Multivalent Host-guest Interactions Research Articles

Reactive oxygen species (ROS)-responsive size-reducible nanoassemblies for deeper atherosclerotic plaque penetration and enhanced macrophage-targeted drug delivery.

Nanoparticle-based therapeutics represent potential strategies for treating atherosclerosis; however, the complex plaque microenvironment poses a barrier for nanoparticles to target the dysfunctional cells. Here, we report reactive oxygen species (ROS)-responsive and size-reducible nanoassemblies, formed by multivalent host-guest interactions between β-cyclodextrins (β-CD)-anchored discoidal recombinant high-density lipoprotein (NP3ST) and hyaluronic acid-ferrocene (HA-Fc) conjugates. The HA-Fc/NP3ST nanoassemblies have extended blood circulation time, specifically accumulate in atherosclerotic plaque mediated by the HA receptors CD44 highly expressed in injured endothelium, rapidly disassemble in response to excess ROS in the intimal and release smaller NP3ST, allowing for further plaque penetration, macrophage-targeted cholesterol efflux and drug delivery. In vivo pharmacodynamicses in atherosclerotic mice shows that HA-Fc/NP3ST reduces plaque size by 53%, plaque lipid deposition by 63%, plaque macrophage content by 62% and local inflammatory factor level by 64% compared to the saline group. Meanwhile, HA-Fc/NP3ST alleviates systemic inflammation characterized by reduced serum inflammatory factor levels. Collectively, HA-Fc/NP3ST nanoassemblies with ROS-responsive and size-reducible properties exhibit a deeper penetration in atherosclerotic plaque and enhanced macrophage targeting ability, thus exerting effective cholesterol efflux and drug delivery for atherosclerosis therapy.

Multivalency Enables Dynamic Supramolecular Host-Guest Hydrogel Formation.

Supramolecular and dynamic biomaterials hold promise to recapitulate the time-dependent properties and stimuli-responsiveness of the native extracellular matrix (ECM). Host–guest chemistry is one of the most widely studied supramolecular bonds, yet the binding characteristics of host–guest complexes (β-CD/adamantane) in relevant biomaterials have mostly focused on singular host–guest interactions or nondiscrete multivalent pendent polymers. The stepwise synergistic effect of multivalent host–guest interactions for the formation of dynamic biomaterials remains relatively unreported. In this work, we study how a series of multivalent adamantane (guest) cross-linkers affect the overall binding affinity and ability to form supramolecular networks with alginate-CD (Alg-CD). These binding constants of the multivalent cross-linkers were determined via NMR titrations and showed increases in binding constants occurring with multivalent constructs. The higher multivalent cross-linkers enabled hydrogel formation; furthermore, an increase in binding and gelation was observed with the inclusion of a phenyl spacer to the cross-linker. A preliminary screen shows that only cross-linking Alg-CD with an 8-arm-multivalent guest results in robust gel formation. These cytocompatible hydrogels highlight the importance of multivalent design for dynamically cross-linked hydrogels. These materials hold promise for development toward cell- and small molecule-delivery platforms and allow discrete and fine-tuning of network properties.

Self-Assembly of Colloidal Molecules Based on Host–Guest Chemistry and Geometric Constraints

The preparation of colloidal molecules, i.e. clusters of colloids with a defined aggregation number and configuration, is of continued and significant interest in colloid chemistry and materials science, and numerous interactions have been utilized to drive their (self-)assembly. However, only very few reports are available on the assembly of colloidal molecules based on host-guest chemistry. In this paper, we investigate the assembly of like charged silica particles into well-defined, core-satellite ABn-type colloidal molecules in water mediated by host-guest interaction and geometric constraints. Exploiting the inherent dynamics of non-covalent attraction and making use of a soft polymer shell to enhance multivalent host-guest interactions, we successfully synthesized AB3, AB4 and AB6 colloidal molecules by selecting the appropriate size ratio of satellite to core particles.

Poly(cyclodextrin)-Polydrug Nanocomplexes as Synthetic Oncolytic Virus for Locoregional Melanoma Chemoimmunotherapy.

