Highly Stable Mesoporous Luminescence-Functionalized MOF with

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Functional Inorganic Materials and Devices

Highly Stable Mesoporous Luminescence-Functionalized MOF with Excellent Electrochemiluminescence Property for Ultrasensitive Immunosensor Construction Gui-Bing Hu, Cheng-Yi Xiong, Wen-Bin Liang, Xiao-Shan Zeng, HuiLing Xu, Yang Yang, Li-Ying Yao, Ruo Yuan, and Dong-Rong Xiao ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b05038 • Publication Date (Web): 20 Apr 2018 Downloaded from http://pubs.acs.org on April 20, 2018

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ACS Applied Materials & Interfaces

Highly Stable Mesoporous Luminescence-Functionalized MOF with Excellent Electrochemiluminescence Property for Ultrasensitive Immunosensor Construction Gui-Bing Hu, Cheng-Yi Xiong, Wen-Bin Liang, Xiao-Shan Zeng, Hui-Ling Xu, Yang Yang, Li-Ying Yao, Ruo Yuan∗, Dong-Rong Xiao∗

College of Chemistry and Chemical Engineering, Southwest University, Chongqing, 400715, PR China.

Abstract:

In

this work,

metal-organic framework

a

novel mesoporous

luminescence-functionalized

(Ru-PCN-777) with high stability and excellent

electrochemiluminescence (ECL) performance was synthesized by immobilizing Ru(bpy)2(mcpbpy)2+ on the Zr6 cluster of PCN-777 via a strong coordination bond between Zr4+ and –COO-. Consequently, the Ru(bpy)2(mcpbpy)2+ could not only cover the surface of PCN-777, but also grafted into the interior of PCN-777, which greatly increased the loading amount of Ru(bpy)2(mcpbpy)2+ and effectively prevented the leaching of the Ru(bpy)2(mcpbpy)2+ resulting in a stable and high ECL response. Considering the above merits, we utilized the mesoporous Ru-PCN-777 to construct a ECL immunosensor to detect mucin 1 (MUC1) based on

∗

Corresponding author. Tel: +86-23-68252360; fax: +86-23-68254000.

E-mail address: [email protected] (R. Yuan). [email protected] (D. R. Xiao) 1

ACS Paragon Plus Environment

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proximity-induced intramolecular DNA strand displacement (PiDSD). The ECL signal was further enhanced by enzyme-assisted DNA recycling amplification strategy. As expected, the immunosensor had excellent sensitivity, specificity, and responded a wide linearly to the concentration of MUC1 from 100 fg/mL to 100 ng/mL with a low detection limit of 33.3 fg/mL (S/N=3). It is the first time that mesoporous Zr-MOF was introduced into ECL system to assay biomolecules, which might expand the application of mesoporous MOFs in bioanalysis. This work indicates that the use of highly stable mesoporous luminescence-functionalized MOFs to enhance the ECL intensity and stability is a feasible strategy for designing and constructing high-performance ECL materials, and therefore may shed light on new ways to develop highly sensitive and selective ECL sensors.

KEYWORDS:

Mesoporous

Luminescence-Functionalized

MOF;

ECL

immunosensor; PiDSD; Ru(bpy)2(mcpbpy)2+; MUC1

1. Introduction Mucin 1 (MUC1) as a transmembrane protein, which is known to be related with a variety of cancers, for example, ovarian, breast, pancreatic, and prostat, so that it was usually used as tumor markers in clinical diagonosis.1 Therefore, it is significant to sensitive detect MUC1 for the preliminary diagnosis of cancer. So far, some methods for detecting MUC1 have been reported, such as electrochemical,2 fluorescence,3 surface plasmon resonance spectroscopy (SPR),4 and electrochemiluminecence (ECL).5 Among them, ECL has attracted more and more attention because of its high 2


