nanohydrophobic cage. Fourier transform infrared spectroscopy (FT-IR) investigations, powder X-ray diffraction (PXRD), and 1H NMR were among the spectroscopic techniques used to describe the inclusion complex. Additionally, Job's plot has been utilized to illustrate how MEP is encapsulated with α-cyclodextrin (α-CD) at a 1:1 molar ratio. The thermal stability of MEP increased after encapsulation according to thermogravimetric analysis (TGA) and differential thermal analysis (DTA) experiments. Mephenesin fits into the cavity of α-cyclodextrin in a 1:1 ratio, as observed by molecular docking for the inclusion complex to find the most appropriate orientation. This observation is further supported by the Job plot. Furthermore, a comparison was carried out based on a cell viability study between the medication and its inclusion complex.

Stabilized, ROS-sensitive β-cyclodextrin-grafted hyaluronic supramolecular nanocontainers for CD44-targeted anticancer drug delivery

Hyaluronic acid (HA)-based tumor microenvironment-responsive nanocontainers are attractive candidates for anticancer drug delivery due to HA's excellent biocompatibility, biodegradability, and CD44-targeting properties. Nevertheless, the consecutive synthesis of stabilized, stealthy, responsive HA-based multicomponent nanomedicines generally requires multi-step preparation and purification procedures, leading to batch-to-batch variation and scale-up difficulties. To develop a facile yet robust strategy for promoted translations, a silica monomer containing a cross-linkable diethoxysilyl unit was prepared to enable in situ crosslinking without any additives. Further combined with the host-guest inclusion complexation between β-cyclodextrin-grafted HA (HA-CD) and ferrocene-functionalized polymers, ferrocene-terminated poly(oligo(ethylene glycol) methyl ether methacrylate (Fc-POEGMA) and Fc-terminated poly(ε-caprolactone)-b-poly(3-(diethoxymethylsilyl)propyl(2-(methacryloyloxy)ethyl) carbamate) (Fc-PCL-b-PDESPMA), a reactive oxygen species (ROS)-sensitive supramolecular polymer construct, Fc-POEGMA/Fc-PCL-b-PDESPMA@HA-CD was readily fabricated to integrate stealthy POEGMA, tumor active targeting HA, and an in situ cross-linkable PDESPMA sequence. Supramolecular amphiphilic copolymers with two different POEGMA contents of 25 wt% (P1) and 20 wt% (P2) were prepared via a simple physical mixing process, affording two core-crosslinked (CCL) micelles via an in situ sol-gel process of ethoxysilyl groups. The P1-based CCL micelles show not only desired colloidal stability against high dilution, but also an intracellular ROS-mimicking environment-induced particulate aggregation that is beneficial for promoted intracellular release of the loaded cargoes. Most importantly, P1-based nanomedicines exhibited greater cytotoxicity in CD44 receptor-positive HeLa cells than that in CD44 receptor-negative MCF-7 cells. Overall, this work developed HA-based nanomedicines with sufficient extracellular colloidal stability and efficient intracellular destabilization properties for enhanced anticancer drug delivery via smart integration of in situ crosslinking and supramolecular complexation.

A Review of Machine Learning and QSAR/QSPR Predictions for Complexes of Organic Molecules with Cyclodextrins.

Cyclodextrins are macrocyclic rings composed of glucose residues. Due to their remarkable structural properties, they can form host-guest inclusion complexes, which is why they are frequently used in the pharmaceutical, cosmetic, and food industries, as well as in environmental and analytical chemistry. This review presents the reports from 2011 to 2023 on the quantitative structure-activity/property relationship (QSAR/QSPR) approach, which is primarily employed to predict the thermodynamic stability of inclusion complexes. This article extensively discusses the significant developments related to the size of available experimental data, the available sets of descriptors, and the machine learning (ML) algorithms used, such as support vector machines, random forests, artificial neural networks, and gradient boosting. As QSAR/QPR analysis only requires molecular structures of guests and experimental values of stability constants, this approach may be particularly useful for predicting these values for complexes with randomly substituted cyclodextrins, as well as for estimating their dependence on pH. This work proposes solutions on how to effectively use this knowledge, which is especially important for researchers who will deal with this topic in the future. This review also presents other applications of ML in relation to CD complexes, including the prediction of physicochemical properties of CD complexes, the development of analytical methods based on complexation with CDs, and the optimisation of experimental conditions for the preparation of the complexes.

