Thermoresponsive and Supramolecular Polymers: Interesting Biomaterials for Drug Delivery.

How to use and deliver drugs to diseased and damaged areas has been one of the main concerns of pharmacologists and doctors for a long time. With the efforts of researchers, the advancement of technology, and the involvement of engineering in the health field, diverse and promising approaches have been studied and used to achieve this goal. A better understanding of biomaterials and the ability of production equipment led researchers to offer new drug delivery systems to the world. In recent decades, responsive polymers (exclusively to temperature and pH) and supramolecular polymers have received much attention due to their unique capabilities. Although this field of research still needs to be scrutinized and studied more, their recognition, examination, and use as drug delivery systems is a start for a promising future. This review study, focusing on temperature-responsive and supramolecular biomaterials and their application as drug delivery systems, deals with their structure, properties, and role in the noninvasive and effective delivery of medicinal agents.

Orthogonal Phase Transfer of Oppositely Charged FeII4L6 Cages.

Coordination cages and their encapsulated cargo can be manoeuvred between immiscible liquid layers in a process referred to as phase transfer. Among the stimuli reported to drive phase transfer, counterion exchange is the most widespread. This method exploits the principle that counterions contribute strongly to the solubility preferences of coordination cages, and involves exchanging hydrophilic and hydrophobic counterions. Nevertheless, phase transfer of anionic cages remains relatively unexplored, as does selective phase transfer of individual cages from mixtures. Here we compare the phase transfer behaviour of two FeII4L6 cages with the same size and geometry, but with opposite charges. As such, this study presents a rare example wherein an anionic cage undergoes phase transfer upon countercation exchange. We then combine these two cages, and demonstrate that their quantitative separation can be achieved by inducing selective phase transfer of either cage. These results represent unprecedented control over the movement of coordination cages between different physical compartments, and are anticipated to inform the development of next-generation supramolecular systems.

Artificial Lithium Channels Built from Polymers with Intrinsic Microporosity.

In sharp contrast to numerous artificial potassium channels developed over the past decade, the study of artificial lithium-transporting channels has remained limited. We demonstrate here the use of an interesting class of polymers with intrinsic microporosity (PIM) for constructing artificial lithium channels. These PIM-derived lithium channels show exceptionally efficient (γLi+ > 40 pS) and highly selective transport of Li+ ions, with selectivity factors of > 10 against both Na+ and K+. By simply adjusting the initial reaction temperature, we can tune the transport property in a way that PIMs synthesized at initial reaction temperatures of 60 °C and 80°C exhibit improved transport efficiency and selectivity, respectively, in the dioleoyl phosphatidylcholine  membrane.

Ultra-High Metal-Ions Selectivity Induced by Intramolecular Cation-π Interaction for the One-Pot Synthesis of Precise Heterometallic Architecture.

Heterometallic supramolecules, known for their unique synergistic effects, have shown broad applications in photochemistry, host-guest chemistry, and catalysis. However, there are great challenges to precisely construct heterometallic supramolecules rather than statistical mixture, due to the limited metal-ions selectivity of coordination units. Especially, heterometallic architectures precisely encoding with different metal ions usually fail to obtain in one-pot method when only one type of coordinated motif exists due to its poor metal-ion selectivity. Herein, we proposed an effective intramolecular cation-π (ICπ) strategy and successfully constructed the heterometallic supramolecule Zn2Cu4L34 by one-pot self-assembly of tritopic terpyridyl ligand L3 with Zn(II) and Cu(II), following the clear self-assembly mechanism that only thermodynamic dimers ZnL12 and Cu2L22 were constructed with model ligands L1, L2, Zn(II) and Cu(II) with perfect self-sorting and ultra-high metal-selectivity feature. The successful construction of the heterometallic supramolecule Zn2Cu4L34, encoding the definite sequence of metal ions Zn(II) and Cu(II) in one-pot method, will offer a novel approach to precisely construct heterometallic architectures.

