Non-covalent Host-guest Interactions Research Articles

Supramolecular Nano-Tracker for Real-Time Tracking of Drug Release and Efficient Combination Therapy.

Real-time tracking of drug release from nanomedicine in vivo is crucial for optimizing its therapeutic efficacy in clinical settings, particularly in dosage control and determining the optimal therapeutic window. However, most current real-time tracking systems require a tedious synthesis and purification process. Herein, a supramolecular nano-tracker (SNT) capable of real-time tracking of drug release in vivo based on non-covalent host-guest interactions is presented. By integrating multiple cavities into a single nanoparticle, SNT achieves co-loading of drugs and probes while efficiently quenching the photophysical properties of the probe through host-guest complexation. Moreover, SNT is readily degraded under hypoxic tumor tissues, leading to the simultaneous release of drugs and probes and the fluorescence recovery of probes. With this spatial and temporal consistency in drug loading and fluorescence quenching, as well as drug release and fluorescence recovery, SNT successfully achieves real-time tracking of drug release in vivo (Pearson r = 0.9166, R2 = 0.8247). Furthermore, the released drugs can synergize effectively with fluorescent probes upon light irradiation, achieving potent chemo-photodynamic combination therapy in 4T1-bearing mice with a significantly improved survival rate (33%), providing a potential platform to significantly advance the development of nanomedicine and achieve optimal therapeutic effects in the clinic.

On the mechanism of intermolecular nitrogen-atom transfer from a lattice-isolated diruthenium nitride intermediate.

Catalyst confinement within microporous media provides the opportunity to site isolate reactive intermediates, enforce intermolecular functionalization chemistry by co-localizing reactive intermediates and substrates in molecular-scale interstices, and harness non-covalent host-guest interactions to achieve selectivities that are complementary to those accessible in solution. As part of an ongoing program to develop synthetically useful nitrogen-atom transfer (NAT) catalysts, we have demonstrated intermolecular benzylic amination of toluene at a Ru2 nitride intermediate confined within the interstices of a Ru2-based metal-organic framework (MOF), Ru3(btc)2X3 (btc = 1,3,5-benzenetricarboxylate, i.e., Ru-HKUST-1 for X = Cl). Nitride confinement within the extended MOF lattice enabled intermolecular C-H functionalization of benzylic C-H bonds in preference to nitride dimerization, which was encountered with soluble molecular analogues. Detailed study of the kinetic isotope effects (KIEs, i.e., kH/kD) of C-H amination, assayed both as intramolecular effects using partially labeled toluene and as intermolecular effects using a mixture of per-labeled and unlabeled toluene, provided evidence for restricted substrate mobility on the time scale of interstitial NAT. Analysis of these KIEs as a function of material mesoporosity provided approximate experimental values for functionalization in the absence of mass transport barriers. Here, we disclose a combined experimental and computational investigation of the mechanism of NAT from a Ru2 nitride to the C-H bond of toluene. Computed kinetic isotope effects for a H-atom abstraction (HAA)/radical rebound (RR) mechanism are in good agreement with experimental data obtained for C-H amination at the rapid diffusion limit. These results provide the first detailed analysis of the mechanism of intermolecular NAT to a C-H bond, bolster the use of KIEs as a probe of confinement effects on NAT within MOF lattices, and provide mechanistic insights unavailable by experiment because rate-determining mass transport obscured the underlying chemical kinetics.

A double-cavity nor-seco-cucurbit[10]uril-based fluorescent probe for detection of ClO- and its application in cell imaging

A supramolecular fluorescent probe based on double-cavity nor-seco-cucurbit[10]uril (ns-Q[10]) was constructed using the non-covalent host-guest interactions between ns-Q[10] and positively charged Astrazon Pink FG (APFG). The intramolecular charge transfer (ICT) effect induces the APFG@ns-Q[10] probe to emit strong orange-red fluorescence. APFG@ns-Q[10] exhibits desirable optical properties and low toxicity, and has been successfully applied to the imaging of HK2 and HeLa cells. When APFG@ns-Q[10] interacts with ClO-, the CC double bond in APFG is oxidized and the molecule is cleaved, which leads to the fluorescence is quenched. The specificity and sensitivity of APFG@ns-Q[10] to ClO- allows it to be used for the detection and tracking of ClO- in cells. APFG@ns-Q[10] demonstrates good biocompatibility, which is an excellent foundation for its application in cell imaging.

