Host-guest Inclusion Complexes Research Articles

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.

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 p-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 believe that our strategy opens new avenues for executing hydrophobic photochemistry in aqueous environments with enhanced control over reactivity, hydrogel topology or programmable mechanical properties.

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.

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.

Saltwater-Induced Rapid Gelation of Photoredox-Responsive Mucomimetic Hydrogels.

Shear-thinning hydrogels represent an important class of injectable soft materials that are often used in a wide range of biomedical applications. Creation of new shear-thinning materials often requires that factors such as viscosity, injection rate/force, and needle gauge be evaluated to achieve efficient delivery, while simultaneously protecting potentially sensitive cargo. Here, a new approach to establishing shear-thinning hydrogels is reported where a host-guest cross-linked network initially remains soluble in deionized water but is kinetically trapped as a viscous hydrogel once exposed to saltwater. The shear-thinning properties of the hydrogel is then "switched on" in response to heating or exposure to visible light. These hydrogels consist of polynorbornene-based bottlebrush copolymers with porphyrin- and oligoviologen-containing side chains that are cross-linked through the reversible formation of β-cyclodextrin-adamantane inclusion complexes. The resultant viscous hydrogels display broad adhesive properties across polar and nonpolar substrates, mimicking that of natural mucous and thus making it easier to distribute onto a wide range of surfaces. Additional control over the hydrogel's mechanical properties (storage/loss moduli) and performance (adhesion) is achieved post-injection using a low-energy (blue light) photoinduced electron-transfer process. This work envisions these injectable copolymers and multimodal hydrogels can serve as versatile next-generation biomaterials capable of light-based mechanical manipulation post-injection.

Physicochemical contrivance for exploring host-guest inclusion complex of a significant green solvent with a cyclic oligosaccharide and its innovative application optimized by computational approach

Abstract Our modern study is going to inspect new inclusion phenomena between the 1-butyl-2,3-dimethylimidazolium tetrafluoroborate [Bdmim]BF4 ionic liquid (IL) and the host α-Cyclodextrin (α-CD) by a 1:1 ratio and newly formed inclusion complex was further explored by the 1H-NMR, FT-IR, UV–vis spectroscopy, PXRD, DSC, and SEM analysis. Molecular docking was also performed to investigate the encapsulation of the inclusion complex in which orientation and it have been seen that the IL [Bdmim]BF4 enters into the α-CD cavity with a 1:1 ratio was further established with the help of Job’s plot. Furthermore, the antibacterial activity of [Bdmim]BF4 IL and its inclusion complex was verified against some Gram-positive and Gram-negative bacterial strains.

A comparative study of green solid contact ion selective electrodes for the potentiometric determination of Letrozole in dosage form and human plasma

Analysis of drugs clinically and their identification in biological samples are of utmost importance in the process of therapeutic drug monitoring, also in pharmacokinetic investigations and tracking of illicit medications. These investigations are carried out using a variety of analytical methods, including potentiometric electrodes. Potentiometric electrodes are a wonderful solution for researchers because they outperform other methods in terms of sustainability, greenness, and cost effectiveness. In the current study, ion-selective potentiometric sensors were assembled for the aim of quantification of the anticancer drug Letrozole (LTZ). The first step was fabrication of a conventional sensor based on the formation of stable host–guest inclusion complex between the cationic drug and 4-tert-butylcalix-8-arene (TBCAX-8). Two additional sensors were prepared through membrane modification with graphene nanocomposite (GNC) and polyaniline (PANI) nanoparticles. Linear responses of 1.00 × 10–5–1.00 × 10–2, 1.00 × 10–6–1.00 × 10–2 and 1.00 × 10–8–1.00 × 10–3 with sub-Nernstian slopes of 19.90, 20.10 and 20.30 mV/decade were obtained for TBCAX-8, GNC, and PANI sensors; respectively. The developed sensors were successful in determining the drug LTZ in bulk powder and dosage form. PANI modified sensor was used to determine LTZ in human plasma with recoveries ranging from 88.00 to 96.30%. IUPAC recommendations were followed during the evaluation of the electrical performance of the developed sensors. Experimental conditions as temperature and pH were studied and optimized. Analytical Eco-scale and Analytical GREEness metric were adopted as the method greenness assessment tools.