Conformational Changes and Coordination Stability of Flexible Tripeptides During Ni(II)-Mediated Self-Assembly.

The rational design of artificial supramolecular structures with specific properties and functions hinges the comprehensive understanding of the coordination and noncovalent interactions driving self-assembly. Herein, the self-assembly of supramolecular systems through octahedral coordination between Ni(II) ions and a flexible tripeptide was theoretically investigated using quantum chemical calculations. These calculations utilized the B3LYP functional with the polarizable continuum model. Our results indicate that tridentate sites have a greater propensity for coordination, and that the presence of chloride anions and conformational shifts enhance bidentate and monodentate coordination. Insights into the effect of counter anions on the stability of octahedral coordination and the prerequisites for self-assembly were gained by determining the stable conformation and potential reaction pathways of the tripeptide before and after adding chloride anions through an efficient automated conformational search. The formation of intramolecular hydrogen bonding interactions during the conformational changes was also studied using model calculations. Possible processes for initial self-assembly of tripeptide were proposed. This study enhances the fundamental understanding of the conformational behavior of building blocks during supramolecular formation and advance the potential for constructing future bioinspired complexes.

Sensitive Coatings Based on Molecular-Imprinted Polymers for Triazine Pesticides' Detection.

Triazine pesticide (atrazine and its derivatives) detection sensors have been developed to thoroughly check for the presence of these chemicals and ultimately prevent their exposure to humans. Sensitive coatings were designed by utilizing molecular imprinting technology, which aims to create artificial receptors for the detection of chlorotriazine pesticides with gravimetric transducers. Initially, imprinted polymers were developed, using acrylate and methacrylate monomers containing hydrophilic and hydrophobic side chains, specifically for atrazine, which shares a basic heterocyclic triazine structure with its structural analogs. By adjusting the ratio of the acid to the cross-linker and introducing acrylate ester as a copolymer, optimal non-covalent interactions were achieved with the hydrophobic core of triazine molecules and their amino groups. A maximum sensor response of 546 Hz (frequency shift/layer height equal to 87.36) was observed for a sensitive coating composed of 46% methacrylic acid and 54% ethylene glycol dimethacrylate, with a demonstrated layer height of 250 nm (6.25 kHz). The molecularly imprinted copolymer demonstrated fully reversible sensor responses, not only for atrazine but also for its metabolites, like des-ethyl atrazine, and structural analogs, such as propazine and terbuthylazine. The efficiency of modified molecularly imprinted polymers for targeted analytes was tested by combining them with a universally applicable quartz crystal microbalance transducer. The stable selectivity pattern of the developed sensor provides an excellent basis for a pattern recognition procedure.

Synergetic Effect of ß-Cyclodextrin and Its Simple Carbohydrate Substituents on Complexation of Folic Acid and Its Structural Analog Methotrexate.

Folic acid (FA) and its structural analog, anticancer medicine methotrexate (MTX), are known to form host/guest complexes with native cyclodextrins, of which the most stable are formed with the medium-sized ß-cyclodextrin. Based on our research, proving that simple sugars (D-glucose, D-galactose, and D-mannose) can form adducts with folic acid, we envisioned that combining these two types of molecular receptors (cyclodextrin and simple carbohydrates) into one may be beneficial for the complexation of FA and MTX. We designed and obtained host/guest inclusion complexes of FA and MTX with two monoderivatives of ß-cyclodextrin-substituted at position 6 with monosaccharide (glucose, G-ß-CD) and disaccharide (maltose, Ma-ß-CD). The complexation was proved by experimental (NMR, UV-vis, IR, TG, DSC) and theoretical methods. We proved that derivatization of ß-cyclodextrin with glucose and maltose has a significant impact on the complexation with FA and MTX, as the addition of one glucose subunit to the structure of the receptor significantly increases the value of association constant for both FA/G-ß-CD and MTX/G-ß-CD, while further extending a pendant chain (incorporation of maltose subunit) results in no additional changes.

Formation and Stability of Benzylic Amide [2]- and [3]Rotaxanes: an Intercomponent Interactions Study.

