Optical Detection of Lithocholic Acid with Liquid Crystal Emulsions

Article pubs.acs.org/Langmuir

Optical Detection of Lithocholic Acid with Liquid Crystal Emulsions Tanmay Bera and Jiyu Fang* Department of Materials Science and Engineering, University of Central Florida, Orlando, Florida 32826, United States ABSTRACT: The concentration level of bile acids is a clinical biomarker for the diagnosis of intestinal diseases because individuals suffering from intestinal diseases have a sharply increased concentration of bile acids at micromolar levels. Here, we report the detection of lithocholic acid (LCA) in aqueous solution by using surfactant-stabilized 4-n-pentyl-4′-cyanobiphenyl (5CB) liquid crystal droplets as an optical probe. We find that the surfactant adsorbed at the 5CB/water interface can be replaced by LCA, triggering a radial-to-bipolar configuration transition of the 5CB in the droplets. By simply observing the LCA-triggered transition with a polarizing optical microscope, micromolar levels of LCA in aqueous solution can be detected. The detection limit and selectivity of surfactant-stabilized 5CB droplets for LCA depend on the chain length and headgroup of the surfactants used for stabilizing 5CB droplets.

1. INTRODUCTION Bile acids are physiologically important metabolites which are biosynthesized from cholesterol in the liver and then stored in the gall bladder for the digestion of fatty foods.1 It has been found that individuals who suffer from intestinal diseases have an elevated concentration of bile acids at micromolar levels because the hepatic synthesis and clearance of bile acids are disturbed. 2 Since there is a clear distinction in the concentration of bile acids between healthy and diseased individuals, the concentration level of bile acids has been used as a valuable biomarker for the clinical diagnosis of intestinal diseases.3 Chromatography coupled with mass spectrometry is a common method for the detection of bile acids.4−6 Although the precision of the chromatography−mass spectrometry method in the detection of bile acids is high, this method is time-consuming and requires expensive instruments. Recently, chemical and optical sensors have been developed for the detection of bile acids in aqueous solution.7−10 For example, Koide et al.7 reported a chemical sensor based on a threeenzyme system (bile acid sulfate sulfatase, β-hydroxysteroid dehydrogenase, and nicotinamide adenine dinucleotide). The hydrogen peroxide produced from the three-enzyme system was used for the detection of bile acids. Wu et al.9 fabricated an optical sensor by filling a molecularly imprinted hydrogel into a three-dimensional colloidal crystal. The resultant photonic hydrogel with hierarchical porous structures showed optical changes in response to the adsorption of bile acids in the hydrogel. Liu and co-workers synthesized β-cyclodextrin (CD) derivatives appended with naphthalene and quinoline as fluorophores, and used them as fluorescence-based sensors for the detection of bile salts.10 The transfer of the chromophore groups from the central cavity to the hydrophobic torus rim could lead to the increase of fluorescent intensity in response to the complexation of bile acids with the β-CD derivatives. Thus, bile acids were detected by measuring the fluorescent intensity changes with a spectrophotometer. © 2012 American Chemical Society

Liquid crystal droplets dispersed in aqueous solution are of particular interest in biosensor applications due to their large surface areas, tunable surface properties, and well-defined director configurations. It has been shown that radial, axial, bipolar, and concentric director configurations can be formed in liquid crystal droplets.11 The transition among the director configurations leads to the optical pattern change of liquid crystal droplets, providing a simple optical sign for the detection of chemically and biologically important species. It has been demonstrated that the sensitivity of liquid crystal droplets in the detection of endotoxin can be as high as 1 pg/ mL.12 The extremely high sensitivity is due to the localized binding of endotoxin at the point defects of bipolar liquid crystal droplets, which triggers a bipolar-to-radial transition of the liquid crystal inside the droplets. The readout of liquid crystal droplet sensors is based on the bare-eye observation under a polarizing optical microscope without needing expensive and complex detection systems for signal transductions. In recent years, there has been increased interest in chemically modifying the surface of liquid crystal droplets to selectively detect chemical and biological species.13−19 For example, Abbott and co-workers showed that polyelectrolyte multilayer-coated liquid crystal droplets could be used in detecting lipid-enveloped viruses by observing the bipolar-toradial configuration transition induced by the transfer of the lipids from the viruses to the liquid crystal droplets.13 Yang and co-workers immobilized immunoglobulin G (IgG) on poly(ethylene imine)-coated liquid crystal droplets and found that the formation of the anti-IgG/IgG complex at the surface of the liquid crystal droplets could lead to a configuration transition.17 We exploited the application of negatively charged polyelectrolyte-coated liquid crystal droplets in detecting positively Received: August 8, 2012 Revised: November 30, 2012 Published: December 19, 2012 387

