Cyclodextrin Host Research Articles

Self-Assembly and Circularly Polarized Luminescence from Achiral Pyrene-Adamantane Conjugates by Selective Inclusion with Cyclodextrins.

The interaction between guest chromophores or lumiphores with host chiral cavity and their induced chirality is an important topic in supramolecular chemistry. Kodaka and Harata proposed a rule to explain the induced circular dichroism of the guest chromophores by host cyclodextrins. However, it remains unknown how a circularly polarized luminescence (CPL) signal will change when the lumiphores interacted with cyclodextrins in different modes. Here, we designed an achiral pyrene-adamantane conjugated guest molecule, N-(pyren-1-yl)adamantane-1-carboxamide (ACNP), and investigated its interactions with α/β/γ-cyclodextrins (CDs) and its induced CPL. Depending on the size match of the pyrene, adamantine with different cyclodextrins, distinct performance was observed. While α-CD could not induce a CPL signal of ACNP, β-CD could induce CPL in two modes, through adamantyl or direct pyrenyl induction, which could produce a CPL signal with opposite signs. γ-CD could always induce a negative CPL signal. Therefore, a rule of induced CPL of lumiphores by cyclodextrins can be proposed.

A reproducible, low cost microfluidic microcavity array SERS platform prepared by soft lithography from a 2 photon 3D printed template

As they are widely implemented as features formed at a continuous metal surface, Surface-enhanced Raman spectroscopy (SERS) substrates are amenable to implementation in a microfluidic format. However, achieving reproducibility and repeatability in platform fabrication often requires methods that are complex and expensive, restricting transfer from laboratory prototyping to mass production. Herein, a new and robust, low cost technique for cavity array SERS substrate fabrication and its integration into a microfluidic device is described. The fabrication relies on 2-photon 3D printing of a master template and enables batch fabrication of reproducible arrays with sub-micron resolution and uncomplicated modification of the cavity architecture. With this approach, significant Raman signal enhancement of up to 6.7 × 107 through incorporation of nanostructures - plasmonic “hot-spots” and straightforward integration into microfluidic device was achieved. In addition, implementing the nano-sub-structuring to the cavities by 2-photon 3D printing approach, we obtain reproducible enhancements of SERS intensity of more than 4 fold in comparison to arrays fabricated using previously established sphere templating techniques. The fabricated microfluidic device showed detection capability for cholesterol analyte in solution in a simple demonstration where the array was modifed with thiolated cyclodextrin host to enable analyte capture.

“ENHANCING TELMESARTAN BY USING SOLID DISPERSION TECHNIQUES”

Telmisartan (TLM) is an angiotensin II receptor antagonist used in the treatment of hypertension. Telmesartan (TLM) is an orally active direct-acting Angiotensin1receptor antagonist and possess therapeutic potential in the pharmacotherapy of hypertension. Telmisartan is classified as a class II medicine by the BCS (biopharmaceutical categorization system), and it is nearly insoluble in water, with a low solubility profile and poor absorption. Drugs with poor aqueous solubility are still an ongoing challenge in the successful formulation of therapeutic products due to their low oral bioavailability. Solid dispersions are a dispersion mixture of one or more active ingredients in an inert carrier at the solid state prepared by melting, solvent, solvent-melting or other methods. Cyclodextrins(CDs) with their cylinder-shaped cavities are capable to form inclusion complexes with a wide range of commonly used drugs. Complexation of molecules to CDs occurs through a non-covalent interaction between the molecule and the CD cavity. This is a dynamic process whereby the guest molecule continuously associates and dissociates from the host CD. The present study is to improve the solubility of Telmisartan by solid dispersion techniques using various methods and proved to be effective for further pharmaceutical usage.

Illustration of a computational pipeline for evaluating cyclodextrin host-guest complex formation through conformational capture of bullvalene.

