This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Article Cite This: ACS Omega 2018, 3, 14665−14670
http://pubs.acs.org/journal/acsodf
Amplified Detection of Chemical Warfare Agents Using TwoDimensional Chemical Potential Gradients Mohammad A. Ali, Tsung-Han Tsai, and Paul V. Braun* Department of Materials Science and Engineering, Department of Chemistry, Beckman Institute for Advanced Science and Technology, and Materials Research Laboratory, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, United States
ACS Omega 2018.3:14665-14670. Downloaded from pubs.acs.org by 91.243.90.39 on 11/05/18. For personal use only.
S Supporting Information *
ABSTRACT: Chemical warfare agents such as sarin are highly toxic, and detection of even trace levels is important. Using a hydrogel film containing a built-in two-dimensional chemical potential gradient, we demonstrate the detection of a sarin simulant under conditions potentially as low as a level 1 (6.90 × 10−9 mg/cm3 for 10 min) Acute Exposure Guideline Level sarin exposure. Specifically, the sarin simulant diisopropyl fluorophosphate (DFP) is aerosol-deposited on a hydrogel film containing a built-in ionic chemical gradient and the enzyme, diisopropyl fluorophosphatase (DFPase). DFPase degrades the DFP, releasing fluoride ions. The fluoride ions are then concentrated by the gradient to a miniature electrochemical sensor embedded in the hydrogel providing a 30-fold amplification of the fluoride ion signal, which is an indication of exposure to DFP, relative to a gradient-free system. This method is general for agents which hydrolyze into chemically detectable ionic species.
■
cascade formation of fluoride ions, with the initial fluoride ion coming from sarin, has been reported; however, this process takes at least 4 h.17 We previously reported that chemical gradients in hydrogel films are able to concentrate model analytes (charged dye molecules) at least 40-fold (over 24 h) by biasing diffusion such that the dye is directionally transported to a central region of the film at a rate of few micrometers per minute.18 This potentially overcomes the “needle in a haystack” problem for nano-sized sensors.19 While we believe the concept of gradientdirected transport is attractive for enhancing the detection limit of a sensor, the slow transport velocity limits the applicability for real-time detection. Here, we demonstrate rapid (minutes) chemical gradient-enhanced detection of a nerve agent stimulant using an approach in which the target molecule is first fragmented by a catalyst into pieces, at least one of which is rapidly diffusing and easy to detect, followed by the gradient-directed transport of these fragments to a chemically specific sensor. In greater detail, the agent first adsorbs into an enzyme-containing gel film. Then, the enzyme degrades the agent, releasing F−. The internal ionic gradient within the gel subsequently directionally transports the F ions to a miniaturized F-ion-specific sensor imbedded in the gel at the focusing point of the chemical gradient. The advantages of this approach over attempting the concentration and detection of the initial agent are several folds. First, realization of a gradient which drives the transport of ions is much more straightforward than the realization of a gradient for the
INTRODUCTION The highly toxic G-type nerve agents, including sarin (GB), soman (GD), and cyclosarin (GF), are considered weapons of mass destruction. Upon inhalation or dermal penetration, the G-agents attack the nervous system by interfering with the degradation of the neurotransmitter acetylcholine, leading to death.1,2 Permanent damage to the nervous system can also occur at nonlethal doses.3 Immediate application of antidotes to an affected person can prevent permanent damage; however, low-level nerve agents’ exposure leads to ambiguous signs and symptoms that cannot be easily discriminated from other conditions, which may result in a delay in treatment and permanent damage.4 Because of this, extensive efforts have been made to develop sensors for sarin and similar compounds; however, detection at Acute Exposure Guideline Level 1 (AEGL-1) (6.9 × 10−9 mg/cm3 for 10 min for sarin) remains challenging.5−9 To detect trace concentration of agents, extensive efforts have been made to develop signal amplification techniques.10−14 Although methods such as polymerase chain reaction enable orders of magnitude amplification of DNA sequences, methods such as this do not work for small molecules. To enhance the detection of small molecules, fluorescence quenching approaches have been suggested, for example, using conjugated polymer-based sensors in which long-range exciton diffusion enables a single analyte molecule to quench a significant volume of materials.15 Such an approach has been demonstrated to enable the detection of nerve agents in solution in the parts per billion level;16 however, in the solid state, only sub-parts per million level detection has been demonstrated.9 Recently, a 4-fold signal amplification method inspired by nature utilizing autoinductive © 2018 American Chemical Society
Received: July 2, 2018 Accepted: October 22, 2018 Published: November 1, 2018 14665
DOI: 10.1021/acsomega.8b01519 ACS Omega 2018, 3, 14665−14670
ACS Omega
Article
Figure 1. (a) Synthesis of cationic quaternary ammonium-functionalized PAAm used for Cl− transport. (b,c) Schematics of setups used to create directional (b) and radially symmetric (c) chemical gradients in the PAAm films. (d) Illustration of the enthalpy profile for Cl− in gradientcontaining PAAm films: (i) directional gradient and (ii) radially symmetric gradient. Blue spheres represent Cl−. The enthalpy landscape is due to electrostatic interactions between the cationic groups in the hydrogel and Cl−.