Riboflavin-induced photo-ATRP electrochemical strategy for detection of biomarker trypsin

The detection of trypsin and its inhibitors is important for both clinical diagnosis and disease treatment. Abnormal trypsin activity affects pancreatic function and leads to corresponding pathological changes in the body. Therefore, the study presented a riboflavin-induced photo-ATRP electrochemical assay of trypsin activity and its inhibitor, including detection of trypsin activity in real urine samples. Experiments were performed on indium tin oxide (ITO) electrodes modified with sulfhydryl groups of 3-mercaptopropionic acid, and target trypsin-specific cleavage of BSA-Au nanocluster (BSA-Au NCs) was followed by the modification of Au NCs to the electrodes using Au–S. The Au NCs immobilized monodeoxy-monomercapto-β-cyclodextrin@adamantan-2-amine (SH-β-CD@2-NH2-Ada) host-guest inclusion complexes to the electrode surfaces via Au–S. In a two-component photo-initiator system consisting of riboflavin as an initiator and ascorbic acid (AA) as a mild reducing agent under mild blue light radiation, a large number of electroactive substances were grafted onto the electrode surface to generate electrochemical signals. In addition, we have successfully realized the detection of clinical drug inhibitors of trypsin. The detection limit of the system is as low as 0.0024 ng/mL, which much littler than the average standard of trypsin in the patient's urine or serum. It's worth noting that this work will provide researchers with a different route to design electrochemical sensors based on non-covalent recognition strategies.

Cyclodextrin 'Chaperones' Enable Quasi-Ideal Supramolecular Network Formation and Enhanced Photodimerization of Hydrophobic, Red-shifted Photoswitches in Water.

Precision-engineered light-triggered hydrogels are important for a diversity of applications. However, fields such as biomaterials require wavelength outside the harsh UV regime to prevent photodamage, typically requiring chromophores with extended π-conjugation that suffer from poor water solubility. Herein, we demonstrate how cyclodextrins can be used as auxiliary agents to not only solubilize such chromophores, but even to preorganize them in a 2 : 2 host-guest inclusion complex to facilitate photodimerization. We apply our concept to styrylpyrene-end-functionalized star-shaped polyethylene glycols (sPEGs). We initially unravel details of the host-guest inclusion complex using spectroscopy and mass spectrometry to give clear evidence of a 2 : 2 complex formation. Subsequently, we show that the resultant supramolecularly linked hydrogels conform to theories of supramolecular quasi-ideal model networks, and derive details on their association dynamics using in-depth rheological measurements and kinetic models. By comparing sPEGs of different arm length, we further elucidate the model network topology and the accessible mechanical property space. The photo-mediated dimerization proceeds smoothly, allowing to transform the supramolecular model networks into covalent ones. We submit that our strategy opens avenues for executing hydrophobic photochemistry in aqueous environments with enhanced control over reactivity, hydrogel topology or programmable mechanical properties.

Hyaluronic acid-based multifunctional bio-active coating integrated with cinnamaldehyde/hydroxypropyl-β-cyclodextrin inclusion complex for fruit preservation

Natural preservatives such as cinnamaldehyde (CIN) are garnering increasing interest to replace their synthetic counterparts in maintaining fruit freshness and safety. However, their long-term effectiveness and widespread application have been greatly limited due to high volatility and potent aroma. To address these challenges, we developed a viable and simple strategy to prepare a multifunctional active coating for fruit preservation by incorporating host-guest inclusion complex of CIN and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) CIN@HP-β-CD into hyaluronic acid (HA), a natural polysaccharide with exceptional film-forming properties. The as-prepared HA/CIN@HP-β-CD coatings exhibited universal surface affinity, excellent antimicrobial performance, and satisfactory antioxidant properties with no potential toxicity. Release kinetic studies have demonstrated that CIN in the coating is continuously and slowly released. Furthermore, freshness preservation experiments on bananas and fresh-cut apples demonstrated that the developed coating is effective in preserving the color of fruit, decreasing the weight loss rate, preventing the microorganism's growth, and significantly extending the period of freshness, exhibiting the potential for application in fruit preservation.

Selective detection of paraquat by a cucurbit[7]uril-based fluorescent probe.