A Promising Review on Cyclodextrin Conjugated Paclitaxel Nanoparticles for Cancer Treatment.

This review presented the unique characteristics of different types of cyclodextrin polymers by non-covalent host–guest interactions to synthesize an inclusion complex. Various cancers are treated with different types of modified cyclodextrins, along with the anticancer drug paclitaxel. PTX acts as a mitotic inhibitor, but due to its low dissolution and permeability in aqueous solutions, it causes considerable challenges for drug delivery system (DDS) designs. To enhance the solubility, it is reformulated with derivatives of cyclodextrins using freeze-drying and co-solvent lyophilization methods. The present supramolecular assemblies involve cyclodextrin as a key mediator, which is encapsulated with paclitaxel and their controlled release at the targeted area is highlighted using different DDS. In addition, the application of cyclodextrins in cancer treatment, which reduces the off-target effects, is briefly demonstrated using various types of cancer cell lines. A new nano-formulation of PTX is used to improve the antitumor activity compared to normal PTX DDS in lungs and breast cancer is well defined in the present review.

Cucurbituril-Based Supramolecular Assemblies: Prospective on Drug Delivery, Sensing, Separation, and Catalytic Applications.

Precise control over the stimuli-responsive noncovalent interactions operative in a complex molecular system has emerged as a convenient way to realize applications in the detection and sensing of trace analytes, metal ion separation, uptake-release, in situ nanoparticle synthesis, and catalytic activity. This feature article focuses on the attributes and advantages of noncovalent host-guest interactions involving cucurbituril homologues (CBs) with a wide range of organic and inorganic guests, starting from organic dyes to drugs, proteins, surfactants, metal ions, and polyoxometalates. The unique structural features of CBs provide interaction sites for cations at the portals, polyanions at the periphery, and hydrophobic groups in its cavity. The facile complexation and consequent compositional and geometrical arrangements of guests such as naphthalenediimides, coumarins, porphyrins, and triphenylpyrylium ions with the host CBs led to remarkable changes in many molecular properties, especially aggregation, the proton binding and release affinity, and novel emissive dimers, and each of such spectroscopic signatures have been appropriately channeled to drug delivery and activation to improve the antibacterial efficacy and shelf life of drugs by increasing their photostability. Several technological advantages have also been extracted from the interaction of CBs with inorganic guests as well. The interaction of CB7 with the heptamolybdate anion resulted in the precipitation of a hybrid complex material which enabled a convenient separation methodology for the use of clinically pure radioactive 99mTc in diagnostic applications. Certain cucurbituril-based hybrid materials have been developed for enhanced SO2 adsorption at low pressures, high-efficiency hydrogen production, and reversible catalytic systems. Thus, this feature article provides a glimpse of the vast potential of cucurbituril homologues with organic and inorganic guests and calls for a dedicated effort to explore supramolecular strategies for better sensors, therapeutics, smart drug delivery modules, and facile devices.

Strength and Nature of Host-Guest Interactions in Metal-Organic Frameworks from a Quantum-Chemical Perspective.

Metal‐organic frameworks (MOFs) offer a convenient means for capturing, transporting, and releasing small molecules. Their rational design requires an in‐depth understanding of the underlying non‐covalent host‐guest interactions, and the ability to easily and rapidly pre‐screen candidate architectures in silico. In this work, we devised a recipe for computing the strength and analysing the nature of the host‐guest interactions in MOFs. By assessing a range of density functional theory methods across periodic and finite supramolecular cluster scale we find that appropriately constructed clusters readily reproduce the key interactions occurring in periodic models at a fraction of the computational cost. Host‐guest interaction energies can be reliably computed with dispersion‐corrected density functional theory methods; however, decoding their precise nature demands insights from energy decomposition schemes and quantum‐chemical tools for bonding analysis such as the quantum theory of atoms in molecules, the non‐covalent interactions index or the density overlap regions indicator.