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charged poly(amido amine) (PAMAM) dendrimers and found that the adsorption of PAMAM dendrimers triggered a bipolarto-radial configuration transition of the liquid crystal inside the droplets.19 Here, we chemically engineered the surface of 4-npentyl-4′-cyanobiphenyl (5CB) liquid crystal droplets dispersed in aqueous solution by the adsorption of surfactants at the 5CB/water interface for the detection of lithocholic acid (LCA), a secondary bile acid. Unlike primary bile acids, LCA in the small intestine is poorly reabsorbed into enterohepatic circulation and moves into the colon, where it accumulates. Individuals who suffer from colon cancer have elevated levels of LCA.20,21 We find that LCA can partially replace the surfactant adsorbed at the 5CB/water interface and trigger a radial-tobipolar configuration transition of the 5CB in the droplets, which provides us a simple optical sign to detect the concentration level of LCA in aqueous solution. The detection limit and selectivity of surfactant-stabilized 5CB droplets for LCA depend on the nature of the surfactants.

Figure 2. (a) Bright-field microscopy image of SC12S-coated 5CB droplets in aqueous solution. (b) Size distribution histogram of SC12Scoated 5CB droplets.

2. RESULTS AND DISCUSSION Chemical structures of 4-n-pentyl-4′-cyanobiphenyl (5CB); lithocholic acid (LCA); sodium alkyl sulfate (SCnS) with n = 16, 12, 8, and 5; alkyl trimethylammonium bromide (CnTAB) with n = 16, 12, and 8; and 1,2-dioleoyl-sn-glycero-3phosphoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl) (18:1, NBD-PE) are shown in Figure 1. The adsorption of

Figure 3. Polarizing optical microscopy images of SC12S-stabilized 5CB droplets (a) before and (b) after exposure to LCA solution. The direction of the polarizer and analyzer is indicated by white arrows.

configuration of the surfactant-stabilized 5CB droplets becomes bipolar (Figure 3b), which reflects parallel surface anchoring. To understand the LCA-triggered configuration transition of the 5CB inside the surfactant-stabilized droplets, we carried out confocal fluorescence microscopy studies of NBD-PE-stabilized 5CB droplets in aqueous solution. In the absence of LCA, NBD-PE-stabilized 5CB droplets show strong fluorescence (Figure 4a). After exposure to LCA solution, the fluorescent intensity of NBD-PE-stabilized 5CB droplets significantly decreases (Figure 4b). This suggests that significant amounts of NBD-PE molecules are removed from the surface of the 5CB droplets. However, the fluorescence of the droplets never completely fades away even after they are exposed to LCA solution for 8 h. The ζ-potential of NBD-PE-stabilized 5CB droplets after they are exposed to LCA solution for 8 h becomes negative (−18 mV), indicating that some NBD-PE molecules are replaced by anionic LCA to form a mixed LCA/ NBD-PE interface. The competitive adsorption of bile acids onto the lipid interface of gastric emulsions has been discovered when they enter the duodenum.22 Several studies have shown that bile acids can disrupt the lipids adsorbed at the oil−water interface,23,24 which agrees with our findings here. LCA contains three methyl groups on the convex face and four hydrogen atoms and one hydroxyl group on the concave face (Figure 1b). It is reasonable to assume that the steroid nucleus of LCA lies flat at the interface with its convex face toward the 5CB phase and its concave face toward the aqueous phase (Figure 4c). The director configuration of surfactant-stabilized 5CB droplets is determined by the balance between the elasticity and the surface anchoring of the 5CB inside the droplets. The surface anchoring of liquid crystals is known to depend on the packing density of surfactants adsorbed at the liquid crystal/water interface. The decrease of surfactant