Despite the approval of oncolytic virus therapy for advanced melanoma, its intrinsic limitations that include the risk of persistent viral infection and cost-intensive manufacturing motivate the development of analogous approaches that are free from the disadvantages of virus-based therapies. Herein, we report a nanoassembly comprised of multivalent host-guest interactions between polymerized paclitaxel (pPTX) and nitric oxide incorporated polymerized β-cyclodextrin (pCD-pSNO) that through its bioactive components and when used locoregionally recapitulates the therapeutic effects of oncolytic virus. The resultant pPTX/pCD-pSNO exhibits significantly enhanced cytotoxicity, immunogenic cell death, dendritic cell activation and T cell expansion in vitro compared to free agents alone or in combination. In vivo, intratumoral administration of pPTX/pCD-pSNO results in activation and expansion of dendritic cells systemically, but with a corresponding expansion of myeloid-derived suppressor cells and suppression of CD8+ T cell expansion. When combined with antibody targeting cytotoxic T lymphocyte antigen-4 that blunts this molecule's signaling effects on T cells, intratumoral pPTX/pCD-pSNO treatment elicits potent anticancer effects that significantly prolong animal survival. This formulation thus leverages the chemo- and immunotherapeutic synergies of paclitaxel and nitric oxide and suggests the potential for virus-free nanoformulations to mimic the therapeutic action and benefits of oncolytic viruses.

A super-stretchable, self-healing and injectable supramolecular hydrogel constructed by a host-guest crosslinker.

Supramolecular hydrogels based on host-guest interactions have drawn considerable attention due to their unique properties and promising applications. However, it is still a great challenge to construct supramolecular hydrogels that simultaneously achieve mechanical strength, processability, and biocompatibility. Herein, we present a rational design of a "supramolecular crosslinker" approach to fabricate a new host-guest hydrogel with super-stretchability, self-healing, and injectable properties and excellent biocompatibility. The star-shaped supramolecular crosslinker is formed by the host-guest interactions between octa-cyclodextrin polyhedral oligomeric silsesquioxane (OCDPOSS) and acrylamide-modified adamantane (Ad-AAm). Supramolecular hydrogels can be briefly prepared by UV-initiated copolymerization of acrylamide and supramolecular crosslinkers. Supramolecular hydrogels present impressive mechanical properties due to rigid POSS as the core of the supramolecular crosslinker. Moreover, multivalent host-guest interactions improve the ductility, rapid self-healing and injectable ability of these hydrogels. Simultaneously, these supramolecular hydrogels possess good biocompatibility and can be utilized as carriers for the sustained release of hydrophobic drugs. Thus, such supramolecular hydrogels will have potential applications for tissue engineering and drug delivery systems.

Stretchable and Bioadhesive Supramolecular Hydrogels Activated by a One-Stone-Two-Bird Postgelation Functionalization Method.

Resembling soft tissues, stretchable hydrogels are promising biomaterials for many biomedical applications due to their excellent mechanical robustness. However, conventional stretchable hydrogels with a synthetic polymer matrix are usually bioinert. The lack of cell and tissue adhesiveness of such hydrogels limits their applications. An easy but reliable postgelation functionalization method is desirable. Herein, we report the fabrication of stretchable supramolecular hydrogels cross-linked by multivalent host-guest interactions. Such hydrogels containing thiourea ( TU) functionalities can be bioactivated with a catechol-modified peptide (Cat-RGD) via thiourea-catechol ( TU-Cat) coupling reaction. This postgelation bioactivation of the otherwise bioinert hydrogels not only conjugates bioactive ligands for cell attachment but also introduces and preserves the catechol structures for tissue adhesion. This straightforward fabrication and one-stone-two-bird bioactivation of the stretchable hydrogels may find broad applications in developing advanced soft biomaterials for tissue repair, wound dressing, and lesion sealing.

Reversible, High-Affinity Surface Capturing of Proteins Directed by Supramolecular Assembly.