One of the most recent focuses in supramolecular chemistry is developing molecules designed to exhibit programmable properties at the molecular level. Rotaxanes, which function as molecular machines with movements controlled by external stimuli, are prime candidates for this purpose. However, the controlled synthesis of rotaxanes, especially amide-benzylic rotaxanes with more than two components, remains an area ripe for exploration. In this study, we aim to elucidate the formation of amide-benzylic [3]rotaxanes using a thread that includes a conventional succinamide station and an innovative triazole-carbonyl station. Including the triazole-carbonyl station introduces new perspectives into the chemistry of rotaxanes, influencing their conformation and dynamics. The synthesis of two-station rotaxanes with varying stoppers demonstrated that the macrocycle consistently occupies the succinamide station, providing greater stability as evidenced by NMR and SC-XRD analyses. The presence of a triazole-carbonyl station facilitated the formation of a second macrocycle exclusively when a secondary amide was employed as the stopper group, presumably due to decreased steric hindrance. Moreover, the second macrocycle directly forms at the triazole-carbonyl station. This investigation reveals that slight modifications in the thread structure can dramatically impact the formation, stability, and interactions between components of rotaxanes.

Nanohoops Favour Light-Induced Energy Transfer over Charge Separation in Porphyrin/[10]CPP/Fullerene Rotaxanes.

[2]Rotaxanes offer unique opportunities for studying and modulating charge separation and energy transfer, because the mechanical bond allows the robust, yet spatially dynamic tethering of photoactive groups. In this work, we synthesized [2]rotaxane triads comprising a central (aza)[10]CPP⊃C60 bis-adduct complex and two zinc porphyrin stoppers to address how the movable nanohoop affects light-induced charge separation and energy transfer between the rotaxane subcomponents. We found that neither the parent nanohoop [10]CPP nor its electron-deficient analogue aza[10]CPP actively participate in charge separation. In contrast, the nanohoops completely prevented through-space charge separation. This result is likely due to supramolecular "shielding", because charge separation was observed in the thread that acted as reference dyad. On the other hand, the suppression of charge transfer allowed the observation of energy transfer from the porphyrin triplet to the fullerene triplet state with a lifetime of ca. 25 ms. The presence of the interlocked nanohoops therefore leads to a dramatic switch between charge separation and energy transfer. We suggest that our results explain observations made by others in photovoltaic devices comprising nanohoops and may pave the way toward strategic uses of mechanically interlocked architectures in devices that feature (triplet) energy transfer.

Switching Sides: Regiochemistry and Functionalization Dictate the Photoswitching Properties of Imines.

Photoswitchable imines demonstrate light-dependent dynamic covalent chemistry and can function as molecular ratchets. However, the design of aryliminopyrazoles (AIPs) has been limited to N-pyrazole derivatives with ortho-pyrrolidine motifs. The impact of other functionalization patterns on the photoswitching properties remains unknown. Here, we present a systematic structure-property analysis and study how the photoswitching properties can be tuned through ortho- and para-functionalization of the phenyl ring in N-pyrazole and N-phenyl AIPs. This study establishes the first set of design rules for these AIP photoswitches and reports the most stable Z-isomer of an AIP to date, enabling its crystallization and resulting in the first reported crystal structure of a metastable Z-aldimine. Finally, we demonstrate that the AIPs are promising candidates for photoswitching in the condensed phase.

An Ultrasound-Activated Supramolecular Modulator Enhancing Autophagy to Prevent Ventricular Arrythmias Post-Myocardial Infarction.

