Supramolecular Inclusion Complexes Research Articles

Cucurbit[7]Uril‐Based Self‐Assembled Supramolecular Complex with Reversible Multistimuli‐Responsive Chromic Behavior and Controllable Fluorescence

AbstractMultistimuli‐responsive color‐changing materials have potential applications in areas such as chemical sensing and anti‐counterfeiting. In this work, a fluoro‐phenyl‐acetyl‐substituted viologen derivative (FPAV·Cl2) is synthesized, which can form a supramolecular inclusion complex with cucurbit[7]uril (Q[7]) via self‐assembly. Significantly, the resulting inclusion complex FPAV2+@Q[7] in the solid‐state exhibits visual color changes in response to multiple external stimuli including light, heat, and vapors of ammonia and organic amines. The electron spin resonance (ESR) and ultraviolet–visible (UV–vis) spectra analysis reveals that the photochromic, thermochromic, and vapochromic behavior of FPAV2+@Q[7] is due to the generation of FPAV+• free radicals resulting from electron transfer. Furthermore, in the solid‐state, FPAV2+@Q[7] shows controllable fluorescence regulated by its chromic process. Based on the multi stimuli‐responsive color‐changes and fluorescence properties of FPAV2+@Q[7], its practical applications in erasable inkless printing, multiple anti‐counterfeiting processes, visible ammonia/organic amines detection, and information encryption are demonstrated. The supramolecular strategy of encapsulating viologen derivatives into macrocycles provides a general method for fabricating multi stimuli‐responsive chromic materials with multiple practical applications.

Development of pH-Responsive Polymeric Pesticides as Supramolecular Inclusion Complexes for Targeted Control of B. cinerea in Precision Agriculture

Development of pH-Responsive Polymeric Pesticides as Supramolecular Inclusion Complexes for Targeted Control of <i>B. cinerea</i> in Precision Agriculture

Codelivery of Doxorubicin and p53 Gene by β-Cyclodextrin-Based Supramolecular Nanoparticles Formed via Host-Guest Complexation and Electrostatic Interaction.

We developed a supramolecular system for codelivery of doxorubicin (Dox) and p53 gene based on a β-CD-containing star-shaped cationic polymer. First, a star-shaped cationic polymer consisting of a β-CD core and 3 arms of oligoethylenimine (OEI), named CD-OEI, was used to form a supramolecular inclusion complex with hydrophobic Dox. The CD-OEI/Dox complex was subsequently used to condense plasmid DNA via electrostatic interactions to form CD-OEI/Dox/DNA polyplex nanoparticles with positive surface charges that enhanced the cellular uptake of both Dox and DNA. This supramolecular drug and gene codelivery system showed high gene transfection efficiency and effective protein expression in cancer cells. The codelivery of Dox and DNA encoding the p53 gene resulted in reduced cell viability and enhanced antitumor effects at low Dox concentrations. With its enhanced cellular uptake and anticancer efficacy, the system holds promise as a delivery carrier for potential combination cancer therapies.

Designing and preparing supramolecular encapsulation systems based on fraxetin and cyclodextrins for highly selective detection of nicotine

Herein, a series of water-soluble supramolecular inclusion complexes (ICs) probes were prepared using cyclodextrins (CDs) and fraxetin (FRA) to detect nicotine (NT) with high selectivity in vitro and in vivo. The FRA/CD ICs prepared through the saturated solution method exhibited excellent water solubility, stability, and biocompatibility. A clear host-guest inclusion model was provided by the theoretical calculations. The investigation revealed that NT was able to enter into the cavities of FRA/β-CD IC and FRA/γ-CD IC, and further formed charge transfer complexes with FRA in the CD cavities, resulting in a rapid and highly selective fluorescence-enhanced response with the lowest detection limits of 1.9 × 10−6 M and 9.7 × 10−7 M, and the linear response ranged from 0.02 to 0.3 mM and 0.01–0.05 mM, respectively. The IC probes showed good anti-interference performance to common interferents or different pH environments, with satisfactory reproducibility and repeatability of response to NT. Furthermore, the potentiality of the probes was confirmed through fluorescence imaging experiments using human lung cancer cells and the lung tissue of mice. This study offers a fresh perspective for detecting NT in environmental and biomedical analysis.