Electrochemical sensor for simultaneous determination of antiviral favipiravir drug, paracetamol and vitamin C based on host–guest inclusion complex of β-CD/CNTs nanocomposite

Favipiravir (FVI) is extensively used as an effective medication against several diverse infectious RNA viruses. It is widely administered as an anti-influenza drug. Combination therapy formed from FVI, paracetamol (PAR) and vitamin C (VC) is needed for treating patients diseased by RNA viruses. Thus, an efficient electrochemical sensor is developed for detecting FVI in human serum samples. The sensor is fabricated by casting a thin layer of carbon nanotubes (CNTs) over a glassy carbon (GC) electrode surface followed by electrodeposition of another layer of β-cyclodextrin (β-CD). Under optimized conditions, the sensor shows excellent catalytic effect for FVI, PAR and VC oxidation in the concentration ranges (0.08 µM → 80 µM), (0.08 µM → 50 µM) and (0.8 µM → 80 µM) with low detection limits of 0.011 μM, 0.042 μM and 0.21 μM, respectively. The combined effect of host–guest interaction ability of β-CD for the drugs, and a large conductive surface area of CNTs improves the sensing performance of the electrode. The sensor exhibits stable response over 4 weeks, good reproducibility, and insignificant interference from common species present in serum samples. The reliability of using the sensor in serum samples shows good recovery of FVI, PAR and VC.

Electrochemically Controlled Release from a Thin Hydrogel Layer.

In this study, we present a thermoresponsive thin hydrogel layer based on poly(N-isopropylacrylamide), functionalized with β-cyclodextrin groups (p(NIPA-βCD)), as a novel electrochemically controlled release system. This thin hydrogel layer was synthesized and simultaneously attached to the surface of a Au quartz crystal microbalance (QCM) electrode using electrochemically induced free radical polymerization. The process was induced and monitored using cyclic voltammetry and a quartz crystal microbalance with dissipation monitoring (QCM-D), respectively. The properties of the thin layer were investigated by using QCM-D and scanning electron microscopy (SEM). The incorporation of β-cyclodextrin moieties within the polymer network allowed rhodamine B dye modified with ferrocene (RdFc), serving as a model metallodrug, to accumulate in the p(NIPA-βCD) layer through host-guest inclusion complex formation. The redox properties of the electroactive p(NIPA-βCD/RdFc) layer and the dissociation of the host-guest complex triggered by changes in the oxidation state of the ferrocene groups were investigated. It was found that oxidation of the ferrocene moieties led to the release of RdFc. It was crucial to achieve precise control over the release of RdFc by applying the appropriate electrochemical signal, specifically, by applying the appropriate potential to the electrode. Importantly, the electrochemically controlled RdFc release process was performed at a temperature similar to that of the human body and monitored using a spectrofluorimetric technique. The presented system appears to be particularly suitable for transdermal delivery and delivery from intrabody implants.

Cyclodextrin Based Host-Guest Inclusion Complex, an Approach to Enhancing the Physicochemical and Biopharmaceutical Application of Poorly Water-soluble Drugs

Cyclodextrin Based Host-Guest Inclusion Complex, an Approach to Enhancing the Physicochemical and Biopharmaceutical Application of Poorly Water-soluble Drugs

Different Conformational Properties and Frequencies of Periodic Motion in the β‐ and γ‐Cyclodextrin

AbstractCyclodextrins (CDs) are cyclic oligosaccharides with application in different fields. These systems can encapsulate hydrophobic molecules and allow their solubilization in water. CDs and CD complexes can self‐associate forming aggregate or micelle‐like structures. Theoretical studies based on molecular mechanics (MM) and molecular dynamics (MD) simulations are demonstrated to be a useful tool for understanding the conformational properties, the stability, their host–guest inclusion complexes in the solid state or in aqueous solution in a good agreement with experimental data. The aim of this work is to compare at atomistic level the conformational properties, the flexibility of the native β‐ and γ‐CD. The β‐CD shows very slightly deviation from C7 symmetry, and its glycosidic oxygens are on a flat plane, while in the γ‐CD they are in different arrangement on a curved plane. From the variation of the distance between opposite glycosidic oxygens in these CDs, the frequencies of motion due to periodic motions are calculated during MD run. These frequencies indicate faster periodic motion for the β‐CD and slower for the γ‐CD having larger dimension and less symmetrical structure. MD simulations are an interesting tool for investigating the flexibility of these systems, their possible periodic motion, and their frequencies of motion.