Supramolecular host-guest hyaluronic acid hydrogels enhance corneal wound healing through dynamic spatiotemporal effects

Severe corneal wounds can lead to ulceration and scarring if not promptly and adequately treated. Hyaluronic acid (HA) has been investigated for the treatment of corneal wounds due to its remarkable biocompatibility, transparency and mucoadhesive properties. However, linear HA has low retention time on the cornea while many chemical moieties used to crosslink HA can cause toxicity, which limits their clinical ocular applications. Here, we used supramolecular non-covalent host-guest interactions between HA-cyclodextrin and HA-adamantane to form shear-thinning HA hydrogels and evaluated their impact on corneal wound healing. Supramolecular HA hydrogels facilitated adhesion and spreading of encapsulated human corneal epithelial cells ex vivo and improved corneal wound healing in vivo as an in situ-formed, acellular therapeutic membrane. The HA hydrogels were absorbed within the corneal stroma over time, modulated mesenchymal cornea stromal cell secretome production, reduced cellularity and inflammation of the anterior stroma, and significantly mitigated corneal edema compared to treatment with linear HA and untreated control eyes. Taken together, our results demonstrate supramolecular HA hydrogels as a promising and versatile biomaterial platform for corneal wound healing.

Guest-Mediated Hierarchical Self-Assembly of Dissymmetric Organic Cages to Form Supramolecular Ferroelectrics

Guest-Mediated Hierarchical Self-Assembly of Dissymmetric Organic Cages to Form Supramolecular Ferroelectrics

Chemically Robust and Bifunctional Co(II)-Framework for Trace Detection of Assorted Organo-toxins and Highly Cooperative Deacetalization-Knoevenagel Condensation with Pore-Fitting-Induced Size-Selectivity.

Acute detection of assorted classes of organo-toxins in a practical environment is an important sustainable agenda, whereas cooperative and recyclable catalysis can mitigate hazards by minimizing energy requirements and reducing waste generation. We constructed an acid-/base-stable Co(II)-framework with a unique network topology, wherein unidirectional porous channels are decorated by anionic [Co2(μ2-OH)(COO)4(H2O)3] secondary building units and neutral [CoN2(COO)2] nodes. An intense luminescent signature of the hydrolytically robust framework is harnessed for the selective, fast-responsive, and regenerable detection of two detrimental organo-aromatics, 4-aminophenol (4-AP) and 2,4,6-trinitrophenol (TNP). Alongside remarkable quenching, their nanomolar detection limits (4-AP: 99.5 nM; TNP: 67.2 nM) rank among the lowest reported values in water and corroborate their ultra-sensitivity. Density functional theory (DFT) calculations verify the electron-transfer route of sensing through portraying redistribution of energy levels of molecular orbitals in a three-dimensional network by each analyte and further envisages non-covalent host-guest interactions. Benefiting from the concurrent existence of an open-metal site and a triphenylamine-moiety-functionalized ligand, the activated framework acts as an outstandingly cooperative heterogeneous catalyst in deacetalization-Knoevenagel condensation under mild conditions. The acid-base dual catalysis is detailed for the first time from combined inputs of control experiments and DFT validations. To the best of tandem reaction, larger-sized substrate exhibits insignificant conversion, and certifies rarest pore-fitting induced size-selectivity.

