Abstract
The design and preparation of synthetic binders (SBs) applicable for small biomolecule sensing in aqueous media remains very challenging. SBs designed by the lock-and-key principle can be selective for their target analyte but usually show an insufficient binding strength in water. In contrast, SBs based on symmetric macrocycles with a hydrophobic cavity can display high binding affinities but generally suffer from indiscriminate binding of many analytes. Herein, a completely new and modular receptor design strategy based on microporous hybrid materials is presented yielding zeolite-based artificial receptors (ZARs) which reversibly bind the neurotransmitters serotonin and dopamine with unprecedented affinity and selectivity even in saline biofluids. ZARs are thought to uniquely exploit both the non-classical hydrophobic effect and direct non-covalent recognition motifs, which is supported by in-depth photophysical, and calorimetric experiments combined with full atomistic modeling. ZARs are thermally and chemically robust and can be readily prepared at gram scales. Their applicability for the label-free monitoring of important enzymatic reactions, for (two-photon) fluorescence imaging, and for high-throughput diagnostics in biofluids is demonstrated. This study showcases that artificial receptor based on microporous hybrid materials can overcome standing limitations of synthetic chemosensors, paving the way towards personalized diagnostics and metabolomics.
Highlights
Linde-type zeolite L nanoparticles (50–200 nm particle size, channel entrance diameter 7.6 Å) were used as water-dispersible receptor scaffolds.[36]. To both render the channels as a perfect environment for the binding of aromatic amine neurotransmitters and to provide an optical signal transduction mechanism, the nanoporous zeolites were loaded with the dicationic fluorescent dyes D1 and D2 (Figure 1c)
The dyes D1 and D2 were selected because they i) fit well into the channels, ii) are strongly bound to the negatively charged zeolite channel walls because of cation exchange, and iii) tend to be monodispersed inside the channels. They iv) engage in direct non-covalent interactions with the neurotransmitters, ensuring the binding strength and selectivity of zeolite-based artificial receptors (ZARs), and v) possess excellent electron-accepting properties. Their electronic coupling with neurotransmitters leads to photoinduced electron transfer processes that can be sensitively monitored by fluorescence and absorbance spectroscopy,[44] and that are specific for each dye-neurotransmitter pair
That besides detecting and quantifying neurotransmitters in a diagnostic assay, ZARs can be used for label-free enzymatic reaction monitoring in real time
Summary
Artificial receptors and nanosensors are envisioned to open exciting new possibilities for home-use and point-of-care diagnostics as they can be chemically/thermally more robust, inexpensive, and faster responding than complementary biosensors.[1,2,3,4,5,6,7,8,9,10] Inspiring examples are the molecular recognition-based glucose sensors developed separately by Senseonics and GlySure Ltd[11,12] and cation-selective chemosensors used in a supramolecular sensor cassette by OPTI Medical Inc for Na+, K+, and Ca2+ sensing in blood.[13,14] the selective and sensitive molecular recognition of small hydrophilic molecules in water remains extremely challenging (Figure 1).[15,16,17] For instance, synthetic binders (SBs) designed to recognize the neurotransmitter dopamine through direct non-covalent binding motifs, for example, salt bridges and stacking interactions (Figure 1a), are relatively selective for their target molecules but are limited by impractically low binding affinities in water.[18]. Www.advmat.de circumstantial evidence was collected showing that the (non-classical) hydrophobic effect is an important driving force for hostguest complex formation in water (Figure 1b).[16,17,19,20] While the underlying physical details are still under debate,[20,21,22] it is empirically clear that SBs with a persistent, shielded, and hydrophobic binding cavity provide the highest affinities.[15,17,20] even cucurbit[n]urils that bind a wide range of hydrophobic compounds with record-high affinities[23,24] fall short with respect to the required Kd values for serotonin or dopamine recognition at physiologically relevant concentrations (Figure 1b–d) Such symmetric macrocycle-based systems are generally unselective binders and complex many metabolites and drugs, both aliphatic and aromatic ones, and are often perturbed by the salts present in biofluids. As a result of the interplay of hydrophobic effect, ionic interactions, cationπ-interactions, and hydrogen bonding, very high binding affinities and selectivity for hydrophilic neurotransmitters such as serotonin can be reached (Figure 1e)
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