The ability to design surfaces with reversible, high-affinity protein binding sites represents a significant step forward in the advancement of analytical methods for diverse biochemical and biomedical applications. Herein, we report a dynamic supramolecular strategy to directly assemble proteins on surfaces based on multivalent host-guest interactions. The host-guest interactions are achieved by one-step nanofabrication of a well-oriented β-cyclodextrin host-derived self-assembled monolayer on gold (β-CD-SAM) that forms specific inclusion complexes with hydrophobic amino acids located on the surface of the protein. Cytochrome c, insulin, α-chymotrypsin, and RNase A are used as model guest proteins. Surface plasmon resonance and static time-of-flight secondary ion mass spectrometry studies demonstrate that all four proteins interact with the β-CD-SAM in a specific manner via the hydrophobic amino acids on the surface of the protein. The β-CD-SAMs bind the proteins with high nanomolar to single-digit micromolar dissociation constants ( KD). Importantly, while the proteins can be captured with high affinity, their release from the surface can be achieved under very mild conditions. Our results expose the great advantages of using a supramolecular approach for controlling protein immobilization, in which the strategy described herein provides unprecedented opportunities to create advanced bioanalytic and biosensor technologies.

Manipulating the mechanical properties of biomimetic hydrogels with multivalent host-guest interactions.

Biomimetic hydrogels with hierarchical network structures are promising biomaterials for tissue engineering due to their unique mechanical properties. One successful biomimetic strategy for facile construction of high-performance hydrogels is to incorporate reversible crosslinks as sacrificial bonds into chemical polymer networks. By mimicking the unfolding-refolding functions of the skeletal muscle protein titin, the reversible crosslinks can reinforce the otherwise weak and brittle hydrogels. However, the contribution of multivalent reversible crosslinks to the overall hydrogel mechanical properties has rarely been investigated. Herein we present the biomimetic hydrogels with multivalent host-guest interactions as reversible crosslinks, which provide not only energy storage capacity, but also elevated energy dissipation capacity to the dually crosslinked networks, therefore leading to the improved hydrogel ductility and tensile strength. Our results also reveal the manner of multivalent host-guest crosslinks contributing to the hydrogel mechanical properties, including gelation rate, energy storage and dissipation, tensile hysteresis, and fast spontaneous recovery.

In vivo stability of supramolecular host–guest complexes monitored by dual-isotope multiplexing in a pre-targeting model of experimental liver radioembolization

IntroductionCyclodextrin (CD)-based supramolecular interactions have been proposed as nanocarriers for drug delivery. We previously explored the use of these supramolecular interactions to perform targeted hepatic radioembolization. In a two-step procedure the appropriate location of the diagnostic pre-targeting vector can first be confirmed, after which the therapeutic vector will be targeted through multivalent host–guest interactions. Such a procedure would prevent therapeutic errors that come from a mismatch between diagnostic and therapeutic procedures. In the current study we explored the use of dual-isotope imaging to assess the in vivo stability of the formed complex and individual components. MethodsDual-isotope imaging of the host and guest vectors was performed after labeling of the pre-targeted guest vector, being adamantane (Ad) functionalized macro-aggregated albumin (MAA) particles, with technetium-99 m (99mTc-MAA-Ad). The host vector, Cy50.5CD9PIBMA39, was labeled with indium-111 (111In-Cy50.5CD9PIBMA39). The in situ stability of both the individual vectors and the resulting [MAA-Ad–111In-Cy50.5CD9PIBMA39] complexes was studied over 44 h at 37 °C in a serum protein-containing buffer. In vivo, the host vector 111In-Cy50.5CD9PIBMA39 was administered two hours after local deposition of 99mTc-MAA-Ad in mice. Dual-isotope SPECT imaging and quantitative biodistribution studies were performed between 2 and 44 h post intravenous host vector administration. ResultsThe individual vectors portrayed <5% dissociation of the radioisotope over the course of 20 h. Dissociation of [MAA-Ad–111In-Cy50.5CD9PIBMA39] complexes remained within a 10–20% range after incubation in serum. In vivo dual-isotope SPECT imaging of host–guest interactions revealed co-localization of the tracer components. Quantitative assessment of the biodistribution revealed that the hepatic accumulation of the host vector nearly doubled between 2 h and 44 h post-injection (from 14.9 ± 6.1%ID/g to 26.2 ± 2.1%ID/g). ConclusionsAssessment of intra-hepatic host–guest complexation was successfully achieved using dual isotope multiplexing, underlining the complex stability that was found in situ (up to 44 h in serum). Overall, the results obtained in this study highlight the potential of supramolecular chemistry as a versatile platform that could advance the field of nanomedicine.