Experimental and computational studies of gliclazide inclusion complexes with β-cyclodextrin

Gliclazide (GLC) inclusion complexes with β-cyclodextrin (βCD) were studied by UV–VIS and FT-IR spectroscopy. The recorded spectra confirmed formation of GLC-βCD binary complexes and GLC-(βCD)2 ternary complexes in aqueous solutions. UV–VIS measurements carried out for a number of temperatures allowed to determine the binding constants of the complexation reactions. The bioavailability of GLC-βCD and GLC-(βCD)2 was determined using the n-octanol/water partition coefficient. Experimental studies were supplemented with theoretical calculations. Quantum-chemical calculations and classical molecular dynamics simulations were used to describe the interactions in the host-guest inclusion complexes.

Host-guest complexation of (pyridinyltriazolylthio) acetic acid with cucurbit[n]urils (n=6,7,8): Molecular calculations and thermogravimetric analysis

Cucurbiturils are cage-like macrocyclic molecules that can form strong host–guest inclusion complexes, offering remarkably higher selectivity over conventional macrocycles towards guests with particular sizes and shapes. Here we use a combination of molecular docking, semiempirical quantum-chemical (PM6, PM7) and high-level DFT calculations along with all-atom molecular dynamics (MD) simulations to characterize 1:1 host-guest complexation between the cucurbit[n]urils (CB[n], where n = 6–8) and biologically active 2-[[5-(4-pyridinyl)-4H-1,2,4-triazol-3-yl]thio]acetic acid (PTTA). While the molecular docking and the semiempirical calculations suggest that PTTA favors inserting into larger size cavities of CB[7] and CB[8], the classical OPLS-AA MD simulations of the potential of the mean force (PMF) in an aqueous solution demonstrate the favorable free binding energy of PTTA with all three studied CB[n]s (n = 6–8). These findings were further examined by refining the binding energy of the MD-derived PTTA-CB[n] structures by the high-level dispersion-corrected DFT calculations. Our combined MD/DFT approach provides the detailed host-guest complexation mechanism and suggests that the stability of the host-guest inclusion complex of PTTA with CB[n]s decreases in the order CB[6]>CB[7]>CB[8]. Finally, the formation of the stable inclusion complex of PTTA with CB[6] was validated by thermogravimetric analysis and differential scanning calorimetry measurements, pointing out that low-level quantum-chemical methods might be unable to capture the correct thermodynamics of host-guest supramolecular structures based on cucurbituril macrocycles.

Stability improvement of UV-filter between methoxy cinnamic acid derivatives and cyclodextrins inclusion complexes based on DFT and TD-DFT investigations

Structures and UV–vis absorption spectra of the host-guest interaction of the methoxy cinnamic acid (MCA) derivatives and cyclodextrins (CDs) were performed by using the density functional theory (DFT) and time-dependent DFT (TD-DFT) calculations. All geometries of MCA derivatives (4-MCA, 245-MCA, 246-MCA), three types of CD (αCD, βCD, γCD), and five host-guest inclusion complexes between MCA and CD consisting of 4-MCA/αCD (1), 4-MCA/βCD (2), 245-MCA/βCD (3), 246-MCA/βCD (4), and 246-MCA/γCD (5) were fully optimized by using the M06-2X/6-31G (d,p) levels of theory. Two orientations (A and B) of the MCA guest molecule were considered. Upon examining the optimized geometry, five complexes of the methoxy cinnamic acid molecules are located inside the cavity of CD. Orientation B was more stable than orientation A because of the stronger intermolecular hydrogen bonds between the hydroxyl group of CD and the carboxylic group of MCA. The results indicated that the intermolecular hydrogen bond is mainly the driving force of formation between methoxy cinnamic acid and cyclodextrins. To reveal the host-guest interaction that is relevant to UV-filter compounds, the UV–vis absorption spectra were performed using TD-DFT calculations. The obtained results confirmed that orientation B is the most stable orientation and can absorb in both UVB and UVA regions which is similar to the parent MCA. Therefore, this knowledge will bring to understand the host-guest interaction between methoxy cinnamic acid and cyclodextrin complexes. The theoretical results are expected to provide valuable information for improving the stability of further UV-filter compounds.

