Supramolecular Systems Research Articles

Towards nanomaterials with tubular pores: synthesis and self-assembly of bis-pillar[5]arene

Recently, materials obtained using supramolecular chemistry approaches, and, in particular, spatially preorganized macrocyclic compounds, have attracted close attention of the researchers. Pillar[n]arenes are of special interest due to their tubular spatial structure and macrocyclic cavity. A similar tubular structure is retained in the supramolecular packaging of pillar[5]arene crystals, forming pores. In this study, we developed a block synthetic approach for the preparation of bis-pillar[5]arene containing amide groups. The ability of the synthesized bis-pillar[5]arene to form stable self-associates in solvents of different polarity (CHCl3 and CH3OH) was demonstrated by the DLS method. In trichloromethane at concentration of 1·10–3 M, monodisperse associates with average hydrodynamic diameter of 227 nm (PDI = 0.28) are formed; in methanol, stable associates (1·10–6 M) have an average hydrodynamic diameter of 136 nm (PDI = 0.21). The results obtained can be used to create new supramolecular systems, molecular machines, or capture and detect various organic molecules.

Study of Drug Delivery Using Purely Organic Macrocyclic Containers-Cucurbit[7]uril and Pillararene.

An impaired immune system is the root of various human ailments provoking the urge to find vehicle-mediated quick delivery of small drug molecules and other vital metabolites to specific tissues and organs. Thus, drug delivery strategies are in need of improvement in therapeutic efficacy. It can be achieved only by increasing the drug-loading capacity, increasing the sustained release of a drug to its target site, easy relocation of drug molecules associated with facile complexation-induced properties of molecular vehicles, and high stimuli-responsive drug administration. Supramolecular drug delivery systems (SDDS) provide a much needed robust yet facile platform for fabricating innovative drug nanocarriers assembled by thermodynamically noncovalent interaction with the tunable framework and above-mentioned properties. Measures of cytotoxicity and biocompatibility are the two main criteria that lie at the root of any promising medicinal applications. This Review features significant advancements in (i) supramolecular host-guest complexation using cucurbit[7]uril (CB[7]), (ii) encapsulation of the drug and its delivery application tailored for CB[7], (iii) self-assembly of supramolecular amphiphiles, (iv) supramolecular guest relay using host-protein nanocavities, (v) pillararene (a unique macrocyclic host)-mediated SDDS for the delivery of smart nanodrugs for siRNA, fluorescent molecules, and insulin for juvenile diabetes. Furthermore, fundamental questions and future hurdles related to smart SDDS based on CB[7] and pillararenes and their future promising breakthrough implementations are also distinctly outlined in this Review.

Injectable Supramolecular Hydrogels for In Situ Programming of Car-T Cells toward Solid Tumor Immunotherapy.

Chimeric antigen receptor (CAR)-T cell immunotherapy is approved in the treatment of hematological malignancies, but remains far from satisfactoryin solid tumor treatment due to inadequate intra-tumor CAR-T cell infiltration. Herein, an injectable supramolecular hydrogel system, based on self-assembly between cationic polymer mPEG-PCL-PEI (PPP) conjugated with T cell targeting anti-CD3e f(ab')2 fragment and α-cyclodextrin (α-CD), is designed to load plasmid CAR (pCAR) with a T cell specific CD2 promoter, which successfully achieves in situ fabrication and effective accumulation of CAR-T cells at the tumor site in humanized mice models. More importantly, due to this tumor microenvironment reprogramming, secretion of cellular inflammatory cytokines (interleukin-2 (IL-2), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ)) or tumor killer protein granzyme B is significantly promoted, which reverses the immunosuppressive microenvironment and significantly enhances the intra-tumor CAR-T cells and cytotoxic T cells infiltration. To the best of the current knowledge, this is a pioneer report of using injectable supramolecular hydrogel for in situ reprogramming CAR-T cells, which might be beneficial for solid tumor CAR-T immunotherapy.

Magnetic Circular Dichroism Elucidates Molecular Interactions in Aggregated Chiral Organic Materials.