Nanofibers of Glycyrrhizin/Hydroxypropyl-β-Cyclodextrin Inclusion Complex: Enhanced Solubility Profile and Anti-inflammatory Effect of Glycyrrhizin.

Despite having a wide range of therapeutic advantages, glycyrrhizin (GL) has few commercial applications due to its poor aqueous solubility. In this study, we combined the benefits of hydroxypropyl β-cyclodextrin (HP-βCD) supramolecular inclusion complexes and electrospun nanofibers to improve the solubility and therapeutic potential of GL. A molecular inclusion complex containing GL and HP-βCD was prepared by lyophilization at a 1:2 molar ratio. GL and hydroxypropyl β-cyclodextrin inclusion complexes were also incorporated into hyaluronic acid (HA) nanofibers. Prepared NF was analyzed for physical, chemical, thermal, and pharmaceutical properties. Additionally, a rat model of carrageenan-induced hind paw edema and macrophage cell lines was used to evaluate the anti-inflammatory activity of GL-HP-βCD NF. The DSC and XRD analyses clearly showed the amorphous state of GL in nanofibers. In comparison to pure GL, GL-HP-βCD NF displayed improved release (46.6 ± 2.16% in 5min) and dissolution profiles (water dissolvability ≤ 6s). Phase solubility results showed a four-fold increase in GL solubility in GL-HP-βCD NF. In vitro experiments on cell lines showed that inflammatory markers like IL-1β, TNF-α, and IL-6 were significantly lower in GL-HP-βCD NF compared to pure GL (p < 0.01 and p < 0.05). According to in vivo results, the prepared nanofiber exhibits a better anti-inflammatory effect than pure GL (63.4% inhibition vs 53.7% inhibition). The findings presented here suggested that GL-HP-βCD NF could serve as a useful strategy for improving the therapeutic effects of GL.

Cover Feature: Inclusion Complex Formation with Tetra‐PEGylated Tetraphenylporphyrin and Face‐to‐Face Cyclodextrin Dimer through Unprecedented Molecular Threading (Chem. Eur. J. 32/2023)

Molecules putting on sleeveless shirts: Porphyrins with four sufficiently long PEG chains can form 1:1 supramolecular inclusion complexes with a 3,3’-linked cyclodextrin dimer in water through a molecular threading process. This phenomenon is similar to the action of putting on a sleeveless shirt, don't you think? More information can be found in the Research Article by Q. Mao and H. Kitagishi (DOI: 10.1002/chem.202300408). Artwork by Nobuyuki Goto (art director) and Ryoko Sekimoto (illustrator) from PEACE PiECE.

COMBINED IN SILICO AND EXPERIMENTAL INVESTIGATIONS OF VITAMIN D3 ENCAPSULATION BY STARCH β-OLIGOSACCHARIDE

The relevance of the research lies in the need to develop methods for encapsulating fat-soluble vitamins with natural oligosaccharides to increase their water solubility and use in the production of functional foods. The production ofnanostructured encapsulated vitamins is a new innovative direction in the food industry. This article presents the results of theoretical and experimental studies on the production of a clathrate complex of fat-soluble vitamin D3 (ViD3, cholecalciferol) with β-cyclodextrin (β-CD). The interaction of fat-soluble ViD3 with β-oligosaccharide was carried out by microwave activation. Encapsulation of ViD3 in the β-CD: ViD3 clathrate complex led to a change in the aggregate state of the ViD3 oil solution. The resulting supramolecular water-soluble ViD3 inclusion complex was investigated in silico by molecular docking and molecular modeling methods. The synthesized β-CD: ViD3 complex belongs to host-guest inclusion compounds and has better solubility. The spectral properties of the β-CD: ViD3 inclusion complex are characterized by the data of IR Fourier spectroscopy and the results of thermographic measurements on a differential scanning calorimeter. The activation energy of the reaction of the thermo-oxidative destruction of the β-CD: ViD3 inclusion complexes is calculated, the kinetic parameters of the thermal destruction of clathrates are determined. It is shown that the decisive role in the formation of the clathrate complex belongs to non-specific (hydrophobic, dispersion and van der Waals) interactions. The results obtained are promising for further understanding of the mechanism of molecular encapsulation of ViD3 compounds.