Ventricular arrhythmias (VAs) triggered by myocardial infarction (MI) are the leading cause of sudden cardiac mortality worldwide. Current therapeutic strategies for managing MI-induced VAs, such as left stellate ganglion resection and ablation, are suboptimal, highlighting the need to explore safer and more effective intervention strategies. Herein, we rationally designed two supramolecular sonosensitizers RuA and RuB, engineered through acceptor modification to generate moderate reactive oxygen species (ROS) to modulate VAs. Both RuA and RuB demonstrated high ultrasound (US)-activated ROS production efficiency, with singlet oxygen (1O2) quantum yield (ΦΔ) of 0.70 and 0.88, respectively, surpassing ligand IR1105 and the conventional sonosensitizer ICG (ΦΔ =0.40). In vitro, RuB, at a modest concentration and under US intensity notably boosts pro-survival autophagy in microglia BV2 cell. To improve in vivo stability and biocompatibility, RuB was further encapsulated into DSPE-PEG5000 to prepare RuB NPs. In vivo studies after microinjection of RuB NPs into the paraventricular nucleus and subsequent US exposure, demonstrated that RuB NPs-mediated US modulation effectively suppresses sympathetic nervous activity (SNA) and inflammatory responses, thereby preventing VAs. Importantly, no tissue injury was observed post RuB NPs-mediated US modulation. This work pioneers the design of long-wave emission supramolecular sonosensitizers, offering new insights into regulating cardiovascular diseases.

Probing Noncovalent Interaction Strengths of Host-Guest Complexes Using Negative Ion Photoelectron Spectroscopy.

Noncovalent interactions (NCIs) are crucial for the formation and stability of host-guest complexes, which have wide-ranging implications across various fields, including biology, chemistry, materials science, pharmaceuticals, and environmental science. However, since NCIs are relatively weak and sensitive to bulk perturbation, direct and accurate measurement of their absolute strength has always been a significant challenge. This concept article aims to demonstrate the gas-phase electrospray ionization (ESI)-negative ion photoelectron spectroscopy (NIPES) as a direct and precise technique to measure the absolute interaction strength, probe nature of NCIs, and reveal the electronic structural information for host-guest complexes. Our recent studies in investigating various host-guest complexes that involve various types of NCIs such as anion-π, (di)hydrogen bonding, charge-separated ionic interactions, are overviewed. Finally, a summary and outlook are provided for this field.

Metallo-Supramolecular Helicates as Surface-Enhanced Raman Scattering (SERS) Substrates with High Tailorability.

The exploration of novel functionalized supramolecular coordination complexes (SCCs) can enable new applications in domains that include purification and sensing. In this study, employing a coordination-driven self-assembly strategy, we designed and prepared a series of benzochalcogenodiazole-based metallohelicates as high-efficiency charge transfer surface-enhanced Raman scattering (SERS) substrates, expanding the range of applications for these metallohelicates. Through structural modifications, including the substitution of single heteroatoms on ligands, replacement of coordinating metals, and alteration of ligand framework linkages, the Raman performance of these metallohelicates as substrates were systematically optimized. Notably, the SERS enhancement factors (EFs) of the metallohelicate-based SERS substrates were significantly enhanced to levels as high as 1.03 × 107, which rivals the EFs of noble metals devoid of "hot spots". Additionally, the underlying Raman enhancement mechanisms of these metallohelicates have been investigated through a combination of control experiments and theoretical calculations. This study not only demonstrates the utility of metallohelicates as SERS substrates but also offers insights and materials for the development of high-efficiency new charge transfer SERS substrates.

Generation of Triplet States by Host-Stabilized Through-Space Conjugation for the Construction of Efficient Supramolecular Photocatalysts.

Promoting the generation of triplet states is essential for developing efficient photocatalytic systems. This research presents a novel approach of host-stabilized through-space conjugation via the combination of covalent and non-covalent methods. The designed building block, 4,4'-(1,4(1,4)-dibenzene cyclohexaphane-1,4-diyl)bis(1-phenylpyridinium) chloride, features inherently stable through-space conjugation. When this block forms a 1:1 host-guest complex with cucurbit[8]uril, the through-space conjugation is further stabilized within the confined cavity. Both the generation and lifetime of triplet state are significantly increased, resulting from the host-stabilized through-space conjugation. Additionally, the ultrahigh binding constant of 6.58 × 1014 M-1 ensures the persistence of host-stabilization effect. As a result, the host-guest complex acts as a highly efficient catalyst in the photocatalytic oxidation of thioether and aromatic alcohol. In the photodegradation of lignin, a complex natural product, the host-guest complex also exhibits high efficiency, demonstrating its robustness. This line of research is anticipated to enrich the toolbox of supramolecular photochemistry and provide a strategy for fabricating efficient supramolecular photocatalysts.