Chiral materials formed by aggregated organic compounds play a fundamental role in chiral optoelectronics, photonics and spintronics. Nonetheless, a precise understanding of the molecular interactions involved remains an open problem. Here we introduce magnetic circular dichroism (MCD) as a new tool to elucidate molecular interactions and structural parameters of a supramolecular system. A detailed analysis of MCD together with electronic circular dichroism spectra combined to ab initio calculations unveils essential information on the geometry and energy levels of a self-assembled thin film made of a carbazole di-bithiophene chiral molecule. This approach can be extended to a generality of chiral organic materials and can help rationalizing the fundamental interactions leading to supramolecular order. This in turn could enable a better understanding of structure-property relationships, resulting in a more efficient material design.

Magnetic Circular Dichroism Elucidates Molecular Interactions in Aggregated Chiral Organic Materials

AbstractChiral materials formed by aggregated organic compounds play a fundamental role in chiral optoelectronics, photonics and spintronics. Nonetheless, a precise understanding of the molecular interactions involved remains an open problem. Here we introduce magnetic circular dichroism (MCD) as a new tool to elucidate molecular interactions and structural parameters of a supramolecular system. A detailed analysis of MCD together with electronic circular dichroism spectra combined to ab initio calculations unveils essential information on the geometry and energy levels of a self‐assembled thin film made of a carbazole di‐bithiophene chiral molecule. This approach can be extended to a generality of chiral organic materials and can help rationalizing the fundamental interactions leading to supramolecular order. This in turn could enable a better understanding of structure–property relationships, resulting in a more efficient material design.

Cell-Like Synthetic Supramolecular Soft Materials Realized in Multicomponent, Non-/Out-of-Equilibrium Dynamic Systems.

Living cells are complex, nonequilibrium supramolecular systems capable of independently and/or cooperatively integrating multiple bio-supramolecules to execute intricate physiological functions that cannot be accomplished by individual biomolecules. These biological design strategies offer valuable insights for the development of synthetic supramolecular systems with spatially controlled hierarchical structures, which, importantly, exhibit cell-like responses and functions. The next grand challenge in supramolecular chemistry is to control the organization of multiple types of supramolecules in a single system, thus integrating the functions of these supramolecules in an orthogonal and/or cooperative manner. In this perspective, the recent progress in constructing multicomponent supramolecular soft materials through the hybridization of supramolecules, such as self-assembled nanofibers/gels and coacervates, with other functional molecules, including polymer gels and enzymes is highlighted. Moreover, results show that these materials exhibit bioinspired responses to stimuli, such as bidirectional rheological responses of supramolecular double-network hydrogels, temporal stimulus pattern-dependent responses of synthetic coacervates, and 3D hydrogel patterning in response to reaction-diffusion processes are presented. Autonomous active soft materials with cell-like responses and spatially controlled structures hold promise for diverse applications, including soft robotics with directional motion, point-of-care disease diagnosis, and tissue regeneration.

Bone Marrow Microenvironment-Responsive Nanomedicine Promotes Anti-Leukemia Activity In Vivo

Background: Leukemia escape and relapse is the leading cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). Work over the past decades has demonstrated that the CD47- signal-regulatory protein α (SIRPa) interaction mediated cancer cell immune escape. Although CD47-SIRPα interaction blockade contributes to cancer cell clearance by macrophages, how to deliver the anti-CD47 to bone marrow niche through an efficient drug delivery strategy and improve the cytotoxic activity of macrophages is an important issue that needs to be addressed. Methods: Here, we performed immunohistochemical (IHC) analysis and flow cytometry analysis of TIM-3 expression using samples of bone marrow from patients with or without relapse. In addition, according to the natural “myeloid niche homing” characteristic of AML cells and the low-oxygen microenvironment in bone marrow, we constructed β-cyclodextrin azobenzene linker (AZO-β-CD)-modified fusion protein and amantadine-modified HSA protein (HSA-ADA), followed by the addition of anti-CD47. Furthermore, the nanogel TIM3-targeting antibodies were modified on the surface of the nanogel to finally construct the supramolecular nanogel delivery system. Moreover, we detected the effect of target nanomedicine in a leukemia xenograft mouse model. Results: We demonstrated that in the bone marrow microenvironment of patients with relapse, the expression of TIM-3 significantly increased, especially in the CD34 +CD38 + leukemic progenitors, but not in the HSCs. Furthermore, we verified using nanomedicine could significantly increase the number of macrophages in the bone marrow. Importantly, the blockade of CD47-SIRPα signaling using nanomedicine markedly improved the anti-tumor activity in a leukemia xenograft mouse model. Conclusion: Thus, our findings reveal that nanomedicine could inhibit CD47-SIRPα signaling and contribute to anti-leukemia function effectively, which may be a new strategy for preventing and treating the recurrence of AML after transplantation.

