Molecularly imprinted micelles for fluorescent sensing of nonsteroidal anti-inflammatory drugs (NSAIDs)
Graphical abstract
Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly administered over-the-counter drugs to reduce pain, decrease fever, and control inflammation [1]. Due to their potential effects on different organisms, their wide usage and uncontrolled disposal are a significant environmental concern [2,3]. Although many NSAIDs are degraded by microorganisms in soil, rate of degradation varies greatly depending on the types of soil and other environmental conditions [4].
The important biological activity of NSAIDs and their environmental risks have motivated many researchers to develop sensitive methods for their detection and monitoring. Traditional analyses include electrophoresis [5] and liquid chromatography–mass spectrometry [6] but the sophisticated instruments utilized are inconvenient for rapid in-field monitoring. Recognition-based fluorescent sensing is a method of choice for its simplicity, high sensitivity, and ease of operation [[7], [8], [9], [10], [11]]. However, NSAIDs have very similar structures, with a carboxylic acid on a similarly sized hydrophobic aromatic moiety (Chart 1). The structural similarity represents a difficult challenge in the selective detection of these drugs by fluorescence [[12], [13], [14]], and traditional macrocyclic supramolecular hosts such as cyclodextrins tend to bind NSAIDs indiscriminately [15]. The difficulty prompted researchers to explore alternative formats of sensing, such as arrays of sensors, which showed good promise [16]. Other choices include enzyme-linked immunosorbent assays (ELISA) [17,18], but the structural similarity even challenges antibodies which are known for their highly specific binding [17].
One way to prepare a receptor for a target analyte is through molecular imprinting [19,20]. The technique uses the analyte (or a surrogate) as the template and, through templated polymerization, creates analyte-complementary binding sites in a highly cross-linked polymer network. Molecularly imprinted polymers (MIPs) have been referred to as “plastic antibodies” and found numerous applications [[21], [22], [23], [24], [25], [26], [27], [28], [29], [30]]. With appropriate functional monomers (FMs), MIPs can have excellent molecular recognition for molecules of many different sizes, making them extremely useful in biomedical applications [[31], [32], [33]]. In fact, MIPs generated for NSAIDs displayed selective adoption of these drugs [[34], [35], [36], [37]], but their conversion into selective fluorescent sensors is hampered by the insolubility, heterogeneous distribution of binding sites, and other challenges associated with traditional MIPs.
Our group developed a method of molecular imprinting in doubly cross-linked micelles (Scheme 1) [38]. The method involves first surface-crosslinking of micelle of 6 with diazide 7 using the click reaction and then core-cross-linking with divinylbenzene (DVB) using free-radical polymerization photolytically initialed by DMPA (2,2-dimethoxy-2-phenylacetophenone). The cross-linked micelles are also functionalized with a layer of hydrophilic ligand (i.e., 8) for increased hydrophilicity and facile purification. The method can be applied to a wide range of small-molecule drugs [38,39], peptides [40], and carbohydrates [41,42]. The resulting molecularly imprinted nanoparticles (MINPs) showed strong abilities to distinguish closely related structures including leucine and isoleucine in peptides [40] and inversion of a single hydroxyl in oligosaccharides [41,42]. MINPs are ~5 nm in diameter, and mimic proteins in their nanosize, hydrophilic exterior, and hydrophobic core. The number of binding sites per MINP can be conveniently controlled by the surfactant/template ratio. For example, when this ratio was kept the same as the surfactant aggregation number of the micelle (~50), MINP obtained was found to have an average of one binding site per nanoparticle [38].
In this work, we report the design and synthesis of several fluorescent FMs for selective NSAID detection. Structure of fluorophore was found to impact the sensing strongly, with minor variation in substitution pattern totally changing the behavior of the resulting sensor. One FM, containing a thiourea group bonded to a sulfonated 1,5-naphthalene derivative, allowed highly selective binding of the drugs. Strong binding between the thiourea group of the FM and the carboxylic acid of NSAID helped the fluorescent probe reside near the imprinted binding site so that the guest binding was readily detected by fluorescent change.
Section snippets
Design and synthesis of fluorescent functional monomers to bind carboxylates
Molecular imprinting can be very effective at creating template-specific binding sites in a polymer network. To create a fluorescent sensor for NSAIDs, however, we need to not only have a strong and selective binding for the drug but also convert the binding into an easy-to-detect fluorescent signal [[34], [35], [36], [37],39]. Our strategy is to employ a functional monomer containing an environmentally sensitive fluorophore and a strong carboxylate-binding moiety in close proximity [43]. In
Conclusions
The high structural similarity among NSAIDs makes it difficult even for natural antibodies to distinguish the drugs. The molecularly imprinted cross-linked micelles, nonetheless, displayed excellent abilities to bind and distinguish these drugs. The choice of fluorescent functional monomer is highly important, with compound 12 being the only one useful among the four synthesized. Once the correct FM and all the other ingredients of MINPs are available, MINP-based fluorescent sensors can be
Materials
A typical procedure for the preparation of MINPs and NINPs is as follows [38]. A solution of compound 1 in methanol (10 μL of 18.5 mg/mL, 0.0004 mmol) was mixed with a solution of compound 12 in methanol (20 μL of 16.7 mg/mL, 0.0008 mmol) in a vial containing methanol (1 mL). After the mixture was stirred for 1 h at room temperature, methanol was removed in vacuo. A micellar solution of compound 6 (9.3 mg, 0.02 mmol) in H2O (2.0 mL), divinyl benzene (DVB, 2.8 μL, 0.02 mmol), and
Declaration of Competing Interest
None.
Acknowledgments
We thank NIGMS (R01GM113883) for financial support of this research.
Data availability statement
The raw/processed data required to reproduce these findings cannot be shared at this time due to technical or time limitations.
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