Supramolecular Sensor Research Articles

Array‐Based Discrimination of Phenolic Acids in Water at Near‐Neutral pH with Chromogenic and Fluorescent Cyclodextrin‐Based Supramolecular Sensors

AbstractPhenolic acids are a class of poorly water‐soluble organic compounds with antioxidant properties that contain a carboxylic acid and a phenol group, common in plants. We used hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) as a supramolecular host to sense phenolic acids in water near physiological pH. The analytes’ complexation was monitored through changes in the optical absorption and emission properties of a series of six organic dyes, acting as indicators in a displacement assay, that were selected from screening a panel of 17 candidates. Binding constants between these dyes and the HP‐β‐CD were in the 102–104 range. We showed that the nuanced differences in the dyes’ optical signatures associated with this displacement process, when analyzed and summarized using multivariate analysis algorithms such as principal component analysis (PCA), can be used to successfully discriminate among six phenolic acids, and to identify six unknown samples of such acids, down to a 0.02 mM concentration.

A facile way to construct sensor array library via supramolecular chemistry for discriminating complex systems

Differential sensing, which discriminates analytes via pattern recognition by sensor arrays, plays an important role in our understanding of many chemical and biological systems. However, it remains challenging to develop new methods to build a sensor unit library without incurring a high workload of synthesis. Herein, we propose a supramolecular approach to construct a sensor unit library by taking full advantage of recognition and assembly. Ten sensor arrays are developed by replacing the building block combinations, adjusting the ratio between system components, and changing the environment. Using proteins as model analytes, we examine the discriminative abilities of these supramolecular sensor arrays. Then the practical applicability for discriminating complex analytes is further demonstrated using honey as an example. This sensor array construction strategy is simple, tunable, and capable of developing many sensor units with as few syntheses as possible.

Proton-Gradient-Driven Sensitivity Enhancement of Liposome-Encapsulated Supramolecular Chemosensors.

An overarching challenge in the development of supramolecular sensor systems is to enhance their sensitivity, which commonly involves the synthesis of refined receptors with increased affinity to the analyte. We show that a dramatic sensitivity increase by 1–2 orders of magnitude can be achieved by encapsulating supramolecular chemosensors inside liposomes and exposing them to a pH gradient across the lipid bilayer membrane. This causes an imbalance of the influx and efflux rates of basic and acidic analytes leading to a significantly increased concentration of the analyte in the liposome interior. The utility of our liposome‐enhanced sensors was demonstrated with various host–dye reporter pairs and sensing mechanisms, and we could easily increase the sensitivity towards multiple biologically relevant analytes, including the neurotransmitters serotonin and tryptamine.

A Fluorescent Cage for Supramolecular Sensing of 3‐Nitrotyrosine in Human Blood Serum

Abstract3‐Nitrotyrosine (NT) is generated by the action of peroxynitrite and other reactive nitrogen species (RNS), and as a consequence it is accumulated in inflammation‐associated conditions. This is particularly relevant in kidney disease, where NT concentration in blood is considerably high. Therefore, NT is a crucial biomarker of renal damage, although it has been underestimated in clinical diagnosis due to the lack of an appropriate sensing method. Herein we report the first fluorescent supramolecular sensor for such a relevant compound: Fluorescence by rotational restriction of tetraphenylethenes (TPE) in a covalent cage is selectively quenched in human blood serum by 3‐nitrotyrosine (NT) that binds to the cage with high affinity, allowing a limit of detection within the reported physiological concentrations of NT in chronic kidney disease.

A Fluorescent Cage for Supramolecular Sensing of 3-Nitrotyrosine in Human Blood Serum.

3‐Nitrotyrosine (NT) is generated by the action of peroxynitrite and other reactive nitrogen species (RNS), and as a consequence it is accumulated in inflammation‐associated conditions. This is particularly relevant in kidney disease, where NT concentration in blood is considerably high. Therefore, NT is a crucial biomarker of renal damage, although it has been underestimated in clinical diagnosis due to the lack of an appropriate sensing method. Herein we report the first fluorescent supramolecular sensor for such a relevant compound: Fluorescence by rotational restriction of tetraphenylethenes (TPE) in a covalent cage is selectively quenched in human blood serum by 3‐nitrotyrosine (NT) that binds to the cage with high affinity, allowing a limit of detection within the reported physiological concentrations of NT in chronic kidney disease.