Figure 2. (a) Schematic and (b) fluorescence images as a function of time after dosing of a ca. 1 mm Cl− spot on a gradient-free hydrogel film. (c) Schematic and (d) fluorescence images as a function of time after dosing a ca. 1 mm Cl− spot on a hydrogel containing a left to right cationic quaternary ammonium gradient. (e) Schematic and (f) optical images as a function of time showing the directional transport of a ca. 1 mm H+ spot on a hydrogel containing an anionic sulfate gradient and two immobilized pH indicator regions.
■
uncharged molecular species. Second, monatomic ions generally diffuse more rapidly than molecules. Third, there are well-established, specific, and quantitative electrochemical sensors for monatomic ions. For a proof-of-concept studies, simulants for highly toxic fluoride-containing “G series” chemical warfare agents (CWAs) containing enzymatically degradable P−F or P−Cl bonds were selected [for safety reasons, we demonstrate the concept using the sarin simulants diisopropyl fluorophosphate (DFP) and diethyl chlorophosphite (DCP)]. Concentrated F− ions were detected electrochemically, whereas Cl− ions were detected fluorometrically.
MATERIALS AND METHODS
Highly water-swollen polyacrylamide (PAAm)-based hydrogels were chosen as the host media because they can be easily functionalized, are known to serve as good hosts for enzymes, and are relatively robust to a variety of chemical environments. The PAAm gels were synthesized by free radical photopolymerization. The chemical modification of PAAm films involved two steps, hydrolysis and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-assisted coupling of functional groups (Figure S2). The gradient shape was controlled during the hydrolysis step as shown in Figure 1b,c.18 Details of the synthesis and chemical modification of 14666
DOI: 10.1021/acsomega.8b01519 ACS Omega 2018, 3, 14665−14670
ACS Omega
Article
Figure 3. (a) Schematic of concentration of aerosol-dosed Cl− by a neutral-to-cationic radially symmetric gradient. Yellow spheres represent Cl−. The ion diffuses randomly outside of the gradient and directionally within the gradient. Black lines illustrate the trajectory of specific Cl−. (b) Fluorescence images of the hydrogel film 1, 3, and 5 min after Cl− dosing. (c) Line profiles of fluorescence intensity crossing the origin of a radially symmetric gradient as indicated by the dashed lines in (b).
PAAm hydrogel films can be found in Supporting Information Section S2. All experiments were performed with ca. 30 μm thick hydrogel films (unless otherwise noted) covalently attached to acrylate-functionalized glass substrates. The thickness of the film is significantly less than the gradient length (several millimeters); therefore, ion transportation is effectively two-dimensional.
