Metal Ion,Light, and Redox Responsive Interaction of Vesicles by a Supramolecular Switch

Chemical, photochemical and electrical stimuli are versatile possibilities to exert external control on self‐assembled materials. Here, a trifunctional molecule that switches between an “adhesive” and a “non‐adhesive” state in response to metal ions, or light, or oxidation is presented. To this end, an azobenzene–ferrocene conjugate with a flexible N,N′‐bis(3‐aminopropyl)ethylenediamine spacer was designed as a multistimuli‐responsive guest molecule that can form inclusion complexes with β‐cyclodextrin. In the absence of any stimulus the guest molecule induces reversible aggregation of host vesicles composed of amphiphilic β‐cyclodextrin due to the formation of intervesicular inclusion complexes. In this case, the guest molecule operates as a noncovalent cross‐linker for the host vesicles. In response to any of three external stimuli (metal ions, UV irradiation, or oxidation), the conformation of the guest molecule changes and its affinity for the host vesicles is strongly reduced, which results in the dissociation of intervesicular complexes. Upon elimination or reversal of the stimuli (sequestration of metal ion, visible irradiation, or reduction) the affinity of the guest molecules for the host vesicles is restored. The reversible cross‐linking and aggregation of the cyclodextrin vesicles in dilute aqueous solution was confirmed by isothermal titration calorimetry (ITC), optical density measurements at 600 nm (OD₆₀₀), dynamic light scattering (DLS), ζ‐potential measurements and cyclic voltammetry (CV). To the best of our knowledge, a dynamic supramolecular system based on a molecular switch that responds orthogonally to three different stimuli is unprecedented.     

Sugar‐Decorated Sugar Vesicles: Lectin–Carbohydrate Recognition at the Surface of Cyclodextrin Vesicles

An artificial glycocalix self‐assembles when unilamellar bilayer vesicles of amphiphilic β‐cyclodextrins are decorated with maltose and lactose by host–guest interactions. To this end, maltose and lactose were conjugated with adamantane through a tetra(ethyleneglycol) spacer. Both carbohydrate–adamantane conjugates strongly bind to β‐cyclodextrin (K_a≈4×10⁴ M ^?1). The maltose‐decorated vesicles readily agglutinate (aggregate) in the presence of the lectin concanavalin A, whereas the lactose‐decorated vesicles agglutinate in the presence of peanut agglutinin. The orthogonal multivalent interaction in the ternary system of host vesicles, guest carbohydrates, and lectins was investigated by using isothermal titration calorimetry, dynamic light scattering, UV/Vis spectroscopy, and cryogenic transmission electron microscopy. It was shown that agglutination is reversible, and the noncovalent interaction can be suppressed and eliminated by the addition of competitive inhibitors, such as D ‐glucose or β‐cyclodextrin. Also, it was shown that agglutination depends on the surface coverage of carbohydrates on the vesicles.     

Light‐Switchable Self‐Healing Hydrogel Based on Host–Guest Macro‐Crosslinking

A self‐healing hydrogel is prepared by crosslinking acrylamide with a host–guest macro‐crosslinker assembled from poly(β‐cyclodextrin) nanogel and azobenzeneacrylamide. The photoisomerizable azobenzene moiety can change its binding affinity with β‐cyclodextrin, therefore the crosslinking density and rheology property of the hydrogel can be tuned with light stimulus. The hydrogel can repair its wound autonomously through the dynamic host–guest interaction. In addition, the wounded hydrogel will lose its ability of self‐healing when exposed to ultraviolet light, and the self‐healing behavior can be recovered upon the irradiation of visible light. The utilizing of host–guest macro‐crosslinking approach manifests the as‐prepared hydrogel reversible and light‐switchable self‐healing property, which would broaden the potential applications of self‐healing polymers.

     

Directed Supramolecular Surface Assembly of SNAP‐tag Fusion Proteins

Supramolecular assembly of proteins on surfaces and vesicles was investigated by site‐selective incorporation of a supramolecular guest element on proteins. Fluorescent proteins were site‐selectively labeled with bisadamantane by SNAP‐tag technology. The assembly of the bisadamantane functionalized SNAP‐fusion proteins on cyclodextrin‐coated surfaces yielded stable monolayers. The binding of the fusion proteins is specific and occurs with an affinity in the order of 10⁶ M ^?1 as determined by surface plasmon resonance. Reversible micropatterns of the fusion proteins on micropatterned cyclodextrin surfaces were visualized by using fluorescence microscopy. Furthermore, the guest‐functionalized proteins could be assembled out of solution specifically onto the surface of cyclodextrin vesicles. The SNAP‐tag labeling of proteins thus allows for assembly of modified proteins through a host–guest interaction on different surfaces. This provides a new strategy in fabricating protein patterns on surfaces and takes advantage of the high labeling efficiency of the SNAP‐tag with designed supramolecular elements.     