Designing and preparing supramolecular encapsulation systems based on fraxetin and cyclodextrins for highly selective detection of nicotine

Herein, a series of water-soluble supramolecular inclusion complexes (ICs) probes were prepared using cyclodextrins (CDs) and fraxetin (FRA) to detect nicotine (NT) with high selectivity in vitro and in vivo. The FRA/CD ICs prepared through the saturated solution method exhibited excellent water solubility, stability, and biocompatibility. A clear host-guest inclusion model was provided by the theoretical calculations. The investigation revealed that NT was able to enter into the cavities of FRA/β-CD IC and FRA/γ-CD IC, and further formed charge transfer complexes with FRA in the CD cavities, resulting in a rapid and highly selective fluorescence-enhanced response with the lowest detection limits of 1.9 × 10−6 M and 9.7 × 10−7 M, and the linear response ranged from 0.02 to 0.3 mM and 0.01–0.05 mM, respectively. The IC probes showed good anti-interference performance to common interferents or different pH environments, with satisfactory reproducibility and repeatability of response to NT. Furthermore, the potentiality of the probes was confirmed through fluorescence imaging experiments using human lung cancer cells and the lung tissue of mice. This study offers a fresh perspective for detecting NT in environmental and biomedical analysis.

Light-Driven Reversible Multicolor Supramolecular Shuttle.

Light-driven multicolor supramolecular systems mainly rely on the doping of dyes or a photo-reaction to produce unidirectional luminescence. Herein, we use visible light to drive the bidirectional reversible multicolor supramolecular shuttle from blue to green, white, yellow, up to orange by simple encapsulation of spiropyran-modified cyanostilbene (BCNMC) by the macrocyclic cucurbit[8]uril (CB[8]) monomer. The resultant host-guest complex displayed enhanced fluorescence properties, i.e. the multicolor fluorescence shuttle changed from blue to orange in the dark within 2 hours and reverted to the original state upon visible light irradiation for 30 s. Benefiting from the sensitivity of the spiropyran moiety to light, it can spontaneously isomerize from the ring-opened state to a ring-closed isomer in aqueous solution, and this photo-isomerization reaction is a reversible process under visible light irradiation, leading to the multicolor luminescence supramolecular shuttle as a result of intramolecular energy transfer. In addition, the light also drove the reversible conversion of the topological morphology of the host-guest complex from two-dimensional nanoplatelets to nanospheres. Different from the widely reported molecular rotaxane "shuttle", the spiropyran supramolecular shuttle confined in the macrocyclic host CB[8] not only modulated a reversible topological morphology by light but also exhibited multicolor luminescence, which was successfully applied in programmed and rewritable information encryption.