Size controllable DNA nanogels from the self-assembly of DNA nanostructures through multivalent host–guest interactions

Nanogels made of biomolecules are one of the potential candidates as a nanocarrier for drug delivery applications. The unique structural characteristics and excellent biocompatibility of DNA suggest that DNA nanogels would be an ideal candidate. Herein, a general design strategy for the crafting of DNA nanogels with controllable size using the multivalent host-guest interaction between β-CD functionalized branched DNA nanostructures as the host and a star-shaped adamantyl-terminated 8-arm poly(ethylene glycol) polymer as the guest is reported. Our results reveal that multivalent host-guest interactions are necessary for the nanogel formation. Nanogels exhibit excellent biocompatibility, good cell permeability and high drug encapsulation ability, which are promising features for their application as a drug carrier. The encapsulation of doxorubicin, an anticancer drug, inside the hydrophobic network of the nanogel and its delivery into cancer cells are also reported. We hope that the general design strategy demonstrated for the creation of DNA nanogels may encourage other researchers to use this approach for the design of DNA nanogels of other DNA nanostructures, and explore the potential of DNA nanogels in drug delivery applications.

Multivalent Host–Guest Hydrogels as Fatigue-Resistant 3D Matrix for Excessive Mechanical Stimulation of Encapsulated Cells

Fatigue resistance of hydrogels is critical to their applications in load-bearing sites of soft tissues that are usually subjected to continuous loadings, such as joint cartilage. However, hydrogels usually swell under physiological conditions and exhibit inevitable fatigue during excessive mechanical loadings. Here we show that hydrogels cross-linked by multivalent host–guest interactions can effectively dissipate a large fraction of the loading energy (>50%) under excessive compressions (over 80% strain, 1000 cycles) despite their high water contents (95%) under physiological conditions. No fatigue is observed in such highly swollen hydrogels during continuous cyclic compressions. We demonstrate that such hydrogels can be used as 3D cell carriers for excessive mechanical stimulation of the encapsulated stem cells, making them promising soft biomaterials for tissue engineering.

Construction of a Repairable Fixed Porous Catalytic Bed Loaded with Gold Nanoparticles via Multivalent Host–Guest Interactions

The reversible combination between gold nanoparticles (AuNPs) and carriers is crucial for the preparation of a recycle system. Here, a repairable catalytic system was constructed on the basis of AuNPs and porous nickel (PNi) which were combined through the multivalent host–guest interactions between βCD-AuNPs and PNi@IPTS-Azo [β-CD, β-cyclodextrin; IPTS, (3-isocyanatopropyl) triethoxysilane; Azo, azobenzene]. The large specific surface area and connected porous structure of PNi provide a good opportunity to achieve the multivalent interactions between βCD-AuNPs and PNi@IPTS-Azo in the nickel. Additionally, the reaction solution could be catalyzed by flowing over the PNi@IPTS-Azo@βCD-AuNPs substrates. This catalytic model showed a high efficiency close to 95%. Because of the reversible host–guest interactions between β-cyclodextrin and azobenzene, the catalytic system could be regenerated by removing the deactivated AuNPs with UV-light irradiation and recombining new ones through multivalent interactions in situ. This type of catalytic system is regenerative, material-saving, and effective. This system could be expected to be constructed as catalytic fixed beds and applied in industry.