Dual‐responsive supramolecular self‐assembly of inclusion complex of an azobenzene‐ended poly(ε‐caprolactone) with a water‐soluble pillar[6]arene and its application in controlled drug release

Dual photo‐ and pH‐responsive polymeric vesicles are constructed from a host–guest complex between a water‐soluble pillar[6]arene and an azobenzene ended functionalized poly(ε‐caprolactone). Reversible morphological transitions between vesicles and solid aggregates are achieved upon repeated UV stimulus and pH stimulus. Moreover, the polymeric vesicles present excellent cytocompatibility toward HepG2 cells and can be further applied for controlled release of a hydrophilic model drug, DOX?HCl. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55 , 2477–2482     

Responsiveness and Morphology Study of Dual Stimuli‐Controlled Supramolecular Polymer

The synthesis and characterization of a linear supramolecular polymer formed by dual host–guest recognitions is presented. The polymer linked by the orthogonal interactions of azobenzene with β‐cyclodextrin and methyl viologen with sulfonatocalix[4]arene is constructed, and the morphology change along with the formation and vanishment of host–guest interaction is investigated. The reversible disassembly–reassembly of the polymer induced by light and the redox process are monitored by UV–vis and cyclic voltammetry, respectively. The interesting morphology differences between the monomer guest (G), supramolecular polymer (P), and light dissembled product pseudorotaxane (D1) are observed and analyzed. G conducts self‐assembly into a short rod with average width of 83 nm due to the molecular amphipathy and π–π interaction between naphthalene nucleuses, while P exhibits 20 nm wide line morphology. Irradiating P with 365 nm light, the corresponding aggregation D1 shows as 35 nm wide short rod.     

A Rapidly Self‐Healing Supramolecular Polymer Hydrogel with Photostimulated Room‐Temperature Phosphorescence Responsiveness

Development of self‐healing and photostimulated luminescent supramolecular polymeric materials is important for artificial soft materials. A supramolecular polymeric hydrogel is reported based on the host–guest recognition between a β‐cyclodextrin (β‐CD) host polymer (poly‐β‐CD) and an α‐bromonaphthalene (α‐BrNp) polymer (poly‐BrNp) without any additional gelator, which can self‐heal within only about one minute under ambient atmosphere without any additive. This supramolecular polymer system can be excited to engender room‐temperature phosphorescence (RTP) signals based on the fact that the inclusion of β‐CD macrocycle with α‐BrNp moiety is able to induce RTP emission (CD‐RTP). The RTP signal can be adjusted reversibly by competitive complexation of β‐CD with azobenzene moiety under specific irradiation by introducing another azobenzene guest polymer (poly‐Azo).     

Design and proof of reversible micelle‐to‐vesicle multistimuli‐responsive morphological regulations

Multistimuli‐responsive precise morphological control over self‐assembled polymers is of great importance for applications in nanoscience as drug delivery system. A novel pH, photoresponsive, and cyclodextrin‐responsive block copolymer were developed to investigate the reversible morphological transition from micelles to vesicles. The azobenzene‐containing block copolymer poly(ethylene oxide)‐b‐poly(2‐(diethylamino)ethyl methacrylate‐co‐6‐(4‐phenylazo phenoxy)hexyl methacrylate) [PEO‐b‐P(DEAEMA‐co‐PPHMA)] was synthesized by atom transfer radical polymerization. This system can self‐assemble into vesicles in aqueous solution at pH 8. On adjusting the solution pH to 3, there was a transition from vesicles to micelles. The same behavior, that is, transition from vesicles to micelles was also realizable on addition of β‐cyclodextrin (β‐CD) to the PEO‐b‐P(DEAEMA‐co‐PPHMA) solution at pH 8. Furthermore, after β‐CD was added, alternating irradiation of the solution with UV and visible light can also induce the reversible micelle‐to‐vesicle transition because of the photoinduced trans‐to‐cis isomerization of azobenzene units. The multistimuli‐responsive precise morphological changes were studied by laser light scattering, transmission electron microscopy, and UV–vis spectra. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Photoresponsive Switches at Surfaces Based on Supramolecular Functionalization with Azobenzene–Oligoglycerol Conjugates