Cyclodextrins have a diverse range of applications, including as supramolecular hosts, as enzyme active-site analogs, in improving drug solubility and delivery, and in molecular selection. We have investigated their ability to form stable complexes with bullvalenes, unusual organic cage molecules that spontaneously interconvert between numerous degenerate isomers. The shape-shifting nature of substituted bullvalenes raises the potential for dynamic adaptive binding to biological targets. We tested whether β- and γ-cyclodextrins can capture particular bullvalene isomers and whether the preferred binding mode(s) differ between isomers. We first applied our computational host-guest interaction potential energy profiling to determine the best binding mode(s) of unsubstituted bullvalene and each isomer of methylenehydroxybullvalene to β- and γ-cyclodextrin. Subsequent molecular dynamics simulations of the predicted host-guest complexes showed that while unsubstituted bullvalene has a single, albeit ill-defined, binding mode with either cyclodextrin, each isomer of methylenehydroxybullvalene has two possible modes of binding to β-cyclodextrin but only a single, nebulous mode of binding to γ-cyclodextrin. Experimental determination of the binding free energy of each methylenehydroxybullvalene-cyclodextrin complex showed that methylenehydroxybullvalene is more likely to bind to β-cyclodextrin than to γ-cyclodextrin, despite its smaller cavity. Together, our results suggest that β-cyclodextrin, but not γ-cyclodextrin, shows promise for conformational capture of mono-substituted bullvalenes. More broadly, our computational pipeline should prove useful for rapid characterization of cyclodextrin host-guest complexes, avoiding the need for costly synthesis of guest molecules that are unlikely to bind stably, as well as providing detailed atomic-level insight into the nature of complexation.

Inclusion of Hydroxycinnamic Acids in Methylated Cyclodextrins: Host-Guest Interactions and Effects on Guest Thermal Stability

There is ongoing interest in exploiting the antioxidant activity and other medicinal properties of natural monophenolic/polyphenolic compounds, but their generally low aqueous solubility limits their applications. Numerous studies have been undertaken to solubilize such compounds via supramolecular derivatization with co-crystal formation with biocompatible coformer molecules and cyclodextrin (CD) complexation being two successful approaches. In this study, eight new crystalline products obtained by complexation between methylated cyclodextrins and the bioactive phenolic acids (ferulic, hydroferulic, caffeic, and p-coumaric acids) were investigated using thermal analysis (hot stage microscopy, thermogravimetry, differential scanning calorimetry) and X-ray diffraction. All of the complexes crystallized as ternary systems containing the host CD, a phenolic acid guest, and water. On heating each complex, the primary thermal events were dehydration and liberation of the respective phenolic acid component, the mass loss for the latter step enabling determination of the host-guest stoichiometry. Systematic examination of the X-ray crystal structures of the eight complexes enabled their classification according to the extent of inclusion of each guest molecule within the cavity of its respective CD molecule. This revealed three CD inclusion compounds with full guest encapsulation, three with partial guest inclusion, and two that belong to the rare class of ‘non-inclusion’ compounds.

In-vitro studies of Curcumin-β-cyclodextrin inclusion complex as sustained release system

Curcumin has always gained attention due to its diverse medicinal properties; concerns are related to its metabolism and aqueous solubility. Researchers are putting forth persistent attempts to improve its water solubility. Out of various methodologies tested, complex formation with β-cyclodextrin has been effective enough to enhance its solubility. A number of reports are available in literature which shows increased aqueous solubility of curcumin-cyclodextrin inclusion complex. In addition to its enhanced aqueous solubility as β-cyclodextrin-inclusion complex by 206 folds, we here studied curcumin-cyclodextrin inclusion complex as a sustained release drug delivery system. Initially synthesized inclusion complex has been characterized using FT-IR, SEM, XRD, UV-Vis, and particle size analysis. Interactions of curcumin, as a guest in cyclodextrin host moiety in context with biological molecules were monitored by anti-oxidant, serum protein protecting, anti-trypsin, anti-amylase, and anti-cathepsin activities. And, for the first time, the sustained release character of curcumin over a period of 5h from the β-cyclodextrin inclusion complex has been reported.

A Polymeric Delivery System Enables Controlled Release of Genipin for Spatially-Confined In Situ Crosslinking of Injured Connective Tissues.

An emerging approach toward repair of connective tissues applies exogenous crosslinkers to mechanically augment injured structures invivo. One crosslinker that has been explored for this purpose is the plant-derived small molecule genipin. However, genipin's high reactivity to primary amines in proteins, small size, and high diffusion coefficient necessitate localizing and controlling its delivery to avoid off-target or adverse effects. In this study, genipin-loaded polymers were evaluated for sustained local administration. Insoluble polymers comprising subunits of α-, β-, or γ-cyclodextrin, cyclic oligosaccharides possessing increasing cavity sizes, were compared to polymers comprising subunits of the non-cyclic polysaccharide dextran. Polymers made from β-cyclodextrin showed prolonged genipin release for over ten times longer than polymers made from α- or γ-cyclodextrins or dextran, indicating that genipin possesses molecular affinity for the β-cyclodextrin cavity. Modeling of complexation between genipin and cyclodextrin hosts supported this finding. Genipin released from all polymers was confirmed to be functional by exogenous collagen crosslinking through fluorometric and mechanical readouts. Co-incubation of genipin-loaded polymers with bovine tendon explants showed genipin crosslink-mediated coloration that was confined to the sites of exposure. Altogether, results indicate that host-guest interactions within a polymeric delivery vehicle can help to control and confine genipin release.

