Fluorescent Nanozeolite Receptors for the Highly Selective and Sensitive Detection of Neurotransmitters in Water and Biofluids

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.

Supramolecular Mitigation of the Cyanine Limit Problem

“…That is, the absorption profile is broadened and the fluorescence is partially quenched upon dye encapsulation, which is a rare finding since the vast majority of fluorescent dyes become brighter when encapsulated by CB7. − , The result is attributed to formation of an unsymmetrical CB7–dye complex which induces the dye to adopt a polar symmetric π-electron state with a localized positive charge at one end of the chromophore (Figure b). Discovery of a near-infrared dye system that exhibits “turn-on” fluorescence when the partially quenched dye is displaced from CB7 (Figure b) is practically important, as it provides a development path toward improved “turn-on” fluorescent sensors for many types of drugs and bioactive molecules. ,,, We envision future designs of near-infrared dye displacement assays that could use either a binary cyanine/CB7 admixture for operation in low salt aqueous solutions or alternatively a covalent conjugate of the two components for more complex media such as blood, serum, or urine …”

“…Discovery of a near-infrared dye system that exhibits "turn-on" fluorescence when the partially quenched dye is displaced from CB7 (Figure 2b) is practically important, as it provides a development path toward improved "turn-on" fluorescent sensors for many types of drugs and bioactive molecules. 36,50,61,62 We envision future designs of near-infrared dye displacement assays that could use either a binary cyanine/ CB7 admixture for operation in low salt aqueous solutions or alternatively a covalent conjugate of the two components for more complex media such as blood, serum, or urine. 50 ■ EXPERIMENTAL SECTION General Methods.…”

Molecular Probes, Chemosensors, and Nanosensors for Optical Detection of Biorelevant Molecules and Ions in Aqueous Media and Biofluids

“…528 To this end, transmitters serotonin and dopamine (amongst others) was possible in buffers and real biofluids. 547 Serotonin and dopamine were shown to bind in the reporter dye-loaded pores of the ZARs (= zeolite-based artificial receptors), exploiting both the nonclassical hydrophobic effect and direct noncovalent recognition motifs. Evidence for this unprecedented binding mechanism was obtained by in-depth photophysical and calorimetric experiments in combination with full atomistic modeling.…”

“…A new and modular receptor design strategy based on microporous hybrid zeolite receptors ( N4.34 in Figure ) was recently described by us. The detection of the neurotransmitters serotonin and dopamine (amongst others) was possible in buffers and real biofluids . Serotonin and dopamine were shown to bind in the reporter dye-loaded pores of the ZARs (= zeolite-based artificial receptors), exploiting both the nonclassical hydrophobic effect and direct noncovalent recognition motifs.…”

Further Dimensions for Sensing in Biofluids: Distinguishing Bioorganic Analytes by the Salt-Induced Adaptation of a Cucurbit[7]uril-Based Chemosensor

“…Synthetic receptors and chemosensing ensembles capable of distinguishing structurally similar bioorganic analytes are crucial for developing facile, low-cost, and parallelizable sensing methods that are applicable in molecular diagnostics. − In particular, macrocyclic systems, for example, cryptands, , calix­[ n ]­arenes, − cavitands, − naphthotubes, − and cucurbit­[ n ]­urils , can strongly bind biorelevant analyte classes, such as metabolites, neurotransmitters, steroids, or metal cations in aqueous media. Unfortunately, macrocyclic hosts are in most cases composed of a fully covalently linked organic framework, − and thus, it can be challenging and time-consuming to tune their binding properties through the synthesis of new macrocyclic derivatives.…”