and the cationic quaternary ammonium-functionalized PAAm on the other end was then investigated. Figure 2d(i) shows the result when a small area (∼1 mm in diameter) of the indicatorcontaining gel was dosed with Cl− using the technique indicated above. The quenched spot spreads anisotropically, with the net transport being toward the quaternary ammonium-rich end of the gradient, driven by interactions between the cationic quaternary ammonium group and Cl−. To determine the gradient-imposed drift velocity, a COMSOL multiphysics simulation (ver. 5.2) was used to model the system using the two-dimensional diffusion−convection equation
■
RESULTS AND DISCUSSION We start by ascertaining the rate of Cl− diffusion in a gradientfree hydrogel and the rate of directional transport of Cl− in an ionic gradient-containing hydrogel. Aqueous lucigenin (1 mM), a fluorescent chloride indicator, was sprayed (dosing of about 75 μg/cm2) on the surface of the 2 × 2 cm2 hydrogel films using a spray atomizer. For determination of the rate of Cl− diffusion in a gradient-free hydrogel, a trace amount of Cl− was dosed on a 1 mm diameter area on the surface of a gel using a sharp needle, which had been dipped into a 0.1 M HCl solution. In presence of Cl−, lucigenin’s fluorescence was quenched as shown in Figure 2b.20 As expected, the quenched spot spread isotropically. The Cl− diffusion constant was determined to be 1 × 10−9 m2/s by observing the evolution of the diameter of the quenched region (see Supporting Information Section S7.1 for details of the analysis). Under these conditions, the hydrogel is ∼90% water, and thus, not surprisingly, the Cl− ion diffusion constant was similar to that found in aqueous solution.21,22 A cationic quaternary ammonium gradient was chosen to transport Cl−, given the affinity of Cl− for the quaternary ammonium group. Both a linear gradient with a length of ca. 7 mm and a radially symmetric gradient with a radius of ca. 4 mm were formed.18 The overall effect of the gradient is to create an enthalpy gradient for Cl− as illustrated in Figure 1d. The directional transport of Cl− using a neutral-to-cationic gradient consisting of a neutral polymer (PAAm) at one end
∂c = ∇[D(x , y)∇c ] + ∇[v (⃗ x , y)c ] ∂t
(1)
where D(x,y) is the local ion diffusion constant, v⃗(x,y) is the gradient-imposed drift velocity, and c is the concentration of ions. The gradient-imposed drift velocity of Cl − was determined to be ∼1.1 × 10−6 m/s, which is ca. 20-fold greater than the drift velocity of charged organic dyes in similar gradients (5 × 10−8 m/s).18 A similar approach was utilized to demonstrate the cation, for example, H+, transport using PAAm hydrogel films containing an anionic sulfate gradient (sulfanilic acid was coupled to the hydrogel through its amine group) (Figure 2f). Prior to analysis, the film was rinsed with deionized water, and the pH of the film was ∼7.0. As a first attempt, a pH sensitive dye was sprayed on the film, and we expected we would observe the movement of H+ through changes over time in the dye color. However, no color changes were observed over time, perhaps because of the strong binding of the dye to the H+. Instead, two drops (0.5 μL) of silica gels (see Supporting Information for the synthesis of dye-silica gels) containing bromothymol blue, a pH 6.0−7.6 indicator, were placed in two different locations on the hydrogel film via a sol−gel 14667
DOI: 10.1021/acsomega.8b01519 ACS Omega 2018, 3, 14665−14670
ACS Omega
Article
method,23,24 one drop in the anionic area and the other drop in the neutral area. Use of a sol−gel approach immobilized the dye molecule in the hydrogel. A 0.2 μL of 0.25 M HCl was placed using a microsyringe at a location centered between the two indicators as shown in Figure 2f. A hint of color change (from blue to yellow) was seen after 40 min in the dye located in the anionic sulfate side. The color change progressed and changed completely within 60 min. No change in color was observed in the dye region in the neutral area, suggesting that H + traveled under the influence of the gradient at approximately 2.7 × 10−5 m/s (about 5 times the velocity observed for Cl− under the influence of a gradient). The reason for the difference in velocity may be in part because lucigenin reversibly binds Cl− and may reduce its transport rate. To evaluate the potential