A combination of a graphene quantum dots-cationic red dye donor-acceptor pair and cucurbit[7]uril as a supramolecular sensor for ultrasensitive detection of cancer biomarkers spermine and spermidine.

In a unique approach, the combination of a donor-acceptor pair of hydroxy graphene quantum dots (GQDs-OH) and a red-emissive donor-two-acceptor (D-2-A) type dye with pyridinium units (BPBP) and the well-known host cucurbit[7]uril (CB[7]) has been exploited as a supramolecular sensing assembly for the detection of cancer biomarkers spermine and spermidine in aqueous media at the sub-ppb level based on the affinity-driven exchange of guests from the CB[7] portal. In the binary conjugate, green fluorescent GQDs-OH transfers energy to trigger the emission of the dye BPBP and itself remains in the turn-off state. CB[7] withdraws the dye from the surface of GQDs-OH by strong host-guest interactions with its portal, making GQDs-OH fluoresce again to produce a ratiometric response. In the presence of spermine (SP) or spermidine (SPD), their strong affinity with CB[7] forces the ejection of the fluorophore to settle on the GQDs-OH surface, and the strong green emission of GQDs-OH turns off to device a supramolecular sensor for the detection of SP/SPD. The DFT studies revealed interesting excited-state charge-transfer conjugate formation between BPBP and GQDs leading to turn-on emission of the dye, and further supported the stronger binding modes of BPBP-CB[7], indicating the retrieval of the emission of GQDs. The assembly-disassembly based sensing mechanism was also established by Job's plot analysis, particle size analysis, zeta potential, time-resolved spectroscopy, ITC studies, microscopic studies, etc. The supramolecular sensing assembly is highly selective to SP and SPD, and showed nominal interference from other biogenic amines, amino acids, various metal ions, and anions. The limits of detection (LODs) were 0.1 ppb and 0.9 ppb for spermine and spermidine, respectively. The potential for the real-world application of this sensing assembly was demonstrated by spiking SP and SPD in human urine and blood serum with a high %recovery.

A heteromultivalent host-guest sensor array for cell recognition and discrimination.

We present a supramolecular sensor array based on a series of heteromultivalent macrocyclic coassemblies using amphiphilic calixarenes and cyclodextrin as the building blocks for cell recognition. The corresponding cross-reactivity between the coassemblies and cells served as the unique fingerprint for cell classification, and successfully identified the normal cell lines, cancerous cell lines, and cross-contaminated cells.

Mathematical Modeling of a Supramolecular Assembly for Pyrophosphate Sensing.

The power of sensing molecules is often characterized in part by determining their thermodynamic/dynamic properties, in particular the binding constant of a guest to a host. In many studies, traditional nonlinear regression analysis has been used to determine the binding constants, which cannot be applied to complex systems and limits the reliability of such calculations. Supramolecular sensor systems include many interactions that make such chemical systems complicated. The challenges in creating sensing molecules can be significantly decreased through the availability of detailed mathematical models of such systems. Here, we propose uncovering accurate thermodynamic parameters of chemical reactions using better-defined mathematical modeling-fitting analysis is the key to understanding molecular assemblies and developing new bio/sensing agents. The supramolecular example we chose for this investigation is a self-assembled sensor consists of a synthesized receptor, DPA (DPA = dipicolylamine)-appended phenylboronic acid (1) in combination with Zn2+(1.Zn) that forms various assemblies with a fluorophore like alizarin red S (ARS). The self-assemblies can detect multi-phosphates like pyrophosphate (PPi) in aqueous solutions. We developed a mathematical model for the simultaneous quantitative analysis of twenty-seven intertwined interactions and reactions between the sensor (1.Zn-ARS) and the target (PPi) for the first time, relying on the Newton-Raphson algorithm. Through analyzing simulated potentiometric titration data, we describe the concurrent determination of thermodynamic parameters of the different guest-host bindings. Various values of temperatures, initial concentrations, and starting pHs were considered to predict the required measurement conditions for thermodynamic studies. Accordingly, we determined the species concentrations of different host-guest bindings in a generalized way. This way, the binding capabilities of a set of species can be quantitatively examined to systematically measure the power of the sensing system. This study shows analyzing supramolecular self-assemblies with solid mathematical models has a high potential for a better understanding of molecular interactions within complex chemical networks and developing new sensors with better sensing effects for bio-purposes.