Enhanced removal and stepwise recovery of inorganic and organic micropollutants from water using novel graphene oxide doped multifunctional β−cyclodextrin chitosan polymer

Herein, graphene oxide (GO) was successfully functionalized on the multifunctional β−cyclodextrin chitosan polymer through EDTA crosslinking (GO@CS−EDTA−β−CD) for the adsorption of toxic inorganic and organic micropollutants from water. This unique adsorbent possesses important adsorptive features from each component: chitosan works as a backbone of the polymer chain, β−CD cavities adsorb the organic micropollutants via the host-guest inclusion complexation, EDTA acts as a crosslinker and provides complexation sites for heavy metal ions and GO can interact with both organic and inorganic micropollutants. After complete characterization, the polymer were explored on the adsorption of inorganic micropollutants (i.e., Hg(II), Pb(II), Cu(II) and Ni(II)) and organic one (i.e., methylene blue, MB) under different experimental conditions. In monocomponent systems, the adsorption followed the pseudo-second order (PSO) kinetics for both heavy metals and MB dye. The adsorption isotherms of heavy metals and MB followed the Langmuir and Sips models, respectively. The maximum adsorption capacities were found to be 364.90 ± 15.20, 287.40 ± 10.0, 130.40 ± 6.50, 98.90 ± 3.10, 158.40 ± 5.10 mg g−1 for Hg(II), Pb(II), Cu(II), Ni(II) and MB, respectively. In binary component systems, dye adsorption was not affected by metal ions, while the adsorption efficiency for metal ions was increased by the MB presence: possibly due to synergism. Additionally, the prepared adsorbent showed good efficiency without any significant loss in adsorption capacity even after six continuous regeneration cycles, confirming its superior reusability and stability. In short, excellent removal efficiencies for the metal ions and MB at environmental levels in model textile effluent, synthetic acid mine water make the adsorbent promising in treating water contaminated by heavy metals and/or dyes.

A cucurbit[8]uril-based fluorescent probe for the selective detection of pymetrozine

Herein, we report a simple fluorescence-enhanced system for the selective recognition and determination of the insecticide pymetrozine. 1H NMR spectroscopic data indicate that 1,2-bis(4-pyridyl)ethylene (BPE) is partially encapsulated in the cavity of the cucurbit[8]uril (Q[8]) in aqueous solution, forming a stable 1:2 host-guest inclusion complex. Good evidence is also provided by other characterization techniques including single crystal X-ray diffraction, UV–Vis and fluorescence spectroscopies. This host-guest inclusion complex shows weak fluorescence in aqueous solution. Interestingly, the addition of pymetrozine greatly enhanced the fluorescence of the host-guest inclusion complex. In contrast, no significant fluorescence enhancement was observed on addition of 10 other pesticides. The concentration of pymetrozine in aqueous solution was easily detected based on the linear relationship between fluorescence intensity and pymetrozine concentration. Therefore, this paper reports a new method to identify and determine pymetrozine by fluorescence enhancement.

Enhancing the Drug-Like Profile of a Potent Peptide PACE4 Inhibitor by the Formation of a Host-Guest Inclusion Complex with β-Cyclodextrin.

The enzyme PACE4 has been validated as a promising therapeutic target to expand the range of prostate cancer (PCa) treatments. In recent years, we have developed a potent peptidomimetic inhibitor, namely, compound C23 (Ac-(DLeu)LLLRVK-4-amidinobenzylamide). Like many peptides, C23 suffers from an unfavorable drug-like profile which, despite our efforts, has not yet benefited from the usual SAR studies. Hence, we turned our attention toward a novel formulation strategy, i.e., the use of cyclodextrins (CDs). CDs can benefit compounds through the formation of "host-guest" complexes, shielding the guest from degradation and enhancing biological survival. In this study, a series of βCD-C23 complexes have been generated and their properties evaluated, including potency toward the enzyme in vitro, a cell-based proliferation assay, and stability in plasma. As a result, a new βCD-formulated lead compound has been identified, which, in addition to being more soluble and more potent, also showed an improved stability profile.