Gold Nanoparticle-Quantum Dot Fluorescent Nanohybrid: Application for Localized Surface Plasmon Resonance-induced Molecular Beacon Ultrasensitive DNA Detection
© The Author(s). 2016
Received: 29 September 2016
Accepted: 21 November 2016
Published: 25 November 2016
In biosensor design, localized surface plasmon resonance (LSPR)-induced signal from gold nanoparticle (AuNP)-conjugated reporter can produce highly sensitive nanohybrid systems. In order to retain the physicochemical properties of AuNPs upon conjugation, high colloidal stability in aqueous solution is needed. In this work, the colloidal stability with respect to the zeta potential (ZP) of four negatively charged thiol-functionalized AuNPs, thioglycolic (TGA)-AuNPs, 3-mercaptopropionic acid (MPA)-AuNPs, l-cysteine-AuNPs and l-glutathione (GSH)-AuNPs, and a cationic cyteamine-capped AuNPs was studied at various pHs, ionic strength, and NP concentration. A strong dependence of the ZP charge on the nanoparticle (NP) concentration was observed. High colloidal stability was exhibited between pH 3 and 9 for the negatively charged AuNPs and between pH 3 and 7 for the cationic AuNPs. With respect to the ionic strength, high colloidal stability was exhibited at ≤104 μM for TGA-AuNPs, l-cysteine-AuNPs, and GSH-AuNPs, whereas ≤103 μM is recommended for MPA-AuNPs. For the cationic AuNPs, very low ionic strength of ≤10 μM is recommended due to deprotonation at higher concentration. GSH-AuNPs were thereafter bonded to SiO2-functionalized alloyed CdZnSeS/ZnSe1.0S1.3 quantum dots (SiO2-Qdots) to form a plasmon-enhanced AuNP-SiO2-Qdots fluorescent nanohybrid. The AuNP-SiO2-Qdots conjugate was afterward conjugated to a molecular beacon (MB), thus forming an ultrasensitive LSPR-induced SiO2-Qdots-MB biosensor probe that detected a perfect nucleotide DNA sequence at a concentration as low as 10 fg/mL. The limit of detection was ~11 fg/mL (1.4 fM) while the biosensor probe efficiently distinguished between single-base mismatch and noncomplementary sequence target.
KeywordsGold nanoparticle Zeta potential Biosensor Colloidal stability Quantum dot DNA detection
The use of nanoparticles (NPs) in the field of chemical and biological-related applications has been unprecedented [1–3]. In particular, thiol-functionalized gold nanoparticles (AuNPs) have been highly utilized in medical therapies, diagnostics, and biological imaging [4–6]. The ease of synthesis, the unique physico-chemical properties (with respect to surface plasmonic feature), biocompatibility, and surface functionalization feature have made AuNPs widely applicable in sensor/biosensor design . Due to their inherent multivalent surface nature, therapeutic and diagnostic applications of functionalized AuNPs have been extensively explored [7, 8]. Passivation with small thiol ligands is one of the most efficient strategies to stabilize the surface of AuNPs as it minimizes nonspecific binding and helps to aid biocompatibility.
Apart from the stabilizing effects of thiol ligands, the terminal functional group moieties allow for conjugation/bioconjugation of AuNPs with other molecules of interest in order to form hybrid systems. Thiol AuNPs-based hybrids exhibit the optical properties of both the NP and the bonded molecule which ultimately has a stimulating effect on the targeted application. The use of thiol AuNP-based hybrids cuts across different spheres of chemical and biological domains. For example, tamoxifen-poly(ethylene glycol)-conjugated thiol AuNP was used to selectively target estrogen receptor of positive breast cancer cells . Wei et al. have reported the utilization of thiol-poly(ethylene glycol)-functionalized Au nanorods for selective photothermal and selective uptake of cancer cell [10, 11] and in the field of sensor/biosensor design, antibody-conjugated thiol-AuNPs have been used for virus detection , while conjugation to multiwall carbon nanotubes have been used for human serum albumin detection .