Application of SPRA Technology for Delivery of Erythropoietin: Stability Evaluation of Conjugated Erythropoietin with Adamantane and in SPRA Inclusion Complex.

As a widely used therapeutic protein, recombinant human erythropoietin (rhEPO) is currently one of the most effective biopharmaceuticals on the market for the treatment of anemia in patients with chronic renal disease. Increasing in vivo rhEPO half-life and its bioactivity is a significant challenge. It was hypothesized that the application of self-assembly PEGylation retaining activity, named supramolecular (SPRA) technology, could prolong the protein half-life without a significant loss of bioactivity. This study aimed to assess the stability of rhEPO during synthetic reactions, including the conjugation with adamantane and the formation of the SPRA complex. To do this, the secondary structure of the protein was also evaluated. FTIR, ATR-FTIR, Far-UV-CD, and SDS-PAGE methods were employed. Thermal stability studies of SPRA-rhEPO complex and rhEPO were investigated at 37°C for ten days using a nanodrop spectrophotometer. The secondary structure of lyophilized rhEPO, AD-rhEPO, and rhEPO (pH 8) was compared to rhEPO. Results showed that the secondary structure of the protein was unaffected by lyophilization, pH change, and the formation of covalent bonds in conjugation reaction. SPRA-rhEPO complex was also stable for seven days in phosphate buffer (pH 7.4) at 37°C. It was concluded that the stability of rhEPO could increase by complexation using SPRA technology.

Supramolecular inclusion complexes of β-cyclodextrin with bathochromic-shifted photochromism and photomodulable fluorescence enable multiple applications

Supramolecular inclusion complexes of conjugation-extended viologens with β-CD exhibit bathochromic-shifted photochromic behavior and photomodulable fluorescence, which endow them with applications in many areas.

Binding behavior and in vitro cytotoxicity of inclusion complexes between aminopterin and cucurbit[7]uril

Aminopterin (AMT) is a kind of universal antineoplastic drugs, but it has severe toxic and side effects, leaving it rarely used in clinic. Herein, we found that cucurbit[7]uril (CB[7]) and AMT can form stable inclusion complexes, and the formation of CB[7]-AMT 2:1 supramolecular inclusion complex was confirmed by UV-visible absorption spectra, fluorescence spectra, 1H NMR, and molecular modeling calculations in aqueous solution. Binding stability constants (Ks) were determined by UV-visible and fluorescence spectra method, with 3.88 × 1010 L2 mol–2 and 5.24 × 1010 L2 mol–2, respectively. The binding energy was calculated to be 102.6 kcal mol–1 for the CB[7]-AMT complex. And then, through a series of cell experiments of CCK8 assay, DAPI staining and hoechst33342/PI double staining, we fully proved that the CB[7]-AMT complex can reduce the toxicity of AMT to normal cells such as hepatocyte line LO2, and improve its anticancer effect on cancer cells overexpressing spermine, typically like human colon cancer cell line HCT116. It confirmed that the CB[7]-AMT complex had the effect of reducing toxicity and increasing efficiency. These results indicated that CB[7]-AMT inclusion complex might be a promising novel formulation of AMT for its clinical development.