A Data-Driven Approach to the Development and Understanding of Chiroptical Sensors for Alcohols with Remote γ-Stereocenters.

Dynamic covalent chemistry-based sensors have recently emerged as powerful tools to rapidly determine the enantiomeric excess of organic small molecules. While a bevy of sensors have been developed, those for flexible molecules with stereocenters remote to the functional group that binds the chiroptical sensor remain scarce. In this study, we develop an iterative, data-driven workflow to design and analyze a chiroptical sensor capable of assessing challenging acyclic γ-stereogenic alcohols. Following sensor optimization, the mechanism of sensing was probed with a combination of computational parametrization of the sensor molecules, statistical modeling, and high-level density functional theory (DFT) calculations. These were used to elucidate the mechanism of stereochemical recognition and revealed that competing attractive noncovalent interactions (NCIs) determine the overall performance of the sensor. It is anticipated that the data-driven workflows developed herein will be generally applicable to the development and understanding of dynamic covalent and supramolecular sensors.

Supramolecular Atropine Potentiometric Sensor

A supramolecular atropine sensor was developed, using cucurbit[6]uril as the recognition element. The solid-contact electrode is based on a polymeric membrane incorporating cucurbit[6]uril (CB[6]) as an ionophore, 2-nitrophenyl octyl ether as a solvent mediator, and potassium tetrakis (4-chlorophenyl) borate as an additive. In a MES-NaOH buffer at pH 6, the performance of the atropine sensor is characterized by a slope of (58.7 ± 0.6) mV/dec with a practical detection limit of (6.30 ± 1.62) × 10−7 mol/L and a lower limit of the linear range of (1.52 ± 0.64) × 10−6 mol/L. Selectivity coefficients were determined for different ions and excipients. The obtained results were bolstered by the docking and spectroscopic studies which demonstrated the interaction between atropine and CB[6]. The accuracy of the potentiometric analysis of atropine content in certified reference material was evaluated by the t-Student test. The herein proposed sensor answers the need for reliable methods providing better management of this hospital drug shelf-life while reducing its flush and remediation costs.

Evolution of Supramolecular Systems Towards Next-Generation Biosensors.

Supramolecular materials, which rely on dynamic non-covalent interactions, present a promising approach to advance the capabilities of currently available biosensors. The weak interactions between supramolecular monomers allow for adaptivity and responsiveness of supramolecular or self-assembling systems to external stimuli. In many cases, these characteristics improve the performance of recognition units, reporters, or signal transducers of biosensors. The facile methods for preparing supramolecular materials also allow for straightforward ways to combine them with other functional materials and create multicomponent sensors. To date, biosensors with supramolecular components are capable of not only detecting target analytes based on known ligand affinity or specific host-guest interactions, but can also be used for more complex structural detection such as chiral sensing. In this Review, we discuss the advancements in the area of biosensors, with a particular highlight on the designs of supramolecular materials employed in analytical applications over the years. We will first describe how different types of supramolecular components are currently used as recognition or reporter units for biosensors. The working mechanisms of detection and signal transduction by supramolecular systems will be presented, as well as the important hierarchical characteristics from the monomers to assemblies that contribute to selectivity and sensitivity. We will then examine how supramolecular materials are currently integrated in different types of biosensing platforms. Emerging trends and perspectives will be outlined, specifically for exploring new design and platforms that may bring supramolecular sensors a step closer towards practical use for multiplexed or differential sensing, higher throughput operations, real-time monitoring, reporting of biological function, as well as for environmental studies.