Reversible regulation of esterase activity via host–guest molecular recognition at the nanoparticle surface

Precise and controlled regulation of enzymes is an important aspect to understand their fundamental complex biological molecular mechanism. While many synthetic receptors were developed to inhibit enzymatic activity, they lack reversible control over their function. Herein, we present an engineered nanoparticle (NP) surface that synergistically combines host–guest assembly with protein surface targeting to reversibly control enzyme activity. We demonstrate the effective inhibition of anionic esterase enzyme activity upon electrostatic binding to dimethyl-benzyl ammonium terminated positively charged gold NPs. The NP surface upon threading by non-covalent host–guest interactions with CB[7] moiety has enabled the reactivation of enzyme catalysis. This reactivation has been further reversed by disrupting NP–CB[7] complex by employing a competitive orthogonal guest, hence leading to the controlled reversibility of enzyme activity. Tuning of NP surfaces by different supramolecular interactions and concomitant protein recognition on the NP surface can thus be emphasized as a significant tool for biotechnology applications.

Biocompatible Polymers Combined with Cyclodextrins: Fascinating Materials for Drug Delivery Applications.

Cyclodextrins (CD) are a group of cyclic oligosaccharides with a cavity/specific structure that enables to form inclusion complexes (IC) with a variety of molecules through non-covalent host-guest interactions. By an elegant combination of CD with biocompatible, synthetic and natural polymers, different types of universal drug delivery systems with dynamic/reversible properties have been generated. This review presents the design of nano- and micro-carriers, hydrogels, and fibres based on the polymer/CD supramolecular systems highlighting their possible biomedical applications. Application of the most prominent hydrophobic aliphatic polyesters that exhibit biodegradability, represented by polylactide and polycaprolactone, is described first. Subsequently, particular attention is focused on materials obtained from hydrophilic polyethylene oxide. Moreover, examples are also presented for grafting of CD on polysaccharides. In summary, we show the application of host-guest interactions in multi-component functional biomaterials for controlled drug delivery.

A designed supramolecular cross-linking hydrogel for the direct, convenient, and efficient administration of hydrophobic drugs.

Hydrogels formed through reversible supramolecular interactions may attain self-healing in the in situ environment. However, the low grafting degree of functional groups and steric hindrance effect of polymer backbones significantly reduced the self-healing efficacy and kinetics. To overcome these deficiencies, we designed a novel hydrogel via non-covalent host-guest interaction between β-cyclodextrin modified hyaluronic acid (HA-CD) and adamantane modified 4-arm-PEG (4-arm-PEG-Ad). The multi-armed monomer enabled to increase the number of functional groups and avoid steric hindrance effects, offering more efficient host-guest interaction. The insoluble dexamethasone could be loaded in the β-CDs' hydrophobic cavities. The designed hydrogels exhibited excellent self-healing properties. The mechanical strengths, swelling rate and release of dexamethasone could be adjusted by adding 4-arm-PEG-Ad. The novel hydrogels significantly improved the therapeutic effect of the dexamethasone in burn wound healing. Herein, these hydrogels had great potential for direct, convenient, and efficient delivery of hydrophobic drugs and improved their therapeutic effects.

Supramolecular interaction of sanguinarine dye with sulfobutylether-β-cyclodextrin: modulation of the photophysical properties and antibacterial activity.

The noncovalent host–guest interaction of sanguinarine (SGR), a benzophenanthridine alkaloid, with a nontoxic, water soluble sulfobutylether-β-cyclodextrin (SBE7βCD, commercially available as Captisol) macrocyclic host has been investigated using ground-state optical absorption, and steady-state and time-resolved fluorescence measurements. The pH-dependent changes in the absorbance of the dye at 327 nm showed a pKa value of 7.5, which has been shifted to 8.1 in the presence of SBE7βCD. The changes in the pKa values, absorption and fluorescence spectra, and fluorescence lifetime values of these two forms of SG with SBE7βCD indicate complex formation between them. The cationic form shows 3 times higher interaction towards SEB7βCD (K = 1.2 × 104 M−1) as compared to the neutral form (K = 3.9 × 103 M−1) which leads to a moderate upward pKa shift (pKa values of SGR shifted by more than 0.6 units). The subsequent fluorescence “turn off” was demonstrated to be responsive to chemical stimuli, such as metal ions (Ca2+ ions). Upon addition of Ca2+ ions, nearly quantitative dissociation of the complex was established to regenerate the free dye and result in fluorescence “turn on”. Apart from improving the stability under ambient light conditions, the upward pKa shift of SGR in the presence of SBE7βCD results in increasing the antibacterial activity of the SBE7βCD:SGR complex compared to that of the free dye towards four pathogenic micro-organisms at the physiological pH range. This work further compares SGR interaction with parent β-cyclodextrin.