2-Methyl-β-cyclodextrin grafted ammonium chitosan: synergistic effects of cyclodextrin host and polymer backbone in the interaction with amphiphilic prednisolone phosphate salt as revealed by NMR spectroscopy.

Reduced molecular weight chitosan was quaternized with 2-chloro-N,N-diethylethylamine to obtain a water soluble derivative (N+-rCh). Methylated-β-cyclodextrin (MCD), with 0.5molar substitution, was covalently linked to N+-rCh through 1,6-hexamethylene diisocyanate spacer to give the derivatized ammonium chitosan N+-rCh-MCD. To shed light on the role of the cyclodextrin pendant in guiding binding interactions with amphiphilic active ingredients, corticosteroid prednisolone phosphate salt (PN) was considered. The deep inclusion of PN into cyclodextrin in PN/MCD model system was pointed out by analysis of 1H NMR complexation shifts, 1D ROESY spectra, and diffusion measurements (DOSY). By using proton selective relaxation rates measurements as investigation tool, the superior affinity of N+-rCh-MCD towards PN was demonstrated in comparison with parent ammonium chitosan N+-rCh.

Enhanced Characterization of Pyrene Binding in Mixed Cyclodextrin Systems via Fluorescence Spectroscopy.

Although significant effort has been expended to analyze the binding of pyrene in β-cyclodextrin and γ-cyclodextrin, little has been published on the binding of this guest in β-cyclodextrin derivatives (methyl-β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin) or in mixtures of such derivatives, despite the fact that these derivatives are known to have different supramolecular properties that facilitate unique modes of complexation. Reported herein is a detailed spectroscopic investigation of the binding of pyrene in β-cyclodextrin derivatives and in binary mixtures of cyclodextrins. Py values, defined as the ratio of representative vibronic bands in the fluorescence emission of pyrene, were used to measure changes in the pyrene microenvironment in the presence of the cyclodextrin hosts, and indicated that unmodified β-cyclodextrin is unique in providing a fully hydrophobic environment for pyrene through the use of two cyclodextrins to bind a single pyrene guest. By comparison, both γ-cyclodextrin and modified β-cyclodextrin analogues bind pyrene in a less hydrophobic environment through 1:1 binding stoichiometries that allow for continued interactions between the incompletely encapsulated pyrene guest and the aqueous solvent system. Binary mixtures of cyclodextrins were also explored and reinforce the unique properties of the unmodified β-cyclodextrin host. Graphical Abstract The unique binding geometries of pyrene in beta-cyclodextrin and its derivatives leads to measurable fluorescence emission signals, whose information can be used to elucidate the highly structurally dependent binding geometries and stoichiometries.

A Cyclodextrin-Based Controlled Release System in the Simulation of In Vitro Small Intestine.

A novel cyclodextrin (CD)-based controlled release system was developed in the small intestine to control the rate of drug release, on the premise of enteric-coated tablets. The system was designed based on the enzymes exogenous β-cyclodextrin glycosyltransferase (β-CGTase) and endogenous maltase-glucoamylase (MG), wherein MG is secreted in the small intestine and substituted by a congenerous amyloglucosidase (AG). The vanillin-/curcumin-β-CD complexes were prepared and detected by Fourier transform infrared (FT-IR), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC), and host CD degradation was measured based on the glucose yield. The combination of β-CGTase and AG was also functional in the CD complex system. The variations in the concentrations of added β-CGTase, with AG constantly in excess, could effectively alter the rate of host CD degradation and guest release by monitoring glucose production and color disappearance, thus, demonstrating that guest release in the CD complex system could be precisely controlled by changing the amount of β-CGTase used. Thus, the in vitro simulation of the system indicated that a novel controlled release system, based on endogenous MG, could be established in the small intestine. The CD-based controlled release system can be potentially applied in drug delivery and absorption in the small intestine.

Multiple-responsive supramolecular vesicle based on azobenzene-cyclodextrin host-guest interaction.