Simultaneous Cycloadditions in the Solid State via Supramolecular Assembly.

Chemical reactions conducted in the solid phase (specifically, crystalline) are much less numerous than solution reactions, primarily due to reduced motion, flexibility, and reactivity. The main advantage of crystalline-state transformations is that reactant molecules can be designed to self-assemble into specific spatial arrangements, often leading to high control over product regiochemistry and/or stereochemistry. In crystalline-phase transformations, typically only one type of reaction occurs, and a sacrificial template molecule is frequently used to facilitate self-assembly, similar to a catalyst or enzyme. Here, we demonstrate the first system designed to undergo two chemically unique and orthogonal cycloaddition reactions simultaneously within a single crystalline solid. Well-controlled supramolecular self-assembly of two molecules containing different reactive moieties affords orthogonal reactivity without use of a sacrificial template. Using only UV light, the simultaneous [2+2] and [4+4] cycloadditions are achieved regiospecifically, stereospecifically, and products are obtained in high yield, whereas a simultaneous solution-state reaction affords a mixture of isomers in low yield. Application of dually-reactive systems toward (supra)molecular solar thermal storage materials is also discussed. This work demonstrates fundamental chemical approaches for orthogonal reactivity in the crystalline state and highlights the complexity and reversibility that can be achieved with supramolecular design.

Structure-Activity Relationships in Supramolecular Hosts Targeting Bacterial Phosphatidylethanolamine (PE) Lipids.

The World Health Organization has described the antimicrobial resistance crisis as one of the top ten global public health threats. New antimicrobial agents that can fight infections caused by antimicrobial resistant pathogens are therefore needed. A potential strategy is the development of small molecules that can selectively interact with bacterial membranes (or membranes of other microbial pathogens), and thereby rapidly kill the bacteria. Here, we report the structure-activity relationship within a group of 22 compounds that were designed to bind the bacterial lipid phosphatidylethanolamine (PE). Liposome-based studies reveal that the lipophilicity of the compounds has the strongest effect on both the affinity and selectivity for PE. The best results were obtained for compounds with logP ≈ 3.75, which showed a 5x to 7x selectivity for bacterial PE lipids over human PC (phosphatidylcholine) lipids. Furthermore, these compounds also showed potent antibacterial activity against the Gram-positive bacterium B. cereus, with minimum inhibitory concentrations (MICs) below 10 µM, a concentration where they showed minimal hemolytic activity against human red blood cells. These results not only show the possibility of PE-binding small molecules to function as antibiotics, but also provide guidelines for the development of compounds targeting other types of biologically relevant membrane lipids.

Controlling the Helical Pitch of Foldamers Through Terminal Functionality: A Solid State Study.

Developing new methods to control the size and shape of the helical structures adopted by foldamers is highly important as the secondary structure displayed by these supramolecular scaffolds often dictates their activity and function. Herein, we report on a systematic study demonstrating that the helical pitch of ortho-azobenzene/2,6-pyridyldicarboamide foldamers can be readily controlled through the nature of the terminal functionality. Remarkably, simply through varying the end group of the foldamer, and without modifying any other structural features of the scaffold, the helical pitch can be over doubled in magnitude (from 3.4 Å to 7.3 Å). Additionally, crystallographic analysis of a library ten foldamers has identified general trends in the influence of a range of terminal functionalities, including carboxylbenzyl (Cbz), diphenylcarbamyl (N(Ph)2), ferrocene (Fc) and tert-butyloxycarbonyl (Boc), in controlling the folding behaviour of these supramolecular scaffolds. These studies could prove useful in the future development of functional foldamers which adopt specific sizes and shapes.