Light‐Driven Reversible Multicolor Supramolecular Shuttle

AbstractLight‐driven multicolor supramolecular systems mainly rely on the doping of dyes or a photo‐reaction to produce unidirectional luminescence. Herein, we use visible light to drive the bidirectional reversible multicolor supramolecular shuttle from blue to green, white, yellow, up to orange by simple encapsulation of spiropyran‐modified cyanostilbene (BCNMC) by the macrocyclic cucurbit[8]uril (CB[8]) monomer. The resultant host–guest complex displayed enhanced fluorescence properties, i.e. the multicolor fluorescence shuttle changed from blue to orange in the dark within 2 hours and reverted to the original state upon visible light irradiation for 30 s. Benefiting from the sensitivity of the spiropyran moiety to light, it can spontaneously isomerize from the ring‐opened state to a ring‐closed isomer in aqueous solution, and this photo‐isomerization reaction is a reversible process under visible light irradiation, leading to the multicolor luminescence supramolecular shuttle as a result of intramolecular energy transfer. In addition, the light also drove the reversible conversion of the topological morphology of the host–guest complex from two‐dimensional nanoplatelets to nanospheres. Different from the widely reported molecular rotaxane “shuttle”, the spiropyran supramolecular shuttle confined in the macrocyclic host CB[8] not only modulated a reversible topological morphology by light but also exhibited multicolor luminescence, which was successfully applied in programmed and rewritable information encryption.

Fluorescence detection of amantadine based on competitive β-Cyclodextrin host-guest inclusion process

Cyclodextrin-based fluorescent probes are promising candidates for chemical or biological sensing due to their wonderful sensitivity and selectivity. Typically, their recognition towards special analysts ascribed from hydrophobic cavity of cyclodextrins. In this work, a cyclodextrin-based fluorescent probe (DASP-β-CD) was synthesized by covalently linking trans-4-[4-(dimethylamino)styryl]-1-methylpyridinium (DASP) and β-cyclodextrin (β-CD). In aqueous dispersion, the DASP-β-CD molecules could form intermolecular inclusion complex which would then generate supramolecular aggregates when increasing DASP-β-CD concentration. However, after adding amantadine (AMD) to DASP-β-CD supramolecular system, AMD molecules would compete with DASP for the cavity site, leading to the destroy of DASP-β-CD intermolecular inclusion complex and disassembly of supramolecular aggregates. Moreover, this AMD-induced collapse of DASP-β-CD intermolecular inclusion complex would also result in the decrease of fluorescence intensity of DASP-β-CD. Based on this, a simple fluorescent assay for the detection of AMD was proposed. This approach provides a rapid, sensitive and selective method for AMD detection and may help designing other cyclodextrin-based sensing strategies for medical analysis and environmental monitoring.

A supramolecular system mimicking the infection process of an enveloped virus through membrane fusion

Membrane fusion is an essential step for the entry of enveloped viruses, such as human immunodeficiency virus and influenza virus, into the host cell, often triggered by the binding of membrane proteins on the viral envelope to host cell membrane. Recently, external stimuli was shown to trigger membrane fusion in an artificial system. Direct observation of artificial membrane fusion using a giant unilamellar vesicle (GUV), which is similar in size to a cell, is useful as a biological model system. However, there are no model systems for studying membrane fusion of enveloped viruses with host cells. Here, we report a supramolecular model system for viral entry into a GUV or cell through membrane fusion. The system was constructed by complexing a cationic lipid bilayer on an anionic artificial viral capsid, self-assembled from viral β-annulus peptides. We demonstrate that the cationic enveloped artificial viral capsid electrostatically interacts with the anionic GUV or cell, and the capsid enters the GUV or cell through membrane fusion. The model system established in this study will be important for analyzing membrane fusion during infection of a natural virus.

Dispersion Interactions in Condensed Phases and inside Molecular Containers.