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sensitivity, low background signal, simple operation and rapid response.6-10 It is well known that tris(2,2'-bipyridyl)ruthenium(II) (Ru(bpy)32+) derivatives have excellent ECL luminescence and superior electrochemical properties.11 Recently, to enhance the ECL intensity, conventional methods were developing various types of nanomaterials as carriers to immobilize the Ru(bpy)32+ derivatives.12-14 However, the load capacity of the Ru(bpy)32+ derivatives was restricted by the relatively low surface area of the carrier materials. Thus, it is of great significant to exploit novel materials and new methods for stably immobilizing abundant Ru(bpy)32+ derivatives to increase the ECL response and improve the sensitivity of ECL sensors. Metal-organic frameworks (MOFs), constructed from organic ligands and metal ions,15-18 have many excellent properties such as large surface areas, permanent porosity, and easily tailorable pores and functions.19-22 As a result, MOFs have potential applications in many fields, such as gas storage,23 separation,24,25 catalysis,26 sensing27 and drug delivery.28-30 More importantly, MOFs can serve as the platform for integrating various functional species to develop novel composite/hybrid materials with excellent chemical properties.31-33 Therefore, MOFs maybe promising carrier materials to load luminophore for the construction of ECL sensors. Recently, some groups have introduced MOFs into the construction of ECL analytical systems.34-37 And our group has synthesized the MOF with good ECL properties by directly using the luminophore Ru(dcbpy)32+ as the ligand to detect NT-proBNP.38 Because of the large surface area of MOFs, it increases the loading number of luminophores, which may greatly enhance the sensitivity of the sensors. However, there are still some 3



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shortcomings in the reported MOF-based ECL sensors. Firstly, because of the low stability of most MOFs in aqueous environments, the leaching of luminophores in the testing process may affect the stability and repeatability of the MOF-based ECL sensors. Secondly, owing to the large steric hindrance of Ru(bpy)32+ derivatives, it is difficult to immobilize Ru(bpy)32+ into the internal of microporous MOFs, which might limit the loading amount of Ru(bpy)32+ derivatives. Finally, the insulating shell of MOFs might block the electron excitation of the luminophores, which might lead to the relatively low efficiency of luminophores.39 Therefore, to overcome the above shortcomings, it is desirable to seek the highly stable mesoporous MOFs40,41 to load Ru(bpy)32+ derivatives through a stable immobilization strategy. As a mesoporous MOF featuring 3.8 nm cages, 6-connected Zr6 clusters and exceptionally high water stability, PCN-777 is an ideal platform to incorporate functional molecular components through postsynthetic modification.42 Thus, herein we chose PCN-777 as carrier to immobilize Ru(bpy)2(mcpbpy)2+ through solvent-assisted ligand incorporation (SALI) approach43-45 and successfully prepared a highly

stable

mesoporous

luminescence-functionalized

MOF

(Ru-PCN-777).

Compared with microporous luminescence-functionalized MOFs,46,47 there are two major advantages for the Ru-PCN-777: (i) PCN-777 is a highly water-stable mesoporous MOF, and therefore the Ru(bpy)2(mcpbpy)2+ could not only cover the surface of PCN-777, but also graft into the interior of PCN-777, which greatly increased the immobilization amount of Ru(bpy)2(mcpbpy)2+. (ii) Because the Ru(bpy)2(mcpbpy)2+ is coordinated to the Zr6 nodes of PCN-777 via a strong bond 4


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between Zr4+ and –COO- (Scheme 1), the Ru-PCN-777 showed good chemical stability in aqueous environments, which effectively prevented the leaching of the Ru(bpy)2(mcpbpy)2+. Furthermore, due to the mesoporosity of Ru-PCN-777, the Ru(bpy)2(mcpbpy)2+ on the surface and interior of Ru-PCN-777 could be excited by the electrons, resulting in the increasing utilization ratio of the Ru(bpy)2(mcpbpy)2+. Because of the above merits, Ru-PCN-777 exhibited excellent ECL property and high stability, making it a promising bioanalysis material. In addition, compared with some amplification strategies, for example, strand-displacement amplification (SDA) and rolling circle amplification (RCA),48-50 enzyme-assisted amplification strategy has attracted increasing interest in sensor fabrication owing to it provide a simpler and faster way to construct the sensitive sensor.51

Scheme 1. (A) Structure of PCN-777. (B) Schematic depiction of the SALI approach to incorporate Ru(bpy)2(mcpbpy)2+ inside the channels of PCN-777. In consideration of the above-mentioned excellent properties, Ru-PCN-777 was employed to fabricate a ECL sensor by proximity-induced intramolecular DNA strand 5