Supramolecular Sensing of Chemical Warfare Agents.

Chemical warfare agents are a class of organic molecules used as chemical weapons due to their high toxicity and lethal effects. For this reason, the fast detection of these compounds in the environment is crucial. Traditional detection methods are based on instrumental techniques, such as mass spectrometry or HPLC, however the use of molecular sensors able to change a detectable property (e. g., luminescence, color, electrical resistance) can be cheaper and faster. Today, molecular sensing of chemical warfare agents is mainly based on the "covalent approach", in which the sensor reacts with the analyte, or on the "supramolecular approach", which involves the formation of non-covalent interactions between the sensor and the analyte. This Review is focused on the recent developments of supramolecular sensors of organophosphorus chemical warfare agents (from 2013). In particular, supramolecular sensors are classified by function of the sensing mechanism: i) Lewis Acids, ii) hydrogen bonds, iii) macrocyclic hosts, iv) multi-topic sensors, v) nanosensors. It is shown how the supramolecular non-covalent approach leads to a reversible sensing and higher selectivity towards the selected analyte respect to other interfering molecules.

Organic transistor-based chemical sensors with self-assembled monolayers

Numerous artificial receptors with noncovalent bonds have been developed to date, whereas chemical sensing devices combined with these receptors have not been fully established. An organic thin-film transistor (OTFT) can potentially operate as a supramolecular sensor chip by appropriately combining it with molecular recognition parts. In this review, the attempts to fabricate devices for electrical chemical sensing utilizing a self-assembled monolayer on a gate electrode or a surface of a semiconductor layer of the OTFT are described. Self-assembled scaffolds provide multi-recognition sites, leading to selective and sensitive detection. Furthermore, the OTFT functionalized with various receptors provide comprehensive sensor platforms for multiple analytes including cations, anions, electrically neutral molecules, and proteins in aqueous media. The OTFT-based sensor successfully detected analytes with size and chemical structural dependences on self-assembled receptors. Moreover, real-time continuous detection was also accomplished by the OTFT-based sensor integrated with a microfluidic system. Thus, this concept implies a promising future for applying an easy-to-use chemical sensor in practical situations by taking advantage of well-developed supramolecular interactions.

Design of Supramolecular Sensors and Their Applications to Optical Chips and Organic Devices

Abstract In nature, molecular recognition is crucial to induce functions as living systems. Bioinspired molecular recognition chemistry has been intensively studied for more than half a century since the discovery of crown ethers. Chemical sensors are a concrete representative example of the application of artificial molecular recognition materials. The sensors have the ability to visualize the recognition phenomena and provide quantitative information on an analyte. However, developing chemical sensors that fully meet the requirements for practical application is still challenging. To this end, the author has focused on a cross-hierarchical and comprehensive development of chemical sensors based on molecular recognition chemistry and supramolecular chemistry. Through the efforts with bottom-up and top-down approaches, the author has contributed to the progress of practical supramolecular analytical chemistry which allows identification of target chemical species in real samples, and realization of sensor devices for on-site detection. This account summarizes the author’s recent achievements for chemical sensors including the design of artificial receptors, optical chemosensor arrays, and organic field-effect transistors.

Recent Development of Supramolecular Sensors Constructed by Hybridization of Organic Macrocycles with Nanomaterials

Macrocyclic compounds have attracted tremendous attention for their superior performance in supramolecular recognition, catalysis, and host-guest interaction. With these admirable properties, macrocyclic compounds were used as modifiers for enhancing the sensitivity and selectivity of electrodes and optical sensors. The classic macrocyclic compounds, including crown ethers, cyclodextrins, calixarenes, cucurbiturils, and pillararenes, were employed as receptors for electrochemical and optical sensors to develop new analytical methods with the wilder detection range, lower detection limit, and better tolerance of interference. Macrocyclic molecules functionalized with nanomaterials, the small entities with dimensions in the nanoscale, realized the versatility and diversification of the nano-hybrid materials, which improved the capabilities of recognition and response with the combining characteristics of two components. Herein, this review focused on the development in the research field of hybridization of organic macrocycles with nanoparticles and their applications for chemosensors, aiming at both existing researchers in the field and who would like to enter into the research.