High colloidal stability of thiol-capped AuNPs prior to conjugation is needed to ensure that the physicochemical properties of the NP are not lost upon binding with external entities. Since chemical and biological systems are known to respond to the stability of NPs with different physicochemical responses , it is therefore crucial to explore the colloidal stability of AuNPs prior to conjugation, which may aid appropriate selection of the NP for the targeted application. Obtaining accurate data with reliable output efficiency when utilizing AuNPs within biological systems depends on appropriate characterization processes. Adequate characterization helps not only to unravel the reactivity of the NPs but also to understand its physico-chemical function. Zeta potential (ZP) is a powerful technique used in determining surface charge of NPs. Within the pharmaceutical domain, ZP has emerged as a useful tool in unraveling the physico-chemical effects of NPs [15–18]. In this study, prior to conjugation of the thiol-capped AuNPs for biosensor application, we have comparatively probed the ZP of negatively charged thioglycolic acid (TGA)-, 3-mercaptopropionic acid (MPA)-, l-cysteine- and l-glutathione (GSH)-capped AuNPs, and cationic cysteamine-capped AuNPs.
In this work, the GSH-capped AuNP was selected based on its higher colloidal stability and conjugated to compact silica (SiO2)-functionalized CdZnSeS/ZnSe1.0S1.3 alloyed quantum dots (Qdots) to form a novel fluorescent AuNP-SiO2 CdZnSeS/ZnSe1.0S1.3 Qdots nanohybrid system. The AuNP-SiO2-CdZnSeS/ZnSe1.0S1.3 Qdots nanohybrid was utilized as a fluorescent signal generator in a molecular beacon (MB) biosensor assay for ultrasensitive DNA detection. The developed biosensor operates based on hybridization of the target DNA with the loop sequence of the MB. Upon hybridization, localized surface plasmon resonance (LSPR) signal from bonded AuNP triggers fluorescence enhancement changes in the Qdots in proportion to the concentration of the targeted DNA. DNA was chosen as a model nucleic acid analyte to test the efficacy of the biosensor. Our LSPR-induced Qdots-MB biosensor can detect ultrasensitive concentration of a perfect complementary DNA and distinguishes between single nucleotide mismatch and noncomplementary sequence. In general, our work is the first to explore a nanohybrid AuNP-SiO2 CdZnSeS/ZnSe1.0S1.3 Qdot fluorophore signal system in a MB assay for DNA detection.
Chlorotrimethylsilane, tetramethylammonium hydroxide pentahydrate (TMAH), cadmium oxide (CdO), octadecene (ODE), zinc oxide (ZnO), trioctylphosphine oxide (TOPO), selenium (Se), (3-aminopropyl)trimethoxysilane (3-APTMS), trioctylphosphine (TOP), hexadecylamine (HDA), sulfur, succinic anhydride, rhodamine 6G, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS), HAuCl4·3H2O, tannic acid, TGA, MPA, l-cysteine, and GSH were purchased from Sigma Aldrich Co. LLC. (Saint Louis, MO, USA). Oleic acid was purchased from Nacalai Tesque Inc. (Kyoto, Japan). Methanol, tri-sodium citrate and potassium hydroxide (KOH), methanol, acetone, and chloroform were purchased from Wako Pure Chemical Ind. Ltd. (Osaka, Japan). An ultrapure Milli-Q Water System was used for sample preparation. The MB and synthetic DNA targets were purchased from FASMAC Co. Ltd. (Atsugi, Kanagawa, Japan). Black hole quencher-2 (BHQ-2) was used as the fluorescence quencher.
MB sequence: 5′-/NH2/GCGACTTTCAGTTATTATGCCGTTGTATTTGTCGC/BHQ-2/-3′
Full complementary DNA: AAATACAACGGCATAATAACTGAAA
Single nucleotide DNA: AAATACAACGTCATAATAACTGAAA
Noncomplementary DNA: TGAAGCTAACCGGTAAGCGCTATAG
The bold sequence is the stem sequence of the MB.
UV/vis absorption and fluorescence emission measurements were performed using a filter-based multimode microplate reader (Infinite® F500, TECAN, Ltd., Männedorf, Switzerland). Powder X-ray diffraction (PXRD) measurements were carried out using a RINT ULTIMA XRD (Rigaku Co., Tokyo, Japan) with a Ni filter and a Cu-Kα source. Data were collected from 2 theta = 5–60° at a scan rate of 0.01°/step and 10 s/point. Transmission electron microscopy (TEM) images were obtained using a TEM JEM-2100F, (JEOL, Ltd., Tokyo, Japan) operated at 100 kV. The instruments used in this work for ZP and dynamic light scattering (DLS) analyses were conducted using a Zetasizer Nano series (Malvern Inst. Ltd., Malvern, UK). Data analysis was performed using the Malvern Instrument Dispersion Technology software (version 7.1).