ConspectusThe past decade has seen significant progress in the understanding and appreciation of the importance of London dispersion interactions (LDIs) in supramolecular systems and solutions. The Slater-Kirkwood formula relates LDIs to the molecular polarizabilities of the two interacting molecular species (α) and their interaction distance (a dependence of R-6). When advancing arguments related to intermolecular interactions, it is frequently assumed that molecules with larger molecular polarizabilities are more amenable to larger LDIs. However, arguments related to molecular polarizabilities are not always transferable to the condensed phase. In fact, the underlying bulk and molecular polarizabilities of common solvents show opposing trends. The intuitive concept that aromatic molecules are more polarizable than saturated hydrocarbons and that perfluorinated molecules are less polarizable than saturated hydrocarbons applies to the condensed phase only. When treating association phenomena in solution, where LDIs are generally very attenuated, the use of bulk polarizabilities is recommended, which are experimentally accessible through either refractive index measurements or suitable solvatochromic probes. Such probes can also be used to assess polarizabilities inside molecular container compounds, such as cucurbit[n]urils (CBn), cyclodextrins, calixarenes, and hemicarcerands. These macrocyclic cavities can have extreme microenvironments. For example, the inner concave phase of CB7 has been shown to be weakly polarizable, falling in between the gas phase and perfluorohexane; those of β-cyclodextrin and p-sulfonatocalix[4]arene have been found to be similarly polarizable as water and alkanes, respectively, and the inside of hemicarcerands displays a very large bulk polarizability, exceeding that of diiodomethane. CBn compounds are privileged molecular container compounds, which we exemplify in this Account through case studies. (1) CBn macrocycles are prime water-soluble receptors for hydrocarbons, allowing for the reduction of the binding free energies to two components: the hydrophobic effect and dispersion interactions. To understand hydrocarbon binding, we initiated the HYDROPHOBE challenge, which revealed the shortcomings of both quantum-chemical and molecular dynamics approaches. (2) The smallest CBn receptor, CB5, is uniquely suited to bind the entire noble gas series, where hydrophobic effects and dispersion interactions operate in opposite directions. CB5 was revaled to be a unique synthetic receptor for noble gases, with the dominant driving force being the recovery of the cavitation energies for the hydration of noble gases in aqueous solution. Computational methods that encounter challenges in predicting hydrocarbon affinities and trends for CB6 and CB7 perform well for noble gases binding to CB5. (3) The larger homologue, CB8, allows one to set up intermolecular interaction chambers by the encapsulation of a (first) aromatic guest, thereby tuning LDIs inside the receptor cavity. In this manner, CB8 can be modulated to preferentially bind unsaturated and aromatic rather than saturated hydrocarbons, while the unmodified cavities of the smaller macrocycles CB6 and CB7 show selective binding of saturated hydrocarbons. (4) The (charged) host-guest complexes of CBn hosts are sufficiently stable in the gas phase, allowing for the study of the influence of LDIs on inner-phase chemical reactions. These studies are particularly interesting for the theoretical analysis of isolated host-guest LDIs, as experimental and computational data are directly comparable in the gas phase due to the absence of the solvation effect.

Recognizing New Types of Stacking Interactions by Analyzing Data in the Cambridge Structural Database

Cambridge Structural Database (CSD) is the largest repository of crystal data, containing over 1.2 million crystal structures of organic, metal–organic and organometallic compounds. It is a powerful research tool in many areas, including the extensive studying of noncovalent interactions. In this review, we show how a thorough analysis of CSD crystal data resulted in recognition of novel types of stacking interactions. Even though stacking interactions were traditionally related to aromatic systems, a number of crystallographic studies have shown that nonaromatic metal–chelate rings, as well as hydrogen-bridged rings, can also form stacking interactions. Joined efforts of a CSD analysis and quantum chemical calculations showed that these new stacking interactions are stronger than stacking interactions of aromatic species and recognized them as very important attractive forces in numerous supramolecular systems.

Morphological Evaluation of Supramolecular Soft Materials Obtained through Co-Assembly Processes.

Low-molecular-weight gelators (LMWGs) are compounds with an intrinsic tendency to self-assemble forming various supramolecular architectures via non-covalent interactions. Considering that the development of supramolecular assemblies through the synergy of molecules is not entirely understood at the molecular level, this study introduced a Fmoc-short peptide and four Fmoc-amino acids as building blocks for the self-assembly/co-assembly process. Hence, we investigated the formation of supramolecular gels starting from the molecular aggregation following two triggering approaches: solvent/co-solvent method and pH switch. The complex morphological analysis (POM, AFM, and STEM) offered an insight into the spontaneous formation of well-ordered nanoaggregates. Briefly, POM and AFM images demonstrated that self-assembled gels present various morphologies like dendrimer, spherulite, and vesicle, whereas all co-assembled supramolecular systems exhibit fibrillar morphologies as a result of the interaction between co-partners of each system. STEM study has confirmed that the molecules interact and join together, finally forming a fibrous network, an aspect seen in both self-assembled and co-assembled gels. XRD allowed the determination of the molecular arrangement. The study emphasized that the Fmoc motif protected the amino groups and facilitated gelation through additional π-π interactions.