The versatility of pyrene and its derivatives on sp2 carbon nanomaterials for bioelectrochemical applications

Pyrene and its derivatives became a standard tool for the immobilization of bioentities on nanostructured sp2 carbon such as graphene and carbon nanotubes (CNTs) for bioelectrochemical applications. Stable π-stacking interaction between these compounds can be formed under mild conditions without affecting sensitive anchor functions of pyrene or introducing defect groups on the carbon material. Pyrene has further beneficial properties for bioelectrochemical studies. Pyrene itself can form supramolecular inclusion complexes with β-cyclodextrin and can even interact with the hydrophobic domain of a laccase enzyme allowing oriented immobilization. Pyrene can further act as cross-linker, be electropolymerized to reinforce the formed layer, and also be electro-oxidized becoming an efficient redox mediator for the electron transfer with a flavin adenine dinucleotide (FAD) co-factor. This versatility of pyrene and its derivatives for bioelectrochemical applications are focused here besides some original anchoring methods for biomolecules.

Discovery and Anticancer Activity of Novel 1,3,4-Thiadiazole- and Aziridine-Based Indolin-2-ones via In Silico Design Followed by Supramolecular Green Synthesis.

Three crucial anticancer scaffolds, namely indolin-2-one, 1,3,4-thiadiazole, and aziridine, are explored to synthesize virtually screened target molecules based on the c-KIT kinase protein. The stem cell factor receptor c-KIT was selected as target because most U.S. FDA-approved receptor tyrosine kinase inhibitors bearing the indolin-2-one scaffold profoundly inhibit c-KIT. Molecular hybrids of indolin-2-one with 1,3,4-thiadiazole (IIIa–m) and aziridine (VIa and VIc) were afforded through a modified Schiff base green synthesis using β-cyclodextrin-SO3H in water as a recyclable proton-donor catalyst. A computational study found that indolin-2,3-dione forms a supramolecular inclusion complex with β-cyclodextrin-SO3H through noncovalent interactions. A molecular docking study of all the synthesized compounds was executed on the c-KIT kinase domain, and most compounds displayed binding affinities similar to that of Sunitinib. On the basis of the pharmacokinetic significance of the aryl thioether linkage in small molecules, 1,3,4-thiadiazole hybrids (IIIa–m) were extended to a new series of 3-((5-(phenylthio)-1,3,4-thiadiazol-2-yl)imino)indolin-2-ones (IVa–m) via thioetherification using bis(triphenylphosphine)palladium(II)dichloride as the catalyst for C–S bond formation. Target compounds were tested against NCI-60 human cancer cell lines for a single-dose concentration. Among all three series of indolin-2-ones, the majority of compounds demonstrated broad-spectrum activity toward various cancer cell lines. Compounds IVc and VIc were further evaluated for a five-dose anticancer study. Compound IVc showed a potent activity of IC50 = 1.47 μM against a panel of breast cancer cell lines, whereas compound VIc exhibited the highest inhibition for a panel of colon cancer cell lines at IC50 = 1.40 μM. In silico ADME property descriptors of all the target molecules are in an acceptable range. Machine learning algorithms were used to examine the metabolites and phase I and II regioselectivities of compounds IVc and VIc, and the results suggested that these two compounds could be potential leads for the treatment of cancer.

Nanofibers from hydroxypropyl β-cyclodextrin/pantothenic acid supramolecular complexes: Physicochemical characterization and potential biomedical applications