Synthesis of Thiol-capped AuNPs
Citrate-capped AuNPs were first synthesized according to literature procedure . Then a ligand exchange reaction, replacing the citrate capping with TGA, MPA, l-cysteine, and GSH, was carried out by our own method . A thiol-KOH-methanolic solution was first prepared. For the ligand exchange reaction with MPA, 3 g of KOH was dissolved in 40 mL of methanol and afterward 2 mL of MPA was added and the solution was stirred at an ambient temperature. Whereas, for the ligand exchange reaction with TGA, l-cysteine, and GSH, 1.5 g of KOH was dissolved separately in 20 mL of methanol and 1 mL of TGA and 1 g of l-cysteine and GSH were each added to separate KOH-methanolic solution. The citrate-capped AuNP solution was added into each of the thiol-KOH-methanol solution and stirred for few minutes at ambient temperature. The thiol-functionalized AuNPs were purified by centrifugation at 1500g for 10 min. The thiol-capped AuNP filtrate was further dissolved in ultrapure deionized water.
Cationic cysteamine-capped AuNPs were synthesized by mixing 1 mL of 1% HAuCl4·3H2O with 40 mL of water. After stirring for ~5 min, 500 μl of 1% cysteamine and 400 μl of 1% NaBH4 were added. Formation of cationic cysteamine-capped AuNPs was evident by the steady change in color of the solution from yellow to deep purple with time. The cysteamine-AuNPs were purified using acetone and acetone/chloroform mixture and stored at 4 °C prior to use.
The concentration of the stock AuNPs were determined from their absorption spectra according to literature procedure . The concentration obtained are 77 nM for TGA-AuNPs, 34 nM for MPA-AuNPs, 25 nM for l-cysteine-AuNPs, 29 nM for GSH-AuNPs, and 535 nM for cysteamine-AuNPs.
Preparation of SiO2-capped CdZnSeS/ZnSe1.0S1.3 Qdots
SiO2-capped CdZnSeS/ZnSe1.0S1.3 Qdots were prepared by silanization [22, 23] of TGA-capped alloyed CdZnSeS/ZnSe1.0S1.3 Qdots. The synthesis of alloyed TGA-capped CdZnSeS/ZnSe1.0S1.3 Qdots has been reported by our group . Briefly, amino-SiO2-CdZnSeS/ZnSe1.0S1.3 Qdots was prepared by the reaction of 10 mL aqueous solution of TGA-capped CdZnSeS/ZnSe1.0S1.3 Qdots with 3-APTMS and methanol at ambient temperature. Quenching of the reaction was performed by adding methanol and chlorotrimethylsilane basified with TMAH pentahydrate. The amino-SiO2-CdZnSeS/ZnSe1.0S1.3 Qdots were purified using acetone and chloroform. Carboxyl-silanized CdZnSeS/ZnSe1.0S1.3 Qdots were prepared by suspension of the wet precipitate of amino-SiO2-CdZnSeS/ZnSe1.0S1.3 Qdots in buffer solution at pH 9 and succinic anhydride was added to generate the carboxyl group and stirred overnight. The carboxyl-silanized CdZnSeS/ZnSe1.0S1.3 Qdots were purified using acetone and chloroform. SiO2-Qdots are used to denote the carboxyl-silanized CdZnSeS/ZnSe1.0S1.3 Qdots.
Conjugation of the SiO2-Qdots to GSH-AuNPs was performed by mixing 1 mL aqueous solution of 0.1 M EDC to 2 mL aqueous solution of the SiO2-Qdots (4 mg/mL) to activate the carboxylate group. The mixture was stirred for ~1 h after which 2 mL solution of GSH-AuNPs (4 nM) was added followed swiftly by the addition of 1 mL 0.1 M NHS. The SiO2-Qdots-AuNP nanohybrid conjugate was purified by centrifugation at 1500g for 3 min via a Nanosep® centrifugal filter having a 30,000 micron molecular weight cut-off (Pall Co., Port Washington, NY, USA).