displacement (PiDSD)52 for MUC1 determination. To improve the ECL signal, polyethylenimine (PEI) was modified on the surface of Ru-PCN-777 as coreactant of the ruthenium complex.53,54 The preparation process of the sensor is displayed in Scheme 2. First, Nafion was placed onto the surface of the electrode to capture AuNPs-PEI@Ru-PCN-777 through electrostatic adsorption. The gold nanoparticles (AuNPs) were modified on PEI to label the ferrocene-labeled hairpin DNA (Fc-H4) with –SH terminal by Au-S bonds, in which the ECL response of the Ru luminophore was quenched by the nearby Fc (the signal off state). At the same time, ssDNA1 (H1) and ssDNA2 (H2) were labeled by Ab1 and Ab2 respectively (Ab1-H1, Ab2-H2). Then, Ab1-H1 and ssDNA3 (H3) were hybridized to prepare Ab1-H1-H3 complex. The H3 was released from Ab1-H1-H3 complex through PiDSD with Ab1-H1-H3 and Ab2-H2 in the presence of MUC1. Finally, the hairpin structure of Fc-H4 was opened in the presence of H3, which separated the Fc from AuNPs-PEI@Ru-PCN-777 to produce a signal on state. To improve the sensitivity of the immunosensor, nicking endonuclease (Nt. BbvCI) was introduced to achieve the H3 recycling, which greatly enhanced the ECL response. Satisfactorily, owing to the excellent ECL property of Ru-PCN-777, the immunosensor exhibits excellent sensitivity, high stability and broad linear range in MUC1 detection. This work using highly stable mesoporous luminescence-functionalized MOFs to enhance the ECL intensity and stability opens a feasible route for the design and fabrication of high-performance ECL materials, and therefore may reveal new opportunities for developing ultrasensitive ECL sensors.

6


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Scheme 2. (A) The preparation of AuNPs-PEI@Ru-PCN-777 and (B) fabrication of the immunosensor for the detection of MUC1.

2. Experimental 2.1 Fabrication of the ECL immunosensor

First, in order to form the hairpin structure, 2.5 µM Fc-H4 was heated to 95 °C for 3 min and cooled to 55 °C. The glassy carbon electrode (GCE) was preconditioned as our previous method55 before modification. After 3 µL Nafion was added into the GCE, 10 µL Au-PEI@Ru-PCN-777 and 10 µL the hairpin structure of Fc-H4 solution were added into the electrode separately and incubated at 37 °C for overnight. Subsequently, 15 µL BSA (1%) was utilized to block the remaining active sites at at

7



room temperature for 1 h. After every modified step, the resultant electrode was cleaned with PBS (pH 7.4).

2.2 Analytical procedure

For MUC1 detection, 10 µL the prepared PiDSD reaction mixture solution was dropped into the prepared immunosensor and then 10 µL nicking endonuclease (Nt. BbvCI) was introduced, followed by incubating 1.5 h at 37 °C. Then, the prepared immunosensor was placed in an ECL detector cell containing 3 mL PBS (pH 7.4) to measure the ECL intensity of the sensor.

3. Results and discussion 3.1 Characterization of PCN-777 and Ru-PCN-777

To characterize the morphologies of the prepared PCN-777, the scanning electron microscopy (SEM) was utilized. As shown in Figure S1, the uniformly distributed octahedron shapes were observed for PCN-777. The X-ray powder diffraction (XRPD) patterns of PCN-777 and Ru-PCN-777 exhibit several peaks in 2θ ranged 1-30° (Figure S2), which match with the simulated XRPD pattern. The combination of PCN-777 with Ru(bpy)2(mcpbpy)2+ through a strong coordination bond between Zr4+ and carboxyl groups was characterized by FTIR spectroscopy. As shown in Figure S3, compared with Ru(bpy)2(mcpbpy)2+, the absence of the absorption peak at around 1700 cm-1 in Ru-PCN-777 ascribed to the protonated carboxyl groups, which indicated that the carboxylate groups of Ru(bpy)2(mcpbpy)2+coordinated to the Zr4+. 8


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The color variation of PCN-777 when loaded with Ru(bpy)2(mcpbpy)2+ through SALI approach was shown in Figure S4. All these results demonstrated the successful preparation of the PCN-777 and Ru-PCN-777.

3.2 The Ru-PCN-777’s possible ECL mechanism

On the basis of previous results,56,57 we assume the Ru-PCN-777’s possible ECL mechanism as follows (1)-(4): [Ru2+-PCN-777] – e- → [Ru3+-PCN-777]

(1a)

PEI – e- → PEI•+

(1b)

PEI•+ → PEI• + H+

(2)

[Ru3+-PCN-777] + PEI• → [Ru2+*-PCN-777] + PEI

(3)

[Ru2+*-PCN-777] → [Ru2+-PCN-777] + hv

(4)

Figure 1. (A) The ECL signals of every modified electrodes: (a) bare GCE, (b) AuNPs-PEI@Ru-PCN-777/Nafion/GCE,

(c)

H4-Fc/AuNPs-PEI@Ru-PCN-

777/Nafion/Nafion/GCE, (d) BSA/H4-Fc/AuNPs-PEI@Ru-PCN-777/Nafion/GCE, and (e) H3/BSA/H4-Fc/AuNPs-PEI@Ru-PCN-777/Nafion/GCE. (B) CVs profiles of (a) bare GCE, (b) Nafion/GCE, (c) AuNPs-PEI@Ru-PCN-777/Nafion/GCE, (d) H4-Fc/AuNPs-PEI@Ru-PCN-777/Nafion/GCE, (e) BSA/H4-Fc/AuNPs-PEI@Ru9



Page 10 of 25

PCN-777/Nafion/GCE.