for gradient-directed concentration (an important property for many detection schemes), a radially symmetric neutral-to-cationic gradient was prepared. Lucigenin dye was introduced into the film using the same method discussed previously. An ∼30 μg/cm2 of a 10 mM aqueous HCl solution (∼11 ng/cm2 of HCl) was dosed onto the film using an atomizer, and fluorescence images were taken overtime (Figure 3b). A line profile of fluorescence over the radially symmetric gradient was plotted against position as a function of time. It was seen that the fluorescence intensity was initially nearly homogeneous (Figure 3b(i)), indicating that after a short time, the atomizer-deposited Cl− has diffused only sufficiently to smear out the spray droplet pattern. A short time later, as sufficient Cl− crossed the “event horizon”, the outer edge of the gradient, and began to accumulate at the gradient center, fluorescence quenching in the gradient center begins.18 Over time, a distinct fluorescence quenching was observed at the center of the radially symmetric gradient indicative of an increase in Cl− concentration. Assuming the Stern−Volmer constant for lucigenin in the hydrogel is the same as in aqueous solution, 390 M−1,20 the concentration enhancement of Cl− in the concentrating region was found to be as high as 30-fold within 5 min. Interestingly, there is a bright ring around the edge of the gradient because of local depletion of Cl− in that region, which is caused by the fact that Cl− is being pulled out of that region over the event horizon into the center of the gradient faster than it is being replenished by free diffusion into that region.18 As a first demonstration of the use of a gradient to detect nerve agents, ∼15 μg/cm2 of a 0.1 M DCP solution in ethyl acetate (∼280 ng/cm2 of the simulant DCP) was sprayed on a PAAm hydrogel. As the DCP molecules diffused into the hydrogel, they hydrolyzed, yielding Cl−. The pH of the hydrogel was set as ca. 10 to accelerate the hydrolysis process by dipping the hydrogel in 5 mM NaOH solution, a pH at which the half-life for the hydrolysis of sarin is 5.4 min.25,26 It is noted that P−Cl bonds are significantly weaker than P−F bonds (326 and 490 kJ mol−1, respectively).27 If needed, the hydrolysis rate could be accelerated by imbedding nucleophilic agents (such as oxime or a catalyst) in the hydrogel.8,28−30 For one specific experiment, the hydrogel film on the substrate was physically separated into two regions by peeling a strip of hydrogel off the substrate, creating a physical barrier for ion exchange. One region contained a radially symmetric gradient and the other was gradient-free. Figure 4b shows a fluorescence image taken 30 min after spraying the stimuli. A clear indication of Cl− concentration in the center of the radially symmetric gradient is the quenching of fluorescence at the
Figure 4. (a) Hydrolysis of a sarin simulant, diethyl chlorophosphate, in presence of water in the PAAm hydrogel. (b) Fluorescence image of a PAAm hydrogel containing both gradient and gradient-free regions, 30 min after diethyl chlorophosphate dosing. The line profile of fluorescence intensity crossing the origin of a radially symmetric gradient shown on the left is indicated by the dashed line.
center of the gradient. One issue with detection using this approach is that as already mentioned, lucigenin reversibly binds Cl− and thus may slow the Cl− transport rate. While an approach for the enhanced detection of Cl− ions is interesting, and perhaps useful for detecting a few nerve agents such as chlorosarin, there are a number of practical issues with the approach described above. First, a turn-off fluorescence detection method is not attractive, as there are a number of effects that could lead to fluorescence quenching. Second, Cl− is ubiquitous in the environment. Third, detection of sarin is of greater importance than the detection of chlorosarin. We decided therefore to look for a selective and quantitative approach that could detect F−, one of the products of hydrolysis of sarin. Fortunately, highly specific and sensitive electrochemical sensors for F− are commercially available.18 In neutral solutions, the detection limit of this sensor is as low as 20 ppb in 30 s. This is comparable to gas chromatography− mass spectrometry (GC−MS), which is considered as the gold