The electrospinning of nanofibers (NFs) from 2-hydroxypropyl β-cyclodextrin supramolecular inclusion complexes (150% HPβ-CD, w/v) with vitamin B5 (pantothenic acid [PA]) was achieved without using any carrier polymeric matrix. The presence of PA and the formation of the HPβ-CD/PA inclusion complex within the NFs structure were confirmed by SEM, FTIR, XRD, and TGA analysis. SEM images depicted the bead-free uniform NFs and confirmed the incorporation of HPβ-CD/PA NFs did not alter the fiber morphology having an average fiber diameter of 512 ± 24 nm, 328 ± 18 nm, and 150 ± 19 nm, respectively. Fourier transform infrared (FTIR) spectrum indicated inclusion complex from the shifting of the peaks of each component in HPβ-CD/PA NFs, whereas XRD pattern revealed that HPβ-CD/PA NFs was achieved due to the formation of a new amorphous structure. TGA studies showed that the stability of PA after HPβ-CD encapsulation was improved. Molecular docking was used to simulate the positions and interactions of the binding sites of the HPβ-CD/PA inclusion complex. The phase solubility test showed enhanced solubility of PA due to the inclusion complexation; in addition, the stoichiometry of HPβ-CD/PA was determined to be 1:1. The release of PA from HPβ-CD/PA NFs prevented the colonization of Escherichia coli (5.0 ± 0.3%) and Staphylococcus aureus (2.0 ± 0.5%) bacteria to a great extent, as observed in the antibacterial activity results. The cell viability of HCT-116 cells treated with 100 μg/mL of HPβ-CD/PA NFs was registered at 97.5 ± 2.1%. It was observed that HPβ-CD/PA NFs had higher anticancer activity compared to pure PA and HPβ-CD due to the solubility increase. In brief, our results suggested that polymer-free HPβ-CD/PA inclusion complex NFs could have potential applications in food, pharmaceuticals, and healthcare thanks to its efficient antibacterial and anticancer activities.

Aβ-responsive metformin-based supramolecular synergistic nanodrugs for Alzheimer's disease via enhancing microglial Aβ clearance

Here, inspired by the concept of supramolecular inclusion complex, we successfully fabricate metformin (Met)-based supramolecular nanodrugs with the Aβ-responsive on-demand drug release for synergistic Alzheimer's disease (AD) therapy via enhancing microglial Aβ clearance. Interestingly, the introduction of low-dosage Met (1.1 mg/kg) can not only significantly improve the structural stability of nanodrugs but also exert a synergistic anti-dementia effect with donepezil (Don). Besides, such nanodrugs with outstanding physiological stability can selectively penetrate the blood-brain barrier (BBB), target brain, increase efficient uptake of microglia and neurons, and then achieve simultaneous spatiotemporal on-demand drug release under stimuli of the overexpressed amyloid-beta (Aβ). Furthermore, Met and Don released from nanodrugs exhibit a superior synergistic anti-dementia effect by enhancing microglial phagocytosis and Aβ clearance through the lysosomal pathway. Taken together, we report a synergistic strategy based on Aβ-responsive supramolecular nanodrugs for AD therapy, which can be expected to provide a novel clinical therapeutic idea for ameliorating central nervous system disease.

Pickering emulgels reinforced with host-guest supramolecular inclusion complexes for high fidelity direct ink writing.

Direct ink writing (DIW) of Pickering emulsions offers great potential for constructing on-demand objects. However, the rheological properties of fluid emulsions greatly undermines the shape fidelity and structural integrity of 3D-printed structures. We solve here these challenges and realize a new route towards complex constructs for actual deployment. A dynamic, supramolecular host-guest hydrogel based on poly(ethylene glycol) and α-cyclodextrin was synthesized in the continuous phase of cellulose nanocrystal-stabilized Pickering emulsions. The storage modulus of the obtained emulgels could reach up to ∼113 kPa, while being shear thinning and yielding precise printability. Diverse complex architectures were possible with high shape fidelity and structural integrity. The printed objects, for example a double-wall cylinder with 75 layers, demonstrated excellent dimensional stability (shrinkage of 7 ± 2% after freeze-drying). With the merits of a simple fabrication process and the high biocompatibility of all the components, the concept of dynamic supramolecular hydrogel-reinforced emulgels represent a potentially versatile route to construct new materials and structures VIA DIW for use in bioproducts and biomedical devices.

An inclusion complex of cucurbit[7]uril with benzimidazolyl benzyl viologen exhibits fluorescence and photochromic properties.