Figure 1. Chemical structures of (a) 4-n-pentyl-4′-cyanobiphenyl (5CB), (b) lithocholic acid (LCA), (c) sodium alkyl sulfate (SCnS), (d) alkyl trimethylammonium bromide (CnTAB), and (e) 1,2dioleoyl-sn-glycero-3-phosphoethanolamine-N-(7-nitro-2-1,3-benzoxadiazol-4-yl) (18:1, NBD-PE).

these surfactants at the 5CB/water interface leads to the formation of stable 5CB droplets in aqueous solution (Figure 2a). Dynamic light scattering measurements show that the surfactant-stabilized 5CB droplets are polydisperse (Figure 2b). The ζ-potential is negative (−42 mV) for SCnS-stabilized 5CB droplets and positive (+45 mV) for CnTAB-stabilized droplets, while the ζ-potential of NBD-PE-coated 5CB droplets is less than +1.5 mV. All the surfactant-stabilized 5CB droplets show a radial director configuration (Figure 3a), which is a result of homeotropic surface anchoring. However, after the droplets are exposed to LCA solution, we find that the director 388

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5CB droplet solution was placed on a glass slide and then covered with a cover glass. A series of optical microscopy images (∼150) were taken to ensure the whole sample was represented. The number of SC12S-stabilized 5CB droplets confined by the two glass slides was carefully counted from these microscopy images, and then the total number of 5CB droplets used for the LCA detection was calculated. As can be seen from Figure 5a, when the number of SC12S-stabilized 5CB droplets used in the detection of LCA is ∼1.5 × 109 mL−1, we find that the configuration transition of SC12S-stabilized 5CB droplets starts at a LCA concentration of ∼150 μM. The starting transition concentration is defined as the detection limit in our studies. In the concentration range of LCA from 150 to 215 μM, both the biopolar and radial configurations are observed. However, the percentage of SC12S-stabilized 5CB droplets transited from radial to bipolar configuration increases rapidly as the increase of LCA concentrations. The slope of the transition curve in this range represents the sensitivity of SC12Sstabilized 5CB droplets for the detection of LCA. The transition curves gradually shift to the left with decreasing number of SC12-stabilized 5CB droplets. Figure 5b shows that the sensitivity of SC12S-stabilized 5CB droplets for the detection of LCA is not affected by the number of droplets. However, the detection limit of SC12S-stabilized 5CB droplets for LCA rapidly drops from ∼150 to ∼30 μM when the number of droplets is reduced from 1.5 × 109 to 7.5 × 107 (Figure 5c). The further reduction of the number of droplets to 1.5 × 107 only leads to small changes in the detection limit. Figure 6a shows the transition curves of SCnS-stabilized 5CB droplets as a function of LCA concentrations, in which the total number of droplets is kept the same (∼7.5 × 107 mL−1). Although the general trend of the percentage of the configuration transition as a function of LCA concentrations is nearly the same for SCnS-stabilized 5CB droplets, the detection limit of SCnS-stabilized 5CB droplets for LCA decreases from ∼45 to ∼10 μM when the chain length of SCnS decreases from n = 16 to n = 8 (Figure 6c). There is no change in the detection limit observed for the further reduction from n = 8 to n = 5. The chain-length-dependent transition should be related to the hydrophobicities of SCnS surfactants, which is proportional to their chain lengths. Therefore, we expect that SCnS surfactants with low hydrophobicities are more easily removed by LCA, compared to SCnS surfactants with high hydrophobicities, which may explain why the detection limit of SCnS-stabilized 5CB droplets is reduced with the decrease of SCnS chain lengths. The chain-length-dependent transition is also observed when CnTAB-stabilized 5CB droplets are used for the detection of

Figure 4. Fluorescent microscopy images of NBD-PE-stabilized 5CB droplets (a) before and (b) after exposure to LCA solution. (c) Schematic illustrations of LCA-induced radial-to-bipolar configuration transition of 5CB in surfactant-stabilized droplets.