standard for nerve agent detection. However, unlike GC−MS, which requires relatively large and sophisticated instrumentation, an electrochemical sensor requires only simple instrumentation. Crucially, an electrochemical sensor could easily be integrated with a hydrogel film. As described in the experimental section, we fabricated a 2 mm diameter electrochemical fluoride ion sensor and placed it at the center of the radially symmetric gradient in the gel. The gel system consisted of a thin layer (∼5 μm) of a diisopropyl fluorophosphatase (DFPase) imbedded hydrogel on top of a thicker (ca. 100 μm) PAAm hydrogel containing a radially symmetric neutral-to-cationic tertiary ammonium gradient, which is attached to a glass substrate using a 17 μm thick SU-8 layer (see Supporting Information Sections S2.3 and S5). The SU-8 layer prevents fluoride ions in the gel from reacting with the glass substrate. Proof-of-concept sarin detection studies were performed by spraying two different doses of a 5 mM solution of DFP in ethanol on the gel surface. After spraying the simulant, the gels were left in a chamber for 30 min at relative humidity = 100%. Because of the presence of DFPase, DFP is rapidly hydrolyzed forming F− (at pH 7, DFP is hydrolyzed by DFPase at a rate of 81 μmol L−1 s−1).2,31,32 The F− ions are then driven to the center of the gradient by the imbedded radially symmetric neutral-to-cationic tertiary 14668
DOI: 10.1021/acsomega.8b01519 ACS Omega 2018, 3, 14665−14670
ACS Omega
Article
Figure 5. (a) Hydrolysis of an aerosol-dosed sarin simulant, DFP, catalyzed by the enzyme, DFPase. (b) Schematic diagram of the gradientenhanced enzyme sensor showing the placement of the fluoride-sensitive and Ag/AgCl reference electrodes. Enzymes were immobilized within a thin PAAm layer (∼5 μm thick) sitting above a PAAm (∼100 μm thick) layer containing an embedded neutral-to-cationic radially symmetric gradient designed to concentrate F−. (c) Activity-corrected F− concentration vs dosed concentration of F− at the center of the gradient and outside the gradient 30 min after DFP dosing, assuming complete hydrolysis of DFP. Arrows indicate the calculated concentration of sarin absorbed in the gel for an AEGL-1 exposure, and the concentration of sarin at the center of the gradient after 30-fold concentration (assuming sarin is fully hydrolyzed). The electrochemical sensor limit of detection is shown by the grayed-out region.
ammonium gradient. F− activities were monitored by the sensor at both the center of the gradient and outside of the gradient. It is important to note that the cationic quaternary ammonium-based gradient directs the transport of F− by means of electrostatic interactions between the cationic quaternary ammonium group and the fluoride ion, reducing the activity of F− in the gradient region of the hydrogel. Because the electrode is measuring the fluoride ion activity, not the concentration, the effect of the gradient on activity needs to be considered. The thermodynamic activity, that is, the effective concentration of F− in presence of ammonium ion, is defined as a=γ×
ci cø
for sarin (see Supporting Information Section S9 for a detailed discussion of our assumptions), the exposure level that generates notable, but still reversible upon cessation of exposure, discomfort, irritation, or certain asymptomatic nonsensory effects.33 In summary, the directional transport of ions up to several millimeters using hydrogel films containing built-in ionic chemical gradients was demonstrated. The gradient-imposed drift velocity was in the range of several micrometers per second, 2 orders of magnitude higher than the gradientdirected transport of a molecular species. For the subset of important CWAs, which hydrolyze into chemically detectable ionic species, yielding an ionic product, this approach provides an unprecedented opportunity for chemical sensing. The gradients used may also find applications in the study of ion diffusion in biological systems and could be used for surfacedirected ion separation.34
(2)