Multiple-responsive supramolecular vesicles have been successfully fabricated by the complexation between β-cyclodextrin (β-CD) and a pH/photo dual-responsive amphiphile 4-(4-(hexyloxy)phenylazo)benzoate sodium (HPB) with azobenzene and carboxylate groups. When mixing β-CD with HPB to reach a host/guest molar ratio of 1 : 1, the azobenzene group of HPB could be spontaneously included by β-CD molecules. Then, the formed inclusion complexes (HPB@β-CD) could self-assemble into vesicles, which was driven by the hydrophobic interaction of the alkyl chain of HPB and the hydrogen bonds between neighboring β-CDs. The reversible assembly/disassembly of the vesicles could be simply regulated under UV or visible light irradiation. The reversible phase transformation between vesicles and microbelts could also be realized by adjusting the pH values of the sample. Adding both competitive guest molecules (1-adamantane carboxylic acid sodium (ADA)) and α-amylase would result in the phase transformation from vesicles to micelles. Moreover, the vesicles would be destroyed when β-CD was continuously added until the ratio of host/guest reached 2 : 1. Such an interesting quintuple-responsive vesicle system reported here not only has potential applications in various fields such as controlled release or drug delivery, but also provides a reference for the design and construction of multiple responsive systems.

Autonomous Shrinking/Swelling Phenomenon Driven By Macromolecular Interchain Cross-Linking via β-Cyclodextrin–Triazole Complexation

Molecular recognition-induced autonomous dynamic motions, which feature in living systems, have been attracting much interest because such biological functions can promote the consequent development of sophisticated functional materials. To realize molecular recognition-induced autonomous dynamic motions using synthetic materials and manipulate them, herein, we designed poly(NIPAM-co-triaz–CD), which bears a cyclodextrin (CD) host and a triazole guest in the side chains of the polymer itself; subsequently, we investigated its phase transition behavior. 2D NOESY NMR analysis evidenced that triazole in the polymer side chains was included into the CD cavity, and DLS measurements indicated that the CD–triazole complexation resulted in the formation of interchain cross-linking. Poly(NIPAM-co-triaz–CD) exhibited autonomous shrinking/swelling of the polymer chains that occurred by itself in water due to the interchain cross-linking via the CD–triazole complexation. Thus, this study enabled the poly(NIPAM) itself to generate the artificial molecular recognition-induced autonomous phenomenon. These findings not only present a unique methodology for polymer phase transition phenomena but also provide a new platform for designing molecular recognition polymeric materials.

Contrasting Modulations in the Photophysics of Chrysazine with Cyclodextrin Hosts

This study explores the differential effects of two cyclodextrin hosts, βCD and γCD, on the photophysics of Chrysazine (CZ), a molecule with interesting excited state intramolecular proton transfer (ESIPT) characteristics. Interaction of CZ with βCD significantly enhances the fluorescence intensity of the dye along with a concomitant increase in the fluorescence lifetime, and at the same time decreases the extent of ESIPT in CZ. In marked contrast, the interaction of CZ with γCD quenches the fluorescence of the dye while the excited state lifetime increases only moderately and the ESIPT process remains effectively unchanged. The overall results indicate that the different binding modes and binding stoichiometries of the host-guest complexes formed between CZ and the two hosts, βCD and γCD, play a crucial role in tuning the photophysics of CZ, thus, imparting the remarkably contrasting modulations in the observed fluorescence properties.

Water inside β-cyclodextrin cavity: amount, stability and mechanism of binding.

Cyclodextrins (CDs) are native host systems with inherent ability to form inclusion complexes with various molecular entities, mostly hydrophobic substances. Host cyclodextrins are accommodative to water molecules as well and contain water in the native state. For β-cyclodextrin (β-CD), there is no consensus regarding the number of bound water molecules and the location of their coordination. A number of intriguing questions remain: (1) Which localities of the host’s macrocycle are the strongest attractors for the guest water molecules? (2) What are the stabilizing factors for the water clusters in the interior of β-CD and what type of interactions between water molecules and cavity walls or between the water molecules themselves are dominating the energetics of the β-CD hydration? (3) What is the maximum number of water molecules inside the cavity of β-CD? (4) How do the thermodynamic characteristics of β-CD hydration compare with those of its smaller α-cyclodextrin (α-CD) counterpart? In this study, we address these questions by employing a combination of experimental (DSC/TG) and theoretical (DFT) approaches.

Exploring the Origins of Enthalpy–Entropy Compensation by Calorimetric Studies of Cyclodextrin Complexes

Cyclodextrin complexes were used as simple model systems to explore the enthalpy-entropy compensation phenomenon, which is often observed in biomolecular processes, e.g., in protein-ligand binding. The complexation thermodynamics for the binding of a series of adamantane derivatives to several cyclodextrin hosts were determined by isothermal titration calorimetry in the temperature range 10-55 °C. As for other cyclodextrin complexes, the thermodynamic parameters depended systematically on the structural modifications of the cyclodextrins. Hydroxypropyl chains at the rims of the cyclodextrin hosts changed the thermodynamic fingerprint of binding to all guests by inducing significant increases in the complexation enthalpies and entropies. Similarly, the heat capacity changes upon complexation also showed a linear dependence on the number of hydroxypropyl chains. The altered complexation thermodynamics was ascribed to the increased dehydration of polar groups on the guest by the hydroxypropyl chains on the host. This unfavorable interaction destabilized the complexes as the enthalpic penalty was only partially compensated by the gain in entropy. The degree of enthalpy-entropy compensation depended on the guest molecule and seems to be related to the hydrophilicity/hydrophobicity of the desolvated molecular surface.