A new sensitization strategy for achieving organic RTP in aqueous solution: tunable RTP and UC emission in supramolecular TTA-UC systems

A new sensitization strategy for achieving organic RTP in aqueous solution: tunable RTP and UC emission in supramolecular TTA-UC systems

Importance of the Amino Moiety of the Hydrazone Group in the Electrochemical and UV‐Vis Absorption Properties of Simple Isomeric Hydrazones

AbstractThe development of new useful supramolecular systems, as well as the optimization of existing ones, depends on the understanding of the intrinsic properties of each of the components that constitute them. A representative component of supramolecular systems are hydrazones, which can undergo three different, orthogonal dynamic processes (conformational, constitutional, and configurational) thanks to the leading role played by the amino‐like moiety of their hydrazone groups. Herein, we study the electrochemical and UV‐Vis absorption properties of two structurally related pyridylhydrazones in different solvents and analyze them in terms of the chemical environment of the corresponding hydrazone group. In this way, we establish that both the electrochemical and UV‐Vis absorption properties are mainly dominated by the additional polarization of the N−H bond, i. e., by the electron density around the nitrogen atom.

A newly fascinating approach to construct pillar[5]arene functionalized ester derivatives for nematic liquid crystalline behavior

A Pillar[5]arene linked 4-n-alkoxy benzoic acid based multifunctional supramolecular systems ((PB1-PB4) with variable alkyl chains were synthesized and well characterized. The microscopic and thermal behaviors of the compounds were investigated by using POM, DSC, and TGA analysis. All four pillar[5]arene-ester based macrocyclic compounds display nematic type mesomorphic properties, with a well-known schlieren and droplets type texture pattern observed in all four ten-side substituted pillarene derivatives. All four materials exhibit enantiotropic mesogenic behavior with a wide temperature range and thermal stability. The material with higher alkyl chain exhibit nematic phase at lower temperatures compared to materials with lower alkyl chain substitutions. Furthermore, we have investigated the structure property relationship to understand the influence of substitution on the rigid core of pillar[5]arene and its ability to induce different types of liquid crystalline behaviors.

Pillar[5]arene-Based Fluorescent Supramolecular Polymers Without Conventional Chromophores.

Fluorescent supramolecular polymers have garnered significant attention due to their successful integration of supramolecular polymers and fluorescence, offering vast potential for applications in sensing, imaging, optoelectronics, and photonics. In this study, we present a novel supramolecular polymer based on P5-OH, derived from mono-substituted pillararene macrocycles. Notably, these formed supramolecular polymeric aggregates exhibit a prominent blue emission, representing a rare instance of fluorescent polymers devoid of conventional chromophores. Furthermore, through the modification of alkyl chain ending groups attached to pillar[5]arenes, slight shifts in the emission peak could be observed. This research expands the scope of functional supramolecular polymeric systems utilizing pillararenes, providing valuable insights for the design of innovative luminescent materials and optical devices.

Thixotropic Hydrogels Based on Laponite® and Cucurbituril for Delivery of Lipophilic Drug Molecules.

Invited for this month's cover are the collaborating groups of Prof. Serena Riela at University of Catania, Prof. César Viseras at University of Granada and Dr. Ignacio Sainz-Diaz at Instituto Andaluz de Ciencias de la Tierra. The cover picture shows the possible application of the developed system. In particular, flufenamic acid, anti-inflammatory and anti-pyretic drug, was complexed into cucurbituril cavity and the supramolecular system obtained was used as filler for laponite® hydrogel for its topical delivery. More information can be found in the Research Article by Viseras-Iborra, Riela, and co-workers.