In order to investigate the photochromic mechanism of photochromic materials based on supramolecular host-guest systems, we designed and synthesized a unique viologen derivative (benzimidazolyl benzyl viologen, guest 1·Cl3), which does not contain oxygen atoms. The binding interaction of guest 13+ with host cucurbit[7]uril (Q[7]) was investigated by various techniques. The obtained supramolecular host-guest complex 13+@Q[7] exhibits interesting fluorescence emission and reversible photochromism. The ESR and XPS experimental data suggest that the photochromic process of the complex 13+@Q[7] comes from the electron transfer from the carbonyl O atoms of the host Q[7] to the bipyridinium N atoms of the guest 13+.

Synthesis of a hydrophilic derivative of ecdysterone and development of its water-soluble form

The article presents materials on the isolation of ecdysterone substance from medicinal plant raw materials Silene wolgensis (Hornem.) Bess. ex. Spreng (Volga smolyovka). For the first time, the optimization of the method for ecdysterone substance obtaining from the aboveground part of the superconcentrator of phytoecdysteroids of the Silene wolgensis was carried out and based on it a pilot industrial regulation for the isolation of ecdysterone and an encapsulated water-soluble form were developed. It was found, that the interaction of the substrate molecule and the clathrate forms a substance that can dissolve in water and other more polar solvents, thereby solving the problem of bioavailability of the main hydrophobic drug. The method developed for producing the substance ecdysterone and its water-soluble encapsulated with β-cyclodextrin form was implemented into production at the Karaganda pharmaceutical plant. NMR studies of changes in the chemical shifts of protons of substrates and receptors illustrated that ecdysterone interacts with β-cyclodextrin to form supramolecular inclusion complexes with stoichiometric composition of 1:1

Solid-State Supramolecular Inclusion Complexes of β-Cyclodextrin with Carboxyphenyl Viologens Showing Photochromic Properties

β-Cyclodextrins (β-CDs) are shown to form 1:1 and 2:1 host–guest inclusion complexes with two carboxyphenyl viologens, 1-(4-carboxyphenyl)-4,4′-bipyridinium chloride (1+·Cl–) and 1,1′-bis(4-carboxyphenyl)-4,4′-bipyridinium dichloride (22+·Cl2–), in an aqueous solution. The solid-state supramolecular host–guest inclusion complexes 1+@β-CD and 22+@β-CD2 demonstrate excellent photochromic properties. The results of the electron-spin resonance (ESR) spectroscopy suggest that their photochromic behaviors are caused by the generation of free radicals (V•+). The energy-minimized structure and the calculated reorientation energy of the inclusion complex 1+@β-CD support the electron transfer from the host β-CD to the guest 1+. The practical applications of the inclusion complex 1+@β-CD as erasable inkless printing media and an anticounterfeiting material were also studied. The present study provides a supramolecular method for the construction of photochromic materials.

Supramolecular complexation between cucurbit[7]uril and folate and analytical applications

Folate (FA) plays a key role in the biosynthesis of amino acids, purines, and pyrimidines in the human body, and intracellular folate metabolism has become an attractive target of tumor chemotherapy. In this work, an inclusion interaction was found between FA and cucurbit[7]uril (CB[7]), and the formation of a CB[7]-FA 2:1 supramolecular inclusion complex was confirmed by fluorescence spectra, UV-Vis absorption spectroscopy, 1H NMR, and molecular modeling calculations. In addition, FA is generally determined through the indirect fluorescent method because it shows weak fluorescence in aqueous solution. Therefore, a simple, direct fluorescence probe method for rapidly measuring FA was investigated, and the linear equation of FA was ΔF = 14.691C + 37.366 within the concentration ranges of 0.82 ~ 18.31 µg mL–1. The proposed direct fluorescence method was applied to the determination of spiked plasma. We demonstrated that this method could provide an experimental basis for the targeted administration of the CB[7]-FA complex, and it could be extended as a promising fluorescence detection method for drugs in vivo.

Supramolecular inclusion complexes of 2-hydroxypropyl-β-cyclodextrin with mefenamic acid: preparation and characterization

Supramolecular inclusion complexes of 2-hydroxypropyl-β-cyclodextrin with mefenamic acid: preparation and characterization