A simple fluorescent "on-off" system that can be utilized for the selective identification and determination of paraquat (PQ) is presented herein. 1H NMR spectroscopic data indicated that in aqueous solution the alkaloid palmatine can be partially encapsulated within the cucurbit[7]uril (Q[7]) cavity, whereby a stable 1 : 1 host-guest inclusion complex is formed. Other characterization techniques including mass spectrometry, UV-Vis and fluorescence spectroscopy also provided further evidence, and the host-guest inclusion complex was found to exhibit reasonable fluorescence intensity. It is noteworthy that the addition of PQ resulted in quenching the fluorescence of the host-guest inclusion complex, whereas the presence of 12 other pesticides did not significantly affect the fluorescence intensity. Given the linear relationship between the intensity of the fluorescence and the PQ concentration, the PQ concentration in aqueous solution was easily detected. Thus, a new method for identifying and determining the fluorescence quenching of PQ has been developed in this work.

Host-Guest Complexation of Itraconazole with Cyclodextrins for Bioavailability Enhancement.

Itraconazole is an antifungal agent included in the triazole pharmacological classification that belongs to the BCS class II, characterized by a low solubility in an aqueous medium (of 1 ng/mL, at neutral pH), which is frequently translated in a low oral bioavailability but with a high permeability. In this sense, it is necessary to find solutions to increase/improve the solubility of itraconazole in the aqueous environment. The main purpose of this study is the preparation and analysis of five different guest-host inclusion complexes containing intraconazole. Initially, a blind docking process was carried out to determine the interactions between itraconazole and the selected cyclodextrins. The second step of the study was to find out if the active pharmaceutical ingredient was entrapped in the cavity of the cyclodextrin, by using spectroscopic and thermal techniques. Also, the antifungal activity of the inclusion complexes was studied to examine if the entrapment of itraconazole influences the therapeutic effect. The results showed that the active substance was entrapped in the cavity of the cyclodextrins, with a molar ratio of 1:3 (itraconazole-cyclodextrin), and that the therapeutic effect was not influenced by the entrapment.

Nanogels Based on N,N-Dimethylacrylamide and β-Cyclodextrin Triacrylate for Enhanced Solubility and Therapeutic Efficacy of Aripiprazole.

Aripiprazole (ARZ) is a medication used for the treatment of various diseases such as schizophrenia, bipolar disorder, major depressive disorder, autism, and Tourette's syndrome. Despite its therapeutic benefits, ARZ is characterized by a poor water solubility which provoked the development of various delivery systems in order to enhance its solubility. In the present work, a nanoscale drug delivery system based on N,N-dimethylacrylamide (DMAA) and β-cyclodextrin triacrylate (β-CD-Ac3) as potential aripiprazole delivery vehicles was developed. The nanogels were synthesized by free radical polymerization of DMAA in the presence of β-CD-Ac3 as a crosslinking agent and then loaded with ARZ via host-guest inclusion complexation. The blank- and drug-loaded nanogels were evaluated using different methods. Fourier transform infrared (FTIR) spectroscopy was employed to confirm the incorporation of β-CD moieties into the polymer network. Dynamic light scattering (DLS) was used to study the size of the developed systems. The samples exhibited a monomodal particle size distribution and a relatively narrow dispersity index. The hydrodynamic diameter (Dh) of the gels varied between 107 and 129 nm, with a tendency for slightly larger particles as the β-CD-Ac3 fraction increased. Loading the drug into the nanocarrier resulted in slightly larger particles than the blank gels, but their size was still in the nanoscopic range (166 to 169 nm). The release profiles in PBS were studied and a sustained release pattern with no significant burst effect was observed. A cytotoxicity assessment was also conducted to demonstrate the non-toxicity and biocompatibility of the studied polymers.

Supramolecular Nano‐Grid Platform to Load and Deliver Liposomes and Exosomes

In general, carriers are designed to deliver pharmaceutical (featuring small drug‐molecules) and biopharmaceutical (featuring large‐molecule drugs, e.g., antibodies, proteins, etc.) active ingredients and platform that is capable of transporting nanoparticles is rare. Herein, the fabrication of a supramolecular carrier with a nano‐grid structure for the entrapment of liposomes and exosomes is reported. The nano‐grid particles (NGP) are made of cyclodextrins as elementary units which are widely used to load drugs through host–guest inclusion complexes, whilst its secondary structure further formed the NGP tertiary architectures, enabling the entrapment of nanoparticles. The NGP features stimuli responsiveness, tunable surface charge, and good biocompatibility. The entrapped liposomes in NGP present enhanced distribution in lungs and extended duration of action in mice. And elongated release profiles for over 14 days is obtained for exosomes—making one‐of‐its‐kind unique platform to load and deliver nanoparticles.