Poly-paclitaxel/cyclodextrin-SPION nano-assembly for magnetically guided drug delivery system

This work demonstrates the development of magnetically guided drug delivery systems and its potential on efficient anticancer therapy. The magnetically guided drug delivery system was successfully developed by utilizing superparamagnetic iron oxide nanoparticle, β-cyclodextrin, and polymerized paclitaxel. Multivalent host-guest interactions between β-cyclodextrin-conjugated superparamagnetic iron oxide nanoparticle and polymerized paclitaxel allowed to load the paclitaxel and the nanoparticle into the nano-assembly. Clusterized superparamagnetic iron oxide nanoparticles in the nano-assembly permitted the rapid and efficient targeted drug delivery. Compared to the control groups, the developed nano-assembly showed the enhanced anticancer effects in vivo as well as in vitro. Consequently, the strategy of the use of superparamagnetic nanoparticles and multivalent host-guest interactions has a promising potential for developing the efficient drug delivery systems.

Bifunctionalized dextrans for surface PEGylation via multivalent host–guest interactions

The main goal of this work was to develop a supramolecular chemistry strategy to decorate interfaces with polyethylene glycol (PEG) grafts. A series of novel bifunctionalized dextrans, bearing 40–60 PEG pending chains and 12–24 hydrophobic adamantyl groups, have been prepared by copper(I)-catalyzed azide-alkyne cycloaddition. Their binding properties toward native βCD and βCD polymers were characterized both in solution and at interface using isothermal titration microcalorimetry and surface plasmon resonance. The polymers were found to form stable layers onto neutral and positively charged βCD-polymer films pre-adsorbed on gold surfaces, due to multivalent interpolymer host–guest interactions. The thickness and stability of the layers could be tuned by varying the ratio between the degrees of substitution by PEG and adamantyl groups.

Folic-Acid-Targeted Self-Assembling Supramolecular Carrier for Gene Delivery.

A targeting gene carrier for cancer-specific delivery was successfully developed through a "multilayer bricks-mortar" strategy. The gene carrier was composed of adamantane-functionalized folic acid (FA-AD), an adamantane-functionalized poly(ethylene glycol) derivative (PEG-AD), and β-cyclodextrin-grafted low-molecular-weight branched polyethylenimine (PEI-CD). Carriers produced by two different self-assembly schemes, involving either precomplexation of the PEI-CD with the FA-AD and PEG-AD before pDNA condensation (Method A) or pDNA condensation with the PEI-CD prior to addition of the FA-AD and PEG-AD to engage host-guest complexation (Method B) were investigated for their ability to compact pDNA into nanoparticles. Cell viability studies show that the material produced by the Method A assembly scheme has lower cytotoxicity than branched PEI 25 kDa (PEI-25KD) and that the transfection efficiency is maintained. These findings suggest that the gene carrier, based on multivalent host-guest interactions, could be an effective, targeted, and low-toxicity carrier for delivering nucleic acid to target cells.

A molecular zipping/unzipping nano-vehicles sensitive to tumor extracellular pH

A new class of pH- responsive multivalent host–guest interactions to manipulate polypeptide-based nano-vehicles was developed. Poly(l-lysine) (poly(Lys)) grafted with β-cyclodextrin and 2,3-dimethylmaleic acid was coupled with oleic acid. This new polymer was utilized to fabricate pH-responsive nano-vehicles for antitumor drug doxorubicin delivery. The host–guest (zipping) interaction between β-cyclodextrin and 2,3-dimethylmaleic acid moieties and the hydrophobic interaction between the oleic acid molecules contributed to form self-assembled nano-vehicles. 2,3-Dimethylmaleic acid moieties were highly degradable at a slightly acidic pH (~pH 6.8). These nano-vehicles increased the release of the encapsulated doxorubicin content (by the unzipping interaction between β-cyclodextrin and degraded 2,3-dimethylmaleic acid moieties) when the pH of the solution decreased to 6.8. This event caused a significant increase in the efficiency of cellular doxorubicin uptake and in vitro tumor inhibition.

Poly-cyclodextrin and poly-paclitaxel nano-assembly for anticancer therapy.