3.3 Characteristics of the ECL immunosensor

The ECL characterization of the sensor was shown in Figure 1A, the bare GCE had almost no ECL response (curve a) while the ECL intensity was significant increased (curve b) after the AuNPs-PEI@RuPCN-777 was added into the electrode. After modification of the hairpin structure of Fc-H4 and BSA, the ECL intensity was greatly reduced (curve c and d), because the ECL emission of Ru luminophore was quenched by the nearby ferrocene and transfer of the electrons was blocked by BSA. However, an increased ECL signal was obtained (curve e) after dropped the prepared PiDSD reaction mixture solution (the MUCI at a final concentration of 10 ng/mL) and 10 µL nicking endonuclease (Nt. BbvCI), because the hairpin structure of Fc-H4 was opened in the presence of H3 that make the Fc separate from AuNPs-PEI@Ru-777 to produce a signal on state. In addition, the ECL signal of the prepared AuNPs-PEI@Ru-PCN-777 has no significant changes under consecutive cyclic (Figure

S5),

which

suggested

the

high

stability

of

the

prepared

AuNPs-PEI@Ru-PCN-777. Furthermore, the stepwise preparation of the immunosensor was characterized by cyclic voltammograms (CVs) with 5 mM [Fe(CN)6]3-/4-. As depicted in Figure 1B, compare to bare GCE (curve a), the current obviously reduced when Nafion was modified on the electrode (curve b) due to Nafion hindered the electron transfer. When Au-PEI@Ru-PCN-777 was placed onto the GCE, the enhanced redox peak 10


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currents (curve c) were observed because the good conductivity and large surface area of Au-PEI@Ru-PCN-777 promotes the electron transfer. However, the redox peak currents were decreased after modification of the hairpin structure of Fc-H4 and BSA (curve d and e) owing to the hindrance of these biomacromolecules. All these results indicated that the ECL immunosensor was successfully fabricated as expected.

3.4 Optimization for the reaction time of PiDSD

The PiDSD reaction time played a critical role in influencing the sensitivity of the immunosensor. To obtain the maximum recovery efficiency of ECL signal, the PiDSD reaction time was optimized with 100 ng/mL MUCI. As displayed in Figure S6, the ECL signal drastically increased with increasing PiDSD reaction time, and the ECL intensity almost reached the maximum at 90 min. Therefore, the optimal reaction time was 90 min.

3.5 Analytical performance of ECL immunosensor

As illustrated in Figure 2A, the ECL signal gradually increased with the concentration of MUC1 increased from 100 fg mL to 100 ng/mL. The linear equation of ECL signals was I=5288.0 + 976.2lgcMUC1 and the correlation coefficient was 0.9963 with detection limit of 33.3 fg/mL. As Figure 2B shown, the stable ECL signals were discovered at different concentration, proving that the sensor has good stability for detecting MUC1. The comparison results of this work with other reported analytical

11



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methods were displayed in Table 1, which indicated that the biosensor could be used as a suitable tool for MUC1 determination. Table 1. Comparison of this work with other methods for detecting MUC1. Method

Detection range

Detection limit

Refs.

electrochemical

10 pM − 1 µM

4 pM (1.2 pg/mL) [a]

2

fluorescence

0.01 − 5 nM

3.33 pM (1 pg/mL) [a]

3

electrochemiluminescence

64.9 − 1036.8 nM

40 nM (12 µg/mL) [a]