Reversible end-to-end assembly of selectively functionalized gold nanorods by light-responsive arylazopyrazole-cyclodextrin interaction.

We propose a two-step ligand exchange for the selective end-functionalization of gold nanorods (AuNR) by thiolated cyclodextrin (CD) host molecules. As a result of the complete removal of the precursor capping agent cetyltrimethylammonium bromide (CTAB) by a tetraethylene glycol derivative, competitive binding to the host cavity was prevented, and reversible, light-responsive assembly and disassembly of the AuNR could be induced by host–guest interaction of CD on the nanorods and a photoswitchable arylazopyrazole cross-linker in aqueous solution. The end-to-end assembly of AuNR could be effectively controlled by irradiation with UV and visible light, respectively, over four cycles. By the introduction of AAP, previous disassembly limitations based on the photostationary states of azobenzenes could be solved. The combination photoresponsive interaction and selectively end-functionalized nanoparticles shows significant potential in the reversible self-assembly of inorganic–organic hybrid nanomaterials.

Responsive surface adhesion based on host–guest interaction of polymer brushes with cyclodextrins and arylazopyrazoles

Polymer brushes functionalized with cyclodextrin host and arylazopyrazole guest monomers provide strong surface adhesion that is water resistent but can be deactivated by UV irradiation.

Affinity Calculations of Cyclodextrin Host-Guest Complexes: Assessment of Strengths and Weaknesses of End-Point Free Energy Methods.

The end-point methods like MM/PBSA or MM/GBSA estimate the free energy of a biomolecule by combining its molecular mechanics energy with solvation free energy and entropy terms. On the one hand, their performance largely depends on the particular system of interest, and despite numerous attempts to improve their reliability that have resulted in many variants, there is still no clear alternative to improve their accuracy. On the other hand, the relatively small cyclodextrin host-guest complexes, for which high-quality binding calorimetric data are usually available, are becoming reference models for testing the accuracy of free energy methods. In this work, we further assess the performance of various MM/PBSA-like approaches as applied to cyclodextrin complexes. To this end, we select a set of complexes between β-cyclodextrin and 57 small organic molecules that has been previously studied with the binding energy distribution analysis method in combination with an implicit solvent model ( Wickstrom, L.; He, P.; Gallicchio, E.; Levy, R. M. J. Chem. Theory Comput. 2013 , 9 , 3136 - 3150 ). For each complex, a conventional 1.0 μs molecular dynamics simulation in explicit solvent is performed. Then we employ semiempirical quantum chemical calculations, several variants of the MM-PB(GB)SA methods, entropy estimations, etc., to assess the reliability of the end-point affinity calculations. The best end-point protocol in this study, which combines DFTB3 energies with entropy corrections, yields estimations of the binding free energies that still have substantial errors (RMSE = 2.2 kcal/mol), but it exhibits a good prediction capacity in terms of ligand ranking ( R2 = 0.66) that is close to or even better than that of rigorous free energy methodologies. Our results can be helpful to discriminate between the intrinsic limitations of the end-point methods and other sources of error, such as the underlying energy and continuum solvation methods.

Physical and Adhesion Properties of Supramolecular Hydrogels Cross-linked by Movable Cross-linking Molecule and Host-guest Interactions

A supramolecular hydrogel was prepared by the introduction of host-guest interactions between polyrotaxane (PRx) having guest parts and poly(acrylamide) with cyclodextrin hosts. Although the chemic...

Surfactant and Cyclodextrin Induced Vesicle to Micelle to Vesicle Transformation in Aqueous Medium.

The physicochemical behavior and characteristics of lipid vesicles and micelles in aqueous medium are greatly tuned by changing the ambient physical parameters, such as temperature, pH, and ionic strength. The process is also controlled by external additives and the nature of the surfactants. In this work, we have used water-soluble surfactant and cyclodextrin to transform lipid vesicles to micelles to vesicles without changing the physical ambience. In this regard, we have used a special pyrene-tagged guest compound that readily forms excimer in water and thus acts as a reporter for the process. Giant lipid vesicles (biological cell mimics) are disrupted by cationic surfactants to form mixed elongated micelles that transform to vesicles on applying a cyclodextrin host.