densities at the interface can trigger a homeotropic-to-planar anchoring transition of liquid crystals.25−28 Therefore, the removal of some surfactants from the 5CB/water interface favors a radial-to-bipolar transition. In addition, the adsorption of LCA to the 5CB/water interface may also affect the surface anchoring of the 5CB inside the droplets. Our controlled experiments show that the adsorption of LCA at the 5CB/ water interface can also lead to the formation of stable bipolar 5CB droplets in aqueous solution. Therefore, we conclude that the radial-to-bipolar transition is a result of the interaction of the 5CB in the droplets with the mixed LCA/surfactant interface. The LCA-induced radial-to-bipolar transition of the 5CB inside the surfactant-stabilized droplets allows us to rapidly detect the LCA concentration in aqueous solution with a polarizing optical microscope. We find that the concentration of LCA required to trigger the configuration transition of SC12S-stabilized 5CB droplets depends on the number of droplets (Figure 5a). Here the total number of SC12S-stabilized 5CB droplets used in the detection of LCA was estimated as follows: a drop (4 μL) of a known dilution of SC12S-stabilized

Figure 5. (a) Radial-to-bipolar transition percentage of SC12S-stabilized 5CB droplets as a function of LCA concentrations. (b) Detection sensitivity of SC12S-stabilized 5CB droplets as a function of number of droplets. (c) Detection limit of SC12S-stabilized 5CB droplets as a function of number of droplets. The data points shown in (a) were obtained from the statistical result of 100 droplets from each sample. 389

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Figure 6. (a) Radial-to-bipolar transition percentage of SCnS-stabilized 5CB droplets as a function of LCA concentrations. (b) Radial-to-bipolar transition percentage of CnTAB-stabilized 5CB droplets as a function of LCA concentrations. (c) Detection limit of SCnS- and CnTAB-stabilized 5CB droplets as a function of their chain lengths. The data points shown in (a) and (b) were obtained from the statistical result of 100 droplets from each sample.

LCA (Figure 6b). The detection limit of CnTAB-stabilized 5CB droplets drops from ∼70 to ∼45 μM when the chain length of CnTAB surfactants decreases from n = 16 to n = 8 (Figure 6c), which is higher than that of SCnS-coated 5CB droplets. It has been shown that CnTAB is more efficient than SCnS in reducing the interfacial tension, which suggests that CnTAB is more surface active than SCnS.27 Thus, the CnTAB at the 5CB/ water interface is more difficult to remove than the SCnS, leading to the increase of the detection limit. Since LCA coexists with other bile acids in biological fluids, the presence of other bile acids may interfere in the detection of surfactant-stabilized 5CB droplets for LCA. It is known that cholic acid (CA) and deoxycholic acid (DCA) comprise 85− 90% of the total bile acids produced in the liver. Like LCA, both CA and DCA are able to trigger a radial-to-bipolar transition of 5CB inside the SC12S-stabilized droplets (Figure 7a). However, C12TAB-stabilized 5CB droplets are less sensitive to CA and DCA, compared to LCA. After being exposed to CA and DCA solutions with concentrations up to 200 μM, C12TAB-stabilized 5CB droplets show no configuration transition (Figure 7b). Similar to DCA and CA, we find that chenodeoxycholic acid (CDCA) is unable to induce the configuration transition of C12TAB-stabilized 5CB droplets. The selectivity of C12TABstabilized 5CB droplets for LCA over DCA, CDCA, and CA should associate with their different chemical structures. Compared to LCA, DCA and CDCA bear one additional hydroxyl group and CA bears two additional hydroxyl groups. The different chemical structures of these bile acids lead to the change of their hydrophilic−hydrophobic indexes in the order LCA > DCA > CDCA > CA.29 Thus, we can expect the different interactions of C12TAB with these bile acids at the surface of the 5CB droplets. Our results suggest that only LCA is more effective in removing C12TAB from the surface of the 5CB droplets, compared to DCA, CDCA, and CA. We also carried out the detection of LCA, CA, and DCA in PBS solution with C12TAB-stabilized 5CB droplets, showing that the high salt concentrations did not affect the selectivity of the droplets for LCA over CA and DCA. Finally, we measure the concentration of LCA required to trigger the radial-to-bipolar transition of C12TAB-stabilized 5CB droplets in the presence CA or/and DCA. The transition curves of C12TAB-stabilized 5CB droplets for the detection of LCA shown in Figure 8 are nearly the same with or without CA and DCA in aqueous solution. Thus, by using C12TAB-stabilized 5CB droplets, we can eliminate the interference of CA and DCA to selectively detect LCA in the concentration range from 0 to 200 μM.