Effective anticancer therapy can be achieved by designing a targeted drug-delivery system with high stability during circulation and efficient uptake by the target tumour cancer cells. We report here a novel nano-assembled drug-delivery system, formed by multivalent host-guest interactions between a polymer-cyclodextrin conjugate and a polymer-paclitaxel conjugate. The multivalent inclusion complexes confer high stability to the nano-assembly, which efficiently delivers paclitaxel into the targeted cancer cells via both passive and active targeting mechanisms. The ester linkages between paclitaxel and the polymer backbone permit efficient release of paclitaxel within the cell by degradation. This novel targeted nano-assembly exhibits significant antitumour activity in a mouse tumour model. The strategy established in this study also provides knowledge for the development of advanced anticancer drug delivery.

Probing Multivalent Host–Guest Interactions between Modified Polymer Layers by Direct Force Measurement

The adhesion behavior between modified polysaccharide layers capable of forming host-guest complexes has been determined by direct force measurements with the atomic force microscope (AFM). Polysaccharides bearing either host or guest moieties were obtained by derivatization of chitosan with pendant β-cyclodextrin (CD) and adamantane (AD) moieties, respectively. These modified polysaccharides were covalently immobilized either to flat surfaces or to AFM-probes. The number of interacting polymer segments has been reduced significantly by covalently immobilizing chitosan to an AFM-tip with small radius and measuring the forces between the protruding polymer segments and a chitosan layer immobilized to a flat surface. By this approach, it was possible to determine the interaction between polymer layers on the level of single polymer strands. To separate contributions to the adhesion due to the formation of host-guest complexes from unspecific interactions, we performed measurements between various combinations of chitosan derivatives. With the same polymer probe of adamantane-modified chitosan, the interaction against a number of different chitosan layers has been determined, including ones that are not able to form host-guest complexes, such as unmodified chitosan or β-cyclodextrin modified chitosan, which has been blocked previously by addition of adamantane. The resulting adhesion behavior has been analyzed in terms of the total work of adhesion, the number of rupture events, and the corresponding lengths of the polymer segments as well as rupture forces. A clear difference has been found for systems where the formation of host-guest complexes is possible in comparison to the absence of specific multivalent interaction between the polysaccharide layers. In particular, the work of adhesion is increasing up to an order of magnitude upon the formation of host-guest complexes between the chitosan layers.

From supramolecular chemistry to nanotechnology: Assembly of 3D nanostructures

Abstract Fabricating well-defined and stable nanoparticle crystals in a controlled fashion receives growing attention in nanotechnology. The order and packing symmetry within a nanoparticle crystal is of utmost importance for the development of materials with unique optical and electronic properties. To generate stable and ordered 3D nanoparticle structures, nanotechnology is combined with supramolecular chemistry to control the self-assembly of 2D and 3D receptor-functionalized nanoparticles. This review focuses on the use of molecular recognition chemistry to establish stable, ordered, and functional nanoparticle structures. The host–guest complexation of β-cyclodextrin (CD) and its guest molecules (e.g., adamantane and ferrocene) are applied to assist the nanoparticle assembly. Direct adsorption of supramolecular guest- and host-functionalized nanoparticles onto (patterned) CD self-assembled monolayers (SAMs) occurs via multivalent host–guest interactions and layer-by-layer (LbL) assembly. The reversibility and fine-tuning of the nanoparticle-surface binding strength in this supramolecular assembly scheme are the control parameters in the process. Furthermore, the supramolecular nanoparticle assembly has been integrated with top-down nanofabrication schemes to generate stable and ordered 3D nanoparticle structures, with controlled geometries and sizes, on surfaces, other interfaces, and as free-standing structures.

Nanometer Arrays of Functional Light Harvesting Antenna Complexes by Nanoimprint Lithography and Host−Guest Interactions

We show an approach based on a combination of site-directed mutagenesis, NIL and multivalent host-guest interactions for the realization of engineered ordered functional arrays of purified components of the photosynthetic system, the membrane-bound LH2 complex. In addition to micrometer-scale patterned structures, we demonstrated the use of nanometer-scale hard NIL stamps to generate functional protein arrays approaching molecular dimensions.