The synthesis, supramolecular complexation, and switching of new bifunctional azobenzene–oligoglycerol conjugates in different environments is reported. Through the formation of host–guest complexes with surface immobilized β‐cyclodextrin receptors, the bifunctional switches were coupled to gold surfaces. The isomerization of the amphiphilic azobenzene derivatives was examined in solution, on gold nanoparticles, and on planar gold surfaces. The wettability of functionalized gold surfaces can be reversibly switched under light‐illumination with two different wavelengths. Besides the photoisomerization processes and concomitant effects on functionality, the thermal cis to trans isomerization of the conjugates and their complexes was monitored. Thermal half‐lives of the cis isomers were calculated for different environments. Surprisingly, the half‐lives on gold nanoparticles were significantly smaller compared to planar gold surfaces.     

Modulating Guest Uptake in Core–Shell MOFs with Visible Light

A two‐component core–shell UiO‐68 type metal–organic framework (MOF) with a nonfunctionalized interior for efficient guest uptake and storage and a thin light‐responsive outer shell was prepared by initial solvothermal MOF synthesis followed by solvent‐assisted linker exchange. The bulky shell linker features two tetra‐ortho‐fluorinated azobenzene moieties to exploit their advantageous photoisomerization properties. The obtained perfect octahedral MOF single crystals can be switched repeatedly and with an unprecedented efficiency between E‐ and Z‐rich states using visible light only. Due to the high photoswitch density per pore of the shell layer, its steric demand and thus molecular uptake (and release) can be conveniently modulated upon green and blue light irradiation. Therefore, the “smart” shell acts as a light‐controlled kinetic barrier or “gate” for the diffusion of cargo molecules in and out of the MOF crystals.     

Dual Photo‐ and pH‐Responsive Supramolecular Nanocarriers Based on Water‐Soluble Pillar[6]arene and Different Azobenzene Derivatives for Intracellular Anticancer Drug Delivery

Two novel types of supramolecular nanocarriers fabricated by the amphiphilic host–guest inclusion complex formed from water‐soluble pillar[6]arene ( WP6 ) and azobenzene derivatives G1 or G2 have been developed, in which G1 is structurally similar to G2 but has an extra phenoxy group in its hydrophobic region. Supramolecular micelles can be initially formed by WP6 with G1 , which gradually transform into layered structures with liquid‐crystalline properties, whereas stable supramolecular vesicles are obtained from WP6 and G2 , which exhibit dual photo‐ and pH‐responsiveness. Notably, the resulting WP6 ? G2 vesicles can efficiently encapsulate anticancer drug mitoxantrone (MTZ) to achieve MTZ‐loaded vesicles, which maintain good stability in a simulated normal physiological environment, whereas in an acid environment similar to that of tumor cells or with external UV irradiation, the encapsulated drug is promptly released. More importantly, cytotoxicity assay indicates that such vesicles have good biocompatibility and the MTZ‐loaded vesicles exhibit comparable anticancer activity to free MTZ, especially with additional UV stimulus, whereas its cytotoxicity for normal cells was remarkably reduced. Flow cytometric analysis further confirms that the cancer cell death caused by MTZ‐loaded vesicles is associated with apoptosis. Therefore, the dual pH‐ and UV‐responsive supramolecular vesicles are a potential platform for controlled release and targeted anticancer drug delivery.     

Analyte‐Triggered DNA‐Probe Release from a Triplex Molecular Beacon for Nanopore Sensing

A new nanopore sensing strategy based on triplex molecular beacon was developed for the detection of specific DNA or multivalent proteins. The sensor is composed of a triplex‐forming molecular beacon and a stem‐forming DNA component that is modified with a host–guest complex. Upon target DNA hybridizing with the molecular beacon loop or multivalent proteins binding to the recognition elements on the stem, the DNA probe is released and produces highly characteristic current signals when translocated through α‐hemolysin. The frequency of current signatures can be used to quantify the concentrations of the target molecules. This sensing approach provides a simple, quick, and modular tool for the detection of specific macromolecules with high sensitivity and excellent selectivity. It may find useful applications in point‐of‐care diagnostics with a portable nanopore kit in the future.     