5


1 fg/mL − 10 ng/mL

0.23 fg/mL

58


0.0001 − 100 ng/mL

33.3 fg/mL

this work

[a] Calculated supposing the formula weight of MUC1 as 300 kDa mol-1.59

3.6 Selectivity, stability and reproducibility of the ECL immunosensor

Some possible interferences, for example, α-1-fetoprotein (AFP), β2-microglobulin (β2-MG), cholesterol, uric acid (UA), were used to explore the selectivity of the immunosensor. Figure 3A shown that the ECL responses have no significant changes compared with the blank sample when AFP (20 ng/mL), β2-MG (20 ng/mL), cholesterol (20 ng/mL) and UA (20 ng/mL) solutions were incubated alone. Meanwhile, there were no significant changes compared to the MUC1 (10 ng/mL) when the ECL sensor was incubated with MUC1 (10 ng/mL) containing different possible interference. All these results showed that the ECL immunesensor has highly selectivity for MUC1. Simultaneously, the ECL signals were no significant changes with 1 pg/mL MUC1 under consecutive cyclic potential scans for 18 cycles and the 12


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relative standard deviations (RSD) was 3.12% (Figure 3B), which proved the good stability of the sensor. In addition, the RSD of the intra- and inter-assay were no more than 5% indicating the excellent reproducibility of the ECL immunosensor for detecting MUC1.

Figure 2. (A) ECL response of the immunosensor with the different concentrations of MUC1. Inset: calibration curve for MUC1 determination. The MUC1 concentrations: (a) 0.0001, (b) 0.001, (c) 0.01, (d) 0.1, (e) 1, (f) 5, (g) 10, and (h) 100 ng/mL. (B) The ECL response of the immunosensor with various concentrations of MUC1.

Figure 3. (A) The selectivity of the ECL sensor with various antigens. (B) Stability of the ECL sensor under a continuous scan for 18 cycles in 1 pg/mL MUC1.

3.7 Analysis of human serum samples

To evaluate the possibility of the immunosensor, recovery experiments were 13



performed in human serum

through

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standard addition methods. Various

concentrations of the MUC1 were dropped into the practical human blood serum (diluted 100 times with PBS). And then the ECL immunosensor was utilized to detect the MUC1 in the same way as described before. The results showed in table 2, the recovery was from 94.41 to 104.5%, which suggested that it was possible to use the ECL sensor for the practical detection of MUC1. Table 2. Analysis of actual samples. Sample number

Detiotion Times

Added (ng/mL)

Found (ng/mL)

Recovery (%)

RSD (%)

1

5

1

1.019

101.9

1.2

2

5

5

4.887

97.74

3.7

3

5

10

9.441

94.41

4.7

4

5

20

20.89

104.5

3.6

4. Conclusion In summary, to enhance the ECL intensity and stability, a highly stable mesoporous luminescence-functionalized MOF (Ru-PCN-777) with large immobilized amount of Ru(bpy)2(mcpbpy)2+ has been judiciously synthesized and applied to fabricate a ECL immunosensor for ultrasensitive sensing of MUC1. Due to the high-efficiency Ru-PCN-777 ECL indicator and enzyme-assisted DNA recycling amplification strategy, the proposed sensor has admirable sensitivity and selectivity, excellent stability for detecting MUC1. It is the first time to develop an ECL sensor based on 14


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mesoporous Zr-MOF. Considering that a variety of stable mesoporous MOFs can be used as carrier to immobilize luminophore, this work may open a promising route for the exploration of high-performance ECL materials, thus providing a new perspective for developing sensitive ECL biosensors for biochemical analysis and clinical applications.

ASSOCIATED CONTENT Supporting Information

Rreagents

and

apparatus,

preparation

of

PCN-777,

AuNPs,

AuNPs-PEI@Ru-PCN-777 and DNA-labeled antibody, the PiDSD reaction, SEM image of PCN-777, XRPD pattern of PCN-777 and Ru-PCN-777, IR spectra of Ru(bpy)2(mcpbpy)2+,

PCN-777

and

Ru-PCN-777,

Color of

PCN-777

and

Ru-PCN-777, ECL stability of AuNPs-PEI@Ru-PCN-777, and effects of reaction time of the PiDSD on ECL response.

AUTHOR INFORMATION ∗

Corresponding authors: Tel.: +86-23-68252360; Fax: +86-23-68254000. E-mail address: [email protected] (R. Yuan), [email protected] (D. R. Xiao)

Notes The authors declare no competing financial interest. 15



ACKNOWLEDGMENT We thank the NSFC (21571149), NSF of Chongqing (cstc2016jcyjA0231), Innovation and Entrepreneurship Project for Chongqing Returned Scholars (cx2017007), 2016 Selected Science and Technology Foundation for Returned Scholars, and Foundation of State Key Laboratory of Structural Chemistry (20160010) for financial support.

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Kim,

Y.;

Kim,

Dendrimer-Encapsulated

J.

Modification

Nanoparticles

To

of

Indium Provide

Tin

Oxide

Enhanced

with Stable

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TOC graphic.

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