Optical Supramolecular Sensing of Creatinine.

Calix[4]pyrrole phosphonate-cavitands were used as receptors for the design of supramolecular sensors for creatinine and its lipophilic derivative hexylcreatinine. The sensing principle is based on indicator displacement assays of an inherently fluorescent guest dye or a black-hole quencher from the receptor's cavity by means of competition with the creatinine analytes. The systems were thermodynamically and kinetically characterized regarding their 1:1 binding properties by means of nuclear magnetic resonance spectroscopy (1H and 31P NMR), isothermal titration calorimetry, and optical spectroscopies (UV/vis absorption and fluorescence). For the use of the black-hole indicator dye, the calix[4]pyrrole was modified with a dansyl chromophore as a signaling unit that engages in Förster resonance energy transfer with the indicator dye. The 1:1 binding constants of the indicator dyes are in the range of 107 M-1, while hexylcreatinine showed values around (2-4) × 105 M-1. The competitive displacement of the indicators by hexylcreatinine produced supramolecular fluorescence turn-on sensors that work at micromolar analyte concentrations that are compatible with those observed for healthy as well as sick patients. The limit of detection for one of the systems reached submicromolar ranges (110 nM).

PH-stimulus response dye-cucurbituril sensor for amino acids in aqueous solution.

The host-guest inclusion complexes that comprise an inverted cucurbit[7]uril (iQ[7]) and a quinoline derivative, 4-(4-dimethylaminostyryl) quinoline (DSQ) at different pHs were exploited as multiple supramolecular sensors to sense l-α-amino acids. DSQ complexation inside iQ[7] at different pHs leads to increased fluorescence and formation of different-colored iQ[7]-DSQ complexes. The enhanced fluorescence of DSQ after iQ[7] encapsulation may be attributed to limited dimethylamine rotation and the formation of a twisted internal charge transfer (TICT) state. The DSQ@iQ[7] sensors have different affinities for l-α-amino acids at different pHs. Therefore, we propose a pH-stimulus response supramolecular sensor for the discrimination of structurally similar l-α-amino acids in aqueous solution.

A novel pillar[5]arene-based emission enhanced supramolecular sensor for dual-channel selective detection and separation of Hg2+

We constructed a supramolecular sensor (APRA–G) via a host–guest inclusion interaction between a rhodamine hydrazide-functionalized pillar[5]arene (APRA) and a bipyridine salt guest (G), which formed a stable dimer.

Supramolecular fluorogenic peptide sensor array based on graphene oxide for the differential sensing of ebola virus.

We report on a supramolecular sensor array using fluorogenic peptide probes and graphene oxide that can target glycoproteins on a viral caspid, facilitating the differentiation of ebola virus from marburg virus and receptor-extensive vesicular stomatitis virus using principal component analysis.

Parallel Synthesis and Screening of Supramolecular Chemosensors That Achieve Fluorescent Turn-on Detection of Drugs in Saliva.

Programming and controlling molecular recognition in aqueous solutions is increasingly common, but creating supramolecular sensors that detect analytes in biologically relevant solutions remains a nontrivial task. We report here a parallel synthesis-driven approach to create a family of self-assembling dimeric sensors that we call DimerDyes and its use for the rapid identification of salt-tolerant sensors for illicit drugs. We developed an efficient method that involves parallel synthesis and screening in crude form without the need to purify each potential sensor. Structurally diverse "hit" DimerDyes were resynthesized and purified and were each shown to assemble into homodimers in water in the programmed way. DimerDyes provided a "turn-on" fluorescence detection of multiple illicit drugs at low micromolar concentrations in water and in saliva. The combination of multiple agents into a sensor array was successfully able to detect and discriminate between closely related drugs and metabolites in multiple important drug families.