where γ is the activity coefficient, ci is the measured concentration of F− in the pristine gel, and cø is the dosing concentration of F−. Because of the electrostatic interactions between the fluoride and tertiary ammonium ions, the activity coefficient of fluoride ions in an ammonium-functionalized gel was reduced to 0.15 ± 0.02 (see Supporting Information S8.2). Thus, at the center of the gradient, the F− activity was determined to be 6-times lower than the F− concentration (see Supporting Information Sections S8.2 and S8.4) relative to that in a pristine PAAm gel. Accounting the activity coefficient, the dosing concentration (assuming all simulants were hydrolyzed to produce the fluoride ion) versus the calibrated concentration at these two regions is shown in Figure 5c. A 30-fold increase in F− concentration was measured at the center of the gradient relative to the dosing concentration [the theoretical upper bound showed a 57-fold concentration enhancement (see Supporting Information Section S9 for the calculation)]. The net effect of the concentration enhancement and the reduction of activity caused by the quaternary ammonium groups were that with the current state system we could directly detect as little as 70 ng of sarin (see Supporting Information Section S9). This detection limit is potentially comparable to AEGL-1
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b01519. Synthesis of hydrogels, formation and characterization of chemical gradients, fabrication of fluoride ion selective sensor and electrochemical measurements, and COMSOL modeling of ion transport within the hydrogel (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected] (P.V.B.). ORCID
Paul V. Braun: 0000-0003-4079-8160 Notes
The authors declare no competing financial interest. 14669
DOI: 10.1021/acsomega.8b01519 ACS Omega 2018, 3, 14665−14670
ACS Omega
■
Article
(21) Amsden, B. Solute diffusion within hydrogels. Mechanisms and models. Macromolecules 1998, 31, 8382−8395. (22) Friedman, A. M.; Kennedy, J. W. The Self-diffusion Coefficients of Potassium, Cesium, Iodide and Chloride Ions in Aqueous Solutions1. J. Am. Chem. Soc. 1955, 77, 4499−4501. (23) Lim, S. H.; Musto, C. J.; Park, E.; Zhong, W.; Suslick, K. S. A colorimetric sensor array for detection and identification of sugars. Org. Lett. 2008, 10, 4405−4408. (24) Feng, L.; Musto, C. J.; Kemling, J. W.; Lim, S. H.; Suslick, K. S. A colorimetric sensor array for identification of toxic gases below permissible exposure limits. Chem. Commun. 2010, 46, 2037−2039. (25) The Homeland Defense and Security Information Analysis Center. Sarin/GB Overview; HDIAC: 104 Union Valley Rd., Oak Ridge, TN 37830, 2016. (26) Organisation for the Prohibition of Chemical Weapons. https://www.opcw.org/about-chemical-weapons/types-of-chemicalagent/nerve-agents/ (date 05, 2018). (27) Kumar, V.; Raviraju, G.; Rana, H.; Rao, V. K.; Gupta, A. K. Highly selective and sensitive chromogenic detection of nerve agents (sarin, tabun and VX): a multianalyte detection approach. Chem. Commun. 2017, 53, 12954−12957. (28) Hay, R. W.; Govan, N. A lanthanum macrocycle catalysed hydrolysis of 2,4-dinitrophenyl diethyl phosphate and O-isopropyl methylfluorophosphote (Sarin). Polyhedron 1997, 16, 4233−4237. (29) Yoza, N.; Nakashima, S.; Nakazato, T. Enzyme-catalyzed P-F bond hydrolysis of monofluorophosphate as a simple model of sarin detoxification. Chem. Lett. 1997, 53−54. (30) Bromberg, L.; Creasy, W. R.; McGarvey, D. J.; Wilusz, E.; Hatton, T. A. Nucleophilic polymers and gels in hydrolytic degradation of chemical warfare agents. ACS Appl. Mater. Interfaces 2015, 7, 22001−22011. (31) https://www.thermofisher.com/order/catalog/product/ 9609BNWP?SID=srch-srp-9609BNWP (date 05, 2018). (32) Allen, B. L.; Johnson, J. D.; Walker, J. P. Hydrolase stabilization via entanglement in poly(propylene sulfide) nanoparticles: stability towards reactive oxygen species. Nanotechnology 2012, 23, 294009. (33) Wymore, T.; Field, M. J.; Langan, P.; Smith, J. C.; Parks, J. M. Hydrolysis of DFP and the nerve agent (S)-sarin by DFPase proceeds along two different reaction pathways: Implications for engineering bioscavengers. J. Phys. Chem. B 2014, 118, 4479−4489. (34) Council, N. R. Acute Exposure Guideline Levels for Selected Airborne Chemicals; The National Academies Press: Washington, DC, 2003; Vol. 3, p 515.
ACKNOWLEDGMENTS This work was supported by Defense Threat Reduction Agency under award number HDTRA 1-12-1-0035 and the Department of Defense/US Army W911NF-17-1-0351. The authors thank Dr. Minho Yang, Dr. Brian Pate (DTRA), and Dr. Dianwen Zhang for helpful discussions, technical advice, and support.