Mechanism for efficient separation of eugenol and eugenol acetate with β-cyclodextrin as a selective solvent

ABSTRACTSeparation of active components from essential oils is very difficult due to some similar chemical and physical properties. In this work, a facile method is developed to reduce the separation cost. β-Cyclodextrin (β-CD) is used for the separation of eugenol and eugenol acetate by forming the inclusion complexation of non-covalent host–guest interactions. The separation was achieved by a co-precipitation method, using ethanol:water (1:4, v/v) as a solvent at the temperature of 50 °C for 2 h. The molar ratio of guests to β-CD for complexation was 4:1. The inclusion rate of eugenol increased to 60% with a separation factor of 2.5, and the purity of eugenol was up to 99% from 50% after one cycle. β-CD can be easily recovered with industrial ethanol (95%,v/v) and used repeatedly. A possible mechanism is also proposed based on the experimental and computational methods. The results indicate that β-CD is suitable to separate the aromatic constituents from the natural products.

Host-Guest-Induced Environment Tuning of 3d Ions in a Polyoxopalladate Matrix.

A series of unprecedented supramolecular associates of phenylarsonate-capped {MII PdII 12 O8 }-type (M=Co, Ni and Zn) polyoxopalladates with α-cyclodextrins (α-CD) was obtained and characterized in the solid state (single-crystal X-ray diffraction (XRD), FT-IR spectroscopy, elemental and thermogravimetric (TGA) analyses), in aqueous solution (1 H and 13 C NMR) and in the gas phase (ESI-MS). The non-covalent host-guest interactions between the organopolyoxoanions and α-CD rings alter the O8 coordination environment of a 3d transition metal ion (MII ) situated at the center of a cuboid polyoxododecapalladate shell. This synthetically controlled "chemical pressure" effectively induces axial distortion of the otherwise cubic polyoxopalladate environment between two trans-positioned α-CD moieties. Its effect on the magnetic properties and the electronic structure of the CoII derivative was assessed in a combined SQUID magnetometry, EPR, X-ray magnetic circular/linear dichroism (XMCD/XMLD), and X-ray absorption near-edge structure (XANES) spectroscopy study.

Organic Guests within a Ferroelastic Host: The Case of High Silica Zeolite ZSM-5

The physical–chemical properties of guest molecules confined within a zeolite framework host are known to be strongly affected by the confinement effects exerted through noncovalent host–guest interactions. On the basis of synchrotron time-resolved powder diffraction measurements and the Landau theory of ferroelastic phase transitions, we provide in this work evidence for the strong coupling existing between the thermodynamic properties of organic molecules (toluene, 1,2-dichloroethane, methyl-tert-butyl-ether) adsorbed within the ZSM-5 zeolite and the lattice strain driving the monoclinic-to-orthorhombic (ferroelastic-to-paraelastic) phase transition which controls connectivity and diffusivity in the zeolite framework.

A flexible core-shell carbon layer MnO nanofiber thin film via host-guest interaction: Construction, characterization, and electrochemical performances

Supermolecular complexation with cyclodextrins by non-covalent host-guest interaction is used for various applications. In this work, we fabricated the freestanding and flexible core-shell MnO/carbon nanofiber (CNF) composite thin films by host-guest interaction and high-voltage electrospining technique. The as-prepared composite thin film with dual carbon layer nanofibers showed smaller MnO particle size, lower electron-transfer resistance, and faster lithium ion migration, which were attributed to intermolecular non-covalent assembling behavior among polyacrylonitrile (PAN), β-cyclodextrin (β-CD) and Mn ion. As expected, the composite film as anode in Li-ion battery showed impressive performance: a high reversible capacity (∼1025 mAh g−1 at ∼0.1 A g−1), excellent rate capability (∼376 mAh g−1 at ∼5 A g−1), and superior cyclability (∼844 mAh g−1 at the current density of ∼1 A g−1 after 800 cycles). Such outstanding electrochemical performance endows the MCNFs composites with great potential as anode material for LIBs.