Effect of Terminal Hydroxy Groups on the Structural Properties of Acyl Thioureas.

The 1-acyl thiourea family [R1C(O)NHC(S)NR2R3] exhibits the flexibility to incorporate a wide variety of substituents into their structure. The structural attributes of these compounds are intricately tied to the type and extent of substitution. In the case of 3-mono-substituted thioureas (R2=H), the conformational behavior is predominantly shaped by the presence of an intramolecular N-H ⋅ ⋅ ⋅ O=C hydrogen bond. This study delves into the structural consequences stemming from the inclusion of substituents possessing hydrogen-donor capabilities within four novel 1-acyl-3-mono-substituted thiourea derivatives. A comprehensive suite of analytical techniques, encompassing FTIR, Raman spectroscopy, multinuclear (1H and 13C) NMR spectroscopy, single-crystal X-ray diffraction, and supported by computational methods, notably NBO (Natural Bond Orbital) population analysis, Hirshfeld analysis, and QTAIM (Quantum Theory of Atoms in Molecules), was harnessed to scrutinize and characterize these compounds. In the crystalline state, these compounds exhibit an intricate interplay of intermolecular interactions, prominently featuring an expansive network of hydrogen bonds between the hydroxy (-OH) groups and the carbonyl and thiocarbonyl bonds within the 1-acyl thiourea fragment. Notably, the topological analysis underscores significant distinctions in the properties of the acyl thiourea fragment and the intramolecular >C=O ⋅ ⋅ ⋅ H-N bond when transitioning from the isolated molecule to the crystalline environment.

Light-Powered Propeller-like Transporter for Boosted Transmembrane Ion Transport.

Membrane-active molecular machines represent a recently emerging, yet important line of expansion in the field of artificial transmembrane transporters. Their hitherto demonstrated limited types (molecular swing, ion fishers, shuttlers, rotors, etc.) certainly call for new inspiring developments. Here, we report a very first motorized ion-transporting carrier-type transporter, i.e., a modularly tunable, light-powered propeller-like transporter derived from Feringa's molecular motor for consistently boosting transmembrane ion transport under continuous UV light irradiation. Based on the EC50 values, the molecular propeller-mediated ion transport activities under UV light irradiation for 300 s are 2.31, 1.74, 2.29, 2.80, and 2.92 times those values obtained without irradiation for Li+, Na+, K+, Rb+, and Cs+ ions, respectively, with EC50 value as low as 0.71 mol % for K+ ion under light irradiation.

Esterase-Responsive Floxuridine-Tethered Multifunctional Nanoparticles for Targeted Cancer Therapy.

Floxuridine is a potential clinical anticancer drug for the treatment of various cancers. However, floxuridine typically causes unfavorable side effects due to its very poor tumor selectivity, and, hence, there is a high demand for the development of novel approaches that permit the targeted delivery of floxuridine into cancerous cells. Herein, the design and synthesis of an esterase-responsive multifunctional nanoformulation for the targeted delivery of floxuridine in esterase-overexpressed cancer cells is reported. Photopolymerization of floxuridine-tethered lipoic acid results in the formation of amphiphilic floxuridine-tethered poly(disulfide). Self-assembly of the amphiphilic polymer results in the formation of nanoparticles with floxuridine decorated on the surfaces of the particles. Integration of aptamer DNA for nucleolin onto the surface of the nanoparticle is demonstrated by exploring the base-pairing interaction of floxuridine with adenine. Targeted internalization of the aptamer-decorated nanoparticle into nucleolin-expressed cancer cells is demonstrated. Esterase triggered cleavage of the ester bond connecting floxuridine with the polymer backbone, and the subsequent targeted delivery of floxuridine into cancer cells is also shown. Excellent therapeutic efficacy is observed both in vitro and also in the 3D tumor spheroid model. This noncovalent strategy provides a simple yet effective strategy for the targeted delivery of floxuridine into cancer cells in a less laborious fashion.