■
REFERENCES
(1) Abu-Qare, A. W.; Abou-Donia, M. B. Sarin: health effects, metabolism, and methods of analysis. Food Chem. Toxicol. 2002, 40, 1327−1333. (2) Kim, K.; Tsay, O. G.; Atwood, D. A.; Churchill, D. G. Destruction and detection of chemical warfare agents. Chem. Rev. 2011, 111, 5345−5403. (3) Abou-Donia, M. B.; Siracuse, B.; Gupta, N.; Sokol, A. S. Sarin (GB, O-isopropyl methylphosphonofluoridate) neurotoxicity: critical review. Crit. Rev. Toxicol. 2016, 46, 845−875. (4) Chao, L. L.; Rothlind, J. C.; Cardenas, V. A.; Meyerhoff, D. J.; Weiner, M. W. Effects of low-level exposure to sarin and cyclosarin during the 1991 Gulf War on brain function and brain structure in US veterans. NeuroToxicology 2010, 31, 493−501. (5) Lei, Z.; Yang, Y. A Concise Colorimetric and Fluorimetric Probe for Sarin Related Threats Designed via the “Covalent-Assembly” Approach. J. Am. Chem. Soc. 2014, 136, 6594−6597. (6) Bhowmick, I.; Neelam. Surface-immobilization of molecules for detection of chemical warfare agents. Analyst 2014, 139, 4154−4168. (7) Rusu, A. D.; Moleavin, I. A.; Hurduc, N.; Hamel, M.; Rocha, L. Fluorescent polymeric aggregates for selective response to sarin surrogates. Chem. Commun. 2014, 50, 9965−9968. (8) Xie, Y.; Popov, B. N. Catalyzed hydrolysis of nerve gases by metal chelate compounds and potentiometric detection of the byproducts. Anal. Chem. 2000, 72, 2075−2079. (9) Belger, C.; Weis, J. G.; Egap, E.; Swager, T. M. Colorimetric stimuli-responsive hydrogel polymers for the detection of nerve agent surrogates. Macromolecules 2015, 48, 7990−7994. (10) Scrimin, P.; Prins, L. J. Sensing through signal amplification. Chem. Soc. Rev. 2011, 40, 4488−4505. (11) Zhu, L.; Anslyn, E. V. Signal amplification by allosteric catalysis. Angew. Chem., Int. Ed. 2006, 45, 1190−1196. (12) Baker, M. S.; Phillips, S. T. A small molecule sensor for fluoride based on an autoinductive, colorimetric signal amplification reaction. Org. Biomol. Chem. 2012, 10, 3595−3599. (13) Goggins, S.; Marsh, B. J.; Lubben, A. T.; Frost, C. G. Signal transduction and amplification through enzyme-triggered ligand release and accelerated catalysis. Chem. Sci. 2015, 6, 4978−4985. (14) Goggins, S.; Frost, C. G. Approaches towards molecular amplification for sensing. Analyst 2016, 141, 3157−3218. (15) Rochat, S.; Swager, T. M. Conjugated amplifying polymers for optical sensing applications. ACS Appl. Mater. Interfaces 2013, 5, 4488−4502. (16) Pangeni, D.; Nesterov, E. E. “Higher Energy Gap” Control in Fluorescent Conjugated Polymers: Turn-On Amplified Detection of Organophosphorous Agents. Macromolecules 2013, 46, 7266−7273. (17) Sun, X.; Dahlhauser, S. D.; Anslyn, E. V. New autoinductive cascade for the optical sensing of fluoride: Application in the detection of phosphoryl fluoride nerve agents. J. Am. Chem. Soc. 2017, 139, 4635−4638. (18) Zhang, C.; Sitt, A.; Koo, H.-J.; Waynant, K. V.; Hess, H.; Pate, B. D.; Braun, P. V. Autonomic molecular transport by polymer films containing programmed chemical potential gradients. J. Am. Chem. Soc. 2015, 137, 5066−5073. (19) Sitt, A.; Hess, H. Directed transport by surface chemical potential gradients for enhancing analyte collection in nanoscale sensors. Nano Lett. 2015, 15, 3341−3350. (20) Biwersi, J.; Tulk, B.; Verkman, A. S. Long-wavelength chloridesensitive fluorescent indicators. Anal. Biochem. 1994, 219, 139−143. 14670
DOI: 10.1021/acsomega.8b01519 ACS Omega 2018, 3, 14665−14670