Modified N-Heterocyclic Carbene Ligand for the Recovery of Olefin Metathesis Catalysts via Noncovalent Host-Guest Interactions.

A general method, focusing upon olefin metathesis, was developed for the recovery of homogeneous olefin metathesis catalysts from crude reaction solutions. This method utilizes the supramolecular host–guest interaction between an azobenzene-modified N-heterocyclic carbene ligand and a silica-grafted β-cyclodextrin to remove homogeneous catalyst in a heterogeneous manner, allowing for the recovery of more than 97% of ruthenium in solution. The robust and simple nature of the guest molecule allows for the application of this method to a wide range of homogeneous catalysts. This study reports the synthesis and characterization of the said precatalyst and host compound as well as proof-of-concept recovery trials for a number of common substrates, with the residual ruthenium content of reaction mixtures evaluated by inductively coupled plasma mass spectrometry.

Stimuli-responsive polymeric materials functioning via host–guest interactions

Molecular recognition is essential for realizing functional supramolecular materials. Non-covalent host–guest interactions are an effective tool to introduce switching and functional properties into materials. This review focuses on the achievement of selective molecular adhesion, self-healing, toughness, and actuation properties. These functions have been achieved by reversible bond formation with cyclodextrins (CDs). Self-healing materials with host–guest interactions involving CDs have been used to achieve redox-responsive healing properties and healing efficiency. Furthermore, the materials, which undergo self-healing by chemical and physical mechanisms, exhibit rapid and efficient self-healing properties under semi-dry conditions. To prepare a supramolecular actuator using host–guest complexes, two approaches have been introduced. The first is the functionalization of a supramolecular gel actuator by changing the cross-linking density, and the second is the functionalization of a topological gel actuator by changing distances between the cross-linking points. Both actuators exhibit contractive bending behavior. This review summarizes advancements within the past 10 years in supramolecular materials that function via the chemical mechanism of host–guest interactions and the physical mechanism of the sliding motion of ring molecules.

Enhancing effectiveness of capillary electrophoresis as an analytical tool in the supramolecular acidity modification

A strategic modification of acidity (pKa values) by the non-covalent host-guest interactions is one of the most promising concepts in current supramolecular chemistry. This work is aimed at enhancing the effectiveness of capillary electrophoresis (CE) in determination of pKa shifts caused by such interactions and their thermal dependencies crucial in a deep thermodynamic description. We show how to (i) minimize the systematic errors related to Joule heating, (ii) minimize the influence of a voltage ramp time, (iii) speed up pKa shift identification and estimation, (iv) interpret thermal effects related to two overlapped dynamic equilibria, and (v) determine pKa shifts by an alternative spectrophotometric method (CE-DAD). The proposed solutions were implemented to examine the supramolecular pKa shifts of several coumarin derivatives, caused by a variety of structurally different cyclodextrins. It was revealed that a specific host substitution pattern determines the magnitude of apparent pKa shifts. Accordingly, heptakis(2,6-di-O-methyl)-β-cyclodextrin induces the much stronger shifts than both non-methylated-β-cyclodextrin and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin applied at the same concentration. We also show that insofar as the complexation of 4-hydroxycoumarin and its derivative (coumatetralyl) are similarly exothermic, the thermal effects accompanying the deprotonation process are remarkably different for both molecules. The pKa shift induced by complexation with calixarene was also for the first time determined by a CE method. These observations throw a new light on the background of acidity modification and confirm the applicability of CE as an analytical tool.