The SiO2-Qdots-AuNP-MB biosensor probe was prepared by mixing 2 mL AuNP-SiO2-Qdots with 500 μl of 0.1 M EDC, 1.5 mL aqueous solution of the MB (0.4 μM in Tris-EDTA buffer) and 500 μl of 0.1 M NHS. The solution was stirred for ~1 h and stored at 4 °C prior to use.
Fluorescence Detection Procedure
The detection of DNA was carried out under ambient condition. The SiO2-Qdots-AuNP-MB probe solution (5 μl) was mixed with 45 μl of Tris-EDTA buffer and 5 μl of the DNA target in a 96 well plate. Afterward, the solution was allowed to hybridize for ~3 min and the fluorescence was measured at a wavelength range of 480–800 nm with an excitation wavelength of 470 nm.
Procedures for the ZP Analysis of the Thiol-capped AuNPs
Sample preparation is crucial in obtaining accurate data from the ZP analysis. Preserving the optical state of the thiol-capped AuNPs during the dilution process was our primary aim. Ideally, highly concentrated samples are not suitable for direct ZP measurements; hence, colloid solution of different thiol-capped Qdots was prepared from their stock solution in ultrapure deionized water and 800 μl of each sample solution was pipetted into a capillary cell (DTS 1060). All samples were prepared and analyzed on the same day. For each sample, the measurements were carried out in triplicate. Each sample analysis gives a mean ZP charge and a corresponding standard deviation.
Detection Principle for DNA Detection
Results and Discussion
TEM Analysis of the Thiol-capped AuNPs
UV/vis Absorption Analysis of the Thiol-capped AuNPs
DLS Analysis of the Thiol-capped AuNPs
Theoretically, the stability of NP dispersion is determined by the balance in repulsive and attractive forces . If the attractive forces are lesser than the repulsive forces, then the NP dispersion remains stable. The thiol-capped AuNPs studied in this study are anchored with negatively charged carboxylate thiol ligands; hence, the electrostatic repulsion with respect to the bulkiness of the thiol ligand is expected to dominate in solution. Also, within the pharmaceutical domain, the ZP guidelines used in classifying colloidal NP dispersion in drug delivery systems are highly unstable (±0–10 mV), relatively stable (±10–20 mV), moderately stable (±20–30 mV), and highly stable (±30 mV), respectively . We have used this guideline to assess the colloidal stability of the thiol-capped AuNPs and also to study trends in their ZP charge as a function of pH, ionic strength, and NP concentration.
The Influence of pH on the ZP of the Thiol-capped AuNPs
Effects of pH on the ZP of thiol-capped AuNPs
−44.3 ± 11.4
−52.1 ± 8.9
−36.7 ± 10.5
−50.6 ± 14.6
+33.1 ± 8.1
−51.7 ± 13.4
−50.5 ± 8.6
−43.8 ± 10.2
−53.5 ± 10.3
+37.0 ± 8.0
−52.0 ± 11.5
−49.7 ± 16.4
−44.5 ± 8.9
−58.4 ± 15.8
+33.3 ± 6.8
−54.7 ± 13.9
−49.7 ± 14.0
−32.9 ± 12.4
−55.5 ± 11.0
−27.9 ± 7.9
For the cationic cysteamine-AuNP, the ZP charge was positive between pH 3 and 7 but dramatically changed to negative at pH 9. This implies that between pH 3 and 7, the cysteamine ligand maintained its functionality as evidence from the strongly positive ZP charge which also indicated high colloidal stability. The transformation of the ZP charge from positive to negative at pH 9 indicates loss of chemical stability of the NP which may arise due to deprotonation of the thiol functional moiety or removal of the cysteamine functional group from the surface. We hereby recommend that the cationic AuNPs should be utilized between pH 3 and 7.