Reversible Stabilization of Vesicles: Redox‐Responsive Polymer Nanocontainers for Intracellular Delivery

We present the self‐assembly of redox‐responsive polymer nanocontainers comprising a cyclodextrin vesicle core and a thin reductively cleavable polymer shell anchored via host–guest recognition on the vesicle surface. The nanocontainers are of uniform size, show high stability, and selectively respond to a mild reductive trigger as revealed by dynamic light scattering, transmission electron microscopy, atomic force microscopy, a quantitative thiol assay, and fluorescence spectroscopy. Live cell imaging experiments demonstrate a specific redox‐responsive release and cytoplasmic delivery of encapsulated hydrophilic payloads, such as the pH‐probe pyranine, and the fungal toxin phalloidin. Our results show the high potential of these stimulus‐responsive nanocontainers for cell biological applications requiring a controlled delivery.     

Load–Collapse–Release Cascades of Amphiphilic Guest Molecules in Charged Dendronized Polymers through Spatial Separation of Noncovalent Forces

The ability to pack guest molecules into charged dendronized polymers (denpols) and the possibility to release these guest molecules from subsequently densely aggregated denpols in a load–collapse–release cascade is described. Charged denpols, which constitute molecular objects with a persistent, well‐defined envelope and interior, are capable of incorporating large amounts of amphiphilic guest molecules. Simultaneously, multivalent ions can coordinate to the surfaces of charged denpols, leading to counterion‐induced aggregation of the already guest‐loaded host structures. Thus, although the local guest concentration in denpol‐based molecular transport might already be initially high due to the dense guest packing inside the dendritic denpol scaffolding, the “local” guest concentration can nonetheless be further increased by packing (through aggregation) of the host–guest complexes themselves. Subsequent release of guest compounds from densely aggregated dendronized polymers is then possible (e.g., through increasing the solution concentration of imidazolium‐based ions). Augmented with this release possibility, the concept of twofold packing of guests, firstly through hosting itself and secondly through aggregation of the hosts, gives rise to a load–collapse–release cascade that strikingly displays the high potential of dendronized macromolecules for future molecular transport applications.     

Design and Construction of a Smart Targeting Drug Delivery System Based on Phototriggered Competition of Host–Guest Interaction

A smart targeting drug delivery nanocarrier is successfully constructed based on phototriggered competition of host–guest interaction. The targeting motif, i.e., biotin is first concealed by β‐cyclodextrin (β‐CD) via host–guest interaction. When the nanoparticles are exposed to UV light, the cleavage of photosensitive groups results in the exposure of adamantane (Ad) groups initially located in the interior of nanoassemblies, and β‐CDs capped on biotin ligands can be replaced by Ad because of the higher binding constant between Ad and β‐CD than that between biotin and β‐CD. The competition of host–guest interaction leads to the recovery of targeting capacity of biotin ligands on the nanocarriers. By virtue of photoregulation, the nanocarriers exhibit controllable ligand‐receptor recognition, which is proved by flow cytometry, laser confocal microscopy, and cytotoxicity assay. This strategy has a potential to improve the selectivity and safety of targeting drug delivery systems.     

Motion Control of Polymeric Nanomotors Based on Host–Guest Interactions

Controlling the motion of artificial self‐propelled micro‐ and nanomotors independent of the fuel concentration is still a great challenge. Here we describe the first report of speed manipulation of supramolecular nanomotors via blue light‐responsive valves, which can regulate the access of hydrogen peroxide fuel into the motors. Light‐sensitive polymeric nanomotors are built up via the self‐assembly of functional block copolymers, followed by bowl‐shaped stomatocyte formation and incorporation of platinum nanoparticles. Subsequent addition of β‐cyclodextrin (β‐CD) leads to the formation of inclusion complexes with the trans‐isomers of the azobenzene derivatives grafted from the surfaces of the stomatocytes. β‐CDs attachment decreases the diffusion rate of hydrogen peroxide into the cavities of the motors because of partly blocking of the openings of the stomatocyte. This results in a lowering of the speed of the nanomotors. Upon blue light irradiation, the trans‐azobenzene moieties isomerize to the cis‐form, which lead to the detachment of the β‐CDs due to their inability to form complexes with the cis‐isomer. As a result, the speed of the nanomotors increases accordingly. Such a conformational change provides us with the unique possibility to control the speed of the supramolecular nanomotor via light‐responsive host–guest complexation. We envision that such artificial responsive nano‐systems with controlled motion could have potential applications in drug delivery.     