Figure 7. (a) Radial-to-bipolar transition percentage of SC12Sstabilized 5CB droplets as a function of bile acid (BA) concentrations. (b) Radial-to-bipolar transition percentage of C12TAB-stabilized 5CB droplets as a function of bile acid (BA) concentrations. The number of droplets is ∼7.5 × 107. Data points shown in (a) and (b) were obtained from the statistical result of 100 droplets from each sample.

In conclusion, we have engineered the surface of 5CB droplets dispersed in aqueous solution by the adsorption of surfactants at the 5CB/water interface for the detection of LCA. We find that the surfactants adsorbed at the 5CB/water interface can be replaced by LCA, which triggers a radial-tobipolar configuration transition of the 5CB in the droplets. The LCA-triggered configuration transition allows the micromolar levels of LCA in aqueous solution to be detected. The detection limit of surfactant-stabilized 5CB droplets for LCA can be tuned in the range from 10 to 70 μM by changing the chain lengths of the surfactants. Furthermore, our results show that the selectivity of surfactant-stabilized 5CB droplets for the detection of LCA in the presence of structurally similar bile 390

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ACKNOWLEDGMENTS

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REFERENCES

Article

This work is supported by the National Science Foundation (CBET 0931778).

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Figure 8. Radial-to-bipolar transition percentage of C12TAB-stabilized 5CB droplets as a function of LCA concentrations in the presence of CA, DCA, and CA−DCA, respectively. Molar ratios LCA:CA = 1:1, LCA:DCA = 1:1, and LCA:CA:DCA = 1:1:1. The data points here were obtained from the statistical result of 100 droplets from each sample.

acids can be achieved by properly choosing the headgroup of the surfactants.

3. EXPERIMENTAL SECTION The liquid crystal used in our experiments was 4-n-pentyl-4′cyanobiphenyl (5CB) from Sigma-Aldrich. It has a nematic phase in the temperature range from 18 to 35.3 °C. Lithocholic acid (LCA); cholic acid (CA); deoxycholic acid (DCA); sodium alkyl sulfate (SCnS) with n = 16, 12, 8, and 5; and alkyl trimethylammonium bromide (CnTAB) with n = 16, 12, and 8 were purchased from SigmaAldrich. 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine-N-(7-nitro-21,3-benzoxadiazol-4-yl) (18:1, NBD-PE) was purchased from Avanti Polar Lipids Inc. All chemicals were used without further purification. Water used in our experiments was purified with an Easypure II system (18.2 MΩ cm and pH 5.7). LCA, CA, and DCA were dissolved in sodium hydroxide aqueous solution at ∼pH 10. The adsorption of SCnS, CnTAB, and NBD-PE at the 5CB/water interface was carried out by mixing 10 μL of 5CB in 10 mL of 1 mM surfactant solution with a bath sonicator (Bradson 2510) for 15 min at room temperature. The sonication broke 5CB into microsized droplets, which were then stabilized by the adsorption of surfactants at the 5CB/water interface. To remove excess surfactants, the surfactant-stabilized 5CB droplets were purified by washing them with deionized water through centrifugation. A polarizing optical microscope (Olympus BX40) was used in transmission mode to observe the director configuration of surfactantstabilized 5CB droplets at room temperature. The ζ-potential of surfactant-stabilized 5CB droplets was measured using a Zetasizer Nano ZS90 (Malvern Instruments Inc.) under a cell-driven voltage of 30 V. Dynamic light scattering (Precision Detector PD 2000DLS) was used to measure the size distribution of surfactant-stabilized 5CB droplets. A confocal fluorescence microscope (Zeiss) with 488 nm excitation from an Ar+ laser was used. Confocal microscopy images of surfactant-stabilized 5CB droplets were acquired by raster scanning the droplets across the focused laser beam.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. 391

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