The Influence of Ionic Strength on the ZP of the Thiol-capped AuNPs
Effects of ionic strength on the ZP of thiol-capped AuNPs
−44.9 ± 11.7
−28.9 ± 12.6
−39.7 ± 14.0
−56.1 ± 16.4
−31.4 ± 12.1
−49.7 ± 8.2
−31.3 ± 5.9
−40.6 ± 12.6
−57.5 ± 12.9
−21.2 ± 12.4
−52.6 ± 13.2
−36.3 ± 15.0
−55.0 ± 16.9
−60.5 ± 13.0
−6.07 ± 4.6
+38.5 ± 7.2
+50.9 ± 11.9
At 104–102 μM ionic strength, the cationic cysteamine-AuNP exhibited a decreasing negative ZP charge (Fig. 6e, Table 2), thus indicating the degree of deprotonation of the functional moiety on the surface of the NP. We found the NP to exhibit high colloidal stability at ionic concentration ≤10 μM. The strong ZP charge at 0.1 μM is indicative of a highly stable colloidal NP state. It is highly recommended that the cationic AuNPs should be utilized at a very low ionic strength, typically ≤10 μM.
The Influence of NP Concentration on the ZP of the Thiol-capped AuNPs
Effects of NP concentration on the ZP of thiol-capped AuNPs
−26.2 ± 12.6
−33.4 ± 5.3
−35.3 ± 17.2
−40.0 ± 9.7
−28.7 ± 15.4
−38.3 ± 5.1
−37.9 ± 23.3
−42.2 ± 13.7
−33.5 ± 5.8
−40.5 ± 13.3
−40.0 ± 11.9
−43.3 ± 17.3
−41.9 ± 10.9
−42.3 ± 9.3
−42.6 ± 11.0
−47.3 ± 17.1
−45.1 ± 10.8
−43.6 ± 8.8
−44.8 ± 10.6
−53.3 ± 14.0
Characterization of SiO2-Qdots, SiO2-Qdots-AuNP, and SiO2-Qdots-AuNP-MB
The TEM images of AuNP-SiO2-Qdots nanohybrid and the AuNP-SiO2-Qdots-MB biosensor conjugate are shown in Fig. 7c, d. The strong coarseness of the particle morphology for AuNP-SiO2-Qdots nanohybrid is due to the strong binding of the AuNPs to the SiO2-Qdots whereas we observe a more monodisperse particle size distribution for the AuNP-SiO2-Qdots-MB conjugate due to the binding of the nanohybrid to the MB. Discussion on the ZP in probing the colloidal stability of AuNP-SiO2-Qdots and AuNP-SiO2-Qdots-MB is presented in Additional file 1: Figure S4.
Distinguishing Single Nucleotide Mismatch and Noncomplementary Sequence
The efficacy of the biosensor to distinguish single nucleotide mismatch sequence and noncomplementary sequence from the perfect nucleotide sequence was investigated. As shown in Fig. 8d, the fluorescence enhancement effect at a fixed concentration of the targets 105 (fg/mL) was slightly higher than for the perfect nucleotide sequence than for the single-base mismatch. However, for the noncomplementary sequence, the fluorescence was quenched. This demonstrates the specificity of our biosensor for the target nucleic acid.
A novel LSPR-induced biosensor for DNA detection has been developed using an AuNP-SiO2-Qdots-MB biosensor. Prior to the detection of DNA, the colloidal stability as a function of the ZP charge for four negatively charged thiol-capped AuNPs and cationic AuNPs was investigated. Results showed that high colloidal stability was maintained for the negatively charged thiol-capped AuNPs from pH 3 to 9. However, for the cationic cyteamine-AuNPs, the colloidal stability was lost at pH > 7, thus indicating that high colloidal stability is maintained between pH 3 and 7. A strong dependence of the ZP charge on the ionic strength and NP concentration was observed for all the thiol-AuNPs. For the cationic cyteamine-AuNPs, it was unraveled that a very low ionic strength of ≤10 μM is needed to achieve high colloidal stability. A plasmon-enhanced AuNP-SiO2-Qdots nanohybrid was developed and further conjugated to a MB, thus forming an AuNP-SiO2-Qdots-MB biosensor. The AuNP-SiO2-Qdots-MB biosensor detected DNA down to 10 fg/mL based on LSPR-induced fluorescence signal while single-base nucleotide mismatch and noncomplementary sequence target were distinguished.
A Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship for overseas researchers (P13454) offered by the JSPS is gratefully acknowledged. This work was supported by a Grant-in-Aid for a JSPS fellow (No. 26-04354).
OA and EYP conceived the study. OA conducted the experiments and wrote the manuscript. EYP supervised the study. All authors reviewed the manuscript. Both authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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