Study on the host-guest interactions between tetramethyl cucurbit[6]uril and 2-heterocyclic-substituted benzimidazoles.

Cucurbit[n]urils (Q[n]s) are a class of supramolecular host compounds with hydrophilic carbonyl ports and hydrophobic cavities, which can selectively form host-guest inclusion complexes with guest molecules to change the properties of guest molecules. In this paper, tetramethyl cucurbit[6]uril (TMeQ[6]) was used as the host and three 2-heterocyclic substituted benzimidazole derivatives as the guests, and their modes of interaction were investigated using X-ray crystallography, 1H NMR spectrometry, and other analytical techniques. The results showed that TMeQ[6] formed a 1 : 1 host-guest inclusion complex with three guest molecules, and the binding process between them was mainly enthalpy-driven. The X-ray diffraction analysis indicated that the main driving forces for the formation of these three inclusion complexes included hydrogen bonding interactions and ion dipole interactions. There are two modes of interaction between G3 and TMeQ[6] in the liquid phase, indicating that the benzimidazole ring and heterocyclic substituents on the guest molecule compete with the cavity of TMeQ[6]. Besides, the addition of TMeQ[6] significantly enhanced the fluorescence of these guests and slightly improved their solubility.

An interfacial host-guest inclusion complex regulated supramolecular nanocomposite hydrogel showing tunable mechanical strength, self-healing, strain sensitivity and NIR responsiveness.

The development of supramolecular nanocomposite hydrogels with good mechanical properties and multifunctional characteristics remains challenging. The reinforced role of interfacial weak interactions is important for the mechanical properties of nanocomposite hydrogels. Here, a dynamic host-guest inclusion complex from the host molecule CB[7] and guest units was employed to prepare Fe3O4 hybrid supramolecular nanocomposite hydrogels. The results show that the as-obtained hydrogel with a porous structure was prepared. The CB[7]-modified Fe3O4 (Fe3O4@CB[7]) nanoparticles severed as a cross-linker for fabricating the hydrogel's network. By changing the Fe3O4@CB[7] content, their tensile stress ranged from 0.102 to 0.403 MPa and their compression stress ranged (70% compression strain) from 0.059 to 0.775 MPa. By changing the guest units, their tensile stress ranged from 0.3 MPa to 0.403 MPa. The self-healing efficiency of the hydrogels was 99% after 48 h at room temperature. The as-obtained hydrogels with strain sensitivity can be applied for detecting the movement of an elbow and finger. The supramolecular hydrogel exhibits NIR responsiveness, self-healing, injectability, tunable mechanical strength and conductive ability, and can be used in flexible electronics.

Supramolecular complexation of phenylephrine by cucurbit[7]uril in aqueous solution.

Cucurbiturils (CBn) are known to establish stable host-guest complexes with a variety of drug molecules. Herein, the supramolecular complexation between cucurbit[7]uril (CB7) and phenylephrine hydrochloride is reported in aqueous solution. Phenylephrine forms inclusion complex with CB7 with high binding affinity (Kaffinity = 4.0 × 106 M-1), which allows for the development of a fluorescence-based sensing assay applying the dye displacement strategy. The structure of the host-guest inclusion complex is investigated by 1H NMR spectroscopy, in which complexation-induced chemical shifts indicate the immersion of the aromatic ring inside the hydrophobic cavity of CB7. Density functional theory (DFT) calculations support the 1H NMR results, and reveal that the complex is stabilized through intermolecular interactions between the polar groups on the phenylephrine and the carbonyl rims of CB7, as well as the hydrophobic effect. Moreover, preferential binding of phenylephrine in its protonated over the neutral form results in a complexation-induced pKa shift.

Pillar[5]arene-based dually crosslinked supramolecular gel as a sensor for the detection of adiponitrile

An SPR-based dually crosslinked gel sensor for adiponitrile bearing pillar[5]arene responsive sites with a low limit of detection was developed.