A Novel pH/Light‐Triggered Surface for DNA Adsorption and Release

A simple strategy for the immobilization of Cy3‐labeled single strand DNA (Cy3‐ssDNA) on a Si(001) surface and its release under control of both light and pH stimuli is presented. In order to prepare a dual pH/light‐triggered surface, positively chargeable azobenzene molecules are self‐assembled on the Si(001) surface. The surface wettability of this substrate can be changed under influence of both light and pH conditions. The substrates can be positively charged under mildly acidic conditions. The pH‐sensitive behavior of the film allows binding of Cy3‐ssDNA on the functionalized Si(001) surface through e?ective electrostatic interactions with the negatively charged polynucleotide backbone. Moreover, irradiation of the film with UVA light induces trans–cis isomerization of the azobenzene units on the surface. As a result, the binding a?nity for DNA decreases due to the changing surface hydrophilicity. In order to understand and control the reversible photoswitchable mechanism of this surface, water contact angles are measured after UVA and visible light irradiation. The release of DNA from a dual pH/light‐sensitive sample is performed using fluorescence microscopy. The results show that irradiation of the film with UVA light induces trans–cis isomerization of the photoresponsive azobenzene units; this leads to significant changes in the surface hydrophilicity and reduces the binding affinity for DNA.     

NIR‐Light‐Activated Combination Therapy with a Precise Ratio of Photosensitizer and Prodrug Using a Host–Guest Strategy

The co‐delivery of photosensitizers with prodrugs sensitive to reactive oxygen species (ROS) for light‐triggered ROS generation and cascaded prodrug activation has drawn tremendous attention. However, the absence of a feasible method to deliver the two components at a precise ratio has impaired the application potential. Herein, we report an efficient method to produce a nanosized platform for the delivery of an optimized ratio of the two components by the means of host–guest strategy for maximizing the combination therapy efficacy of cancer treatment. The key features of this host–guest strategy for the combination therapy are that the ratio between photosensitizer and ROS‐sensitive prodrug can be easily tuned, near‐infrared (NIR) irradiation can sensitize the photosensitizer and activate the paclitaxel prodrug for its release, and the accumulation process can be tracked by NIR imaging to maximize the efficacy of photodynamic and chemotherapy.     

A Dynamic Hydrogen‐Bonded Azo‐Macrocycle for Precisely Photo‐Controlled Molecular Encapsulation and Release

A light‐responsive system constructed from hydrogen‐bonded azo‐macrocycles demonstrates precisely controlled propensity in molecular encapsulation and release process. A significant decrease in the size of the cavity is observed in the course of the E→Z photoisomerization based on the results from DFT calculations and traveling wave ion mobility mass spectrometry. These macrocyclic hosts exhibit a rare 2:1 host–guest stoichiometry and guest‐dependent slow or fast exchange on the NMR timescale. With the slow host–guest exchange and switchable shape change of the cavity, quantitative release and capture of bipyridinium guests is achieved with the maximum release of 68 %. This work underscores the importance of slow host–guest exchange on realizing accurate release of organic cations in a stepwise manner under light irradiation. The light‐responsive system established here could advance further design of novel photoresponsive molecular switches and mechanically interlocked molecules.     

Molecular printboards: versatile platforms for the creation and positioning of supramolecular assemblies and materials

This tutorial review describes the development of molecular printboards, which are tailor-made surfaces functionalized with receptor (host) molecules. Such substrates can be used for the binding of complementary ligand (guest) molecules through multivalent interactions. Supramolecular multivalent interactions are ideal to attain a quantitative and fundamental understanding of multivalency at interfaces. Because of their quantitative interpretation, the focus is on (i) the interaction of cyclodextrin host surfaces with multivalent hydrophobic guest molecules, (ii) the vancomycin-oligopeptide system, and (iii) the multivalent binding of histidine-tagged proteins to NiNTA receptor surfaces. The review will be of interest to researchers in the fields of supramolecular chemistry, chemical biology, surface chemistry, and molecular recognition.