Insight into the Unique Fluorescence Quenching Property of Metal

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Insight into the Unique Fluorescence Quenching Property of Metal-Organic Frameworks upon DNA Binding Huai-song Wang, Hai-Ling Liu, Kang Wang, Ya Ding, Jing-Juan Xu, Xing-Hua Xia, and Hong-Yuan Chen Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.7b02256 • Publication Date (Web): 02 Oct 2017 Downloaded from http://pubs.acs.org on October 2, 2017

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Analytical Chemistry

Insight into the Unique Fluorescence Quenching Property of Metal-Organic Frameworks upon DNA Binding Huai-Song Wang,†,‡ Hai-Ling Liu,† Kang Wang,† Ya Ding,* ‡ Jing-Juan Xu, † Xing-Hua Xia*†, Hong-Yuan Chen† †

State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and

Chemical Engineering, Nanjing University, Nanjing 210093, China. ‡

Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing 210009,

China.

1 ACS Paragon Plus Environment


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ABSTRACT

Metal-organic frameworks (MOFs) have been successfully used as efficient quenchers for fluorescent DNA detection. However, the surface charge property of MOFs can inevitably affect their fluorescence quenching behavior. Herein, nanoscale MOFs (NMOFs), including MOF nanosheets and nanoparticles, have been employed to investigate the relationship between the fluorescence quenching and surface properties of NMOFs. We find that the positively and negatively charged NMOFs exhibited totally opposite fluorescence quenching properties toward negatively charged FAM-labeled double-stranded DNA (dsDNA). On the contrast, they show negligible influence on the sensing of positively charged TAMRA-labeled dsDNA. This study provides a new insight of the fluorescence quenching property of NMOFs and offers a new concept for construction of ratiometric fluorescence DNA biosensors.


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Fluorescent nanoprobes have shown widespread applications in the fields of biomolecular analysis, drug discovery, food safety and environmental monitoring. These nanoprobes are usually fluorophore-quencher pairs if nanomaterials are used as the quenchers.1-4 In the recent decade, the most adopted nanomaterials as nanoprobes include graphene oxide (GO),5,6 carbon nanotubes (CNTs),7 gold nanoparticles (AuNPs)8,9 and MoS2 nanosheets.10-12 These nanomaterials show good affinity to fluorophore labeled biomolecules, resulting in fluorescence quenching due to occurrence of fluorescence resonance energy transfer (FRET). The typical fluorescent DNA sensing processes by using dye-ssDNA/nano-quencher systems is illustrated in Scheme 1. The nano-quencher can adsorb dye-labeled ssDNA probe via the van der Waals force, resulting in a decrease of fluorescence intensity due to FRET from dye molecules to the nanoquencher. If target DNA is present, it hybridizes with the dye-labeled one on nano-quencher. The formed dye-labeled dsDNA will leave away from the nano-quencher due to the decreased adsorption affinity caused by the rigidity of double-chain structure, thus, the fluorescence of dye molecules is recovered. This fluorescence quenching mechanism coupling with biomolecular recognition events shows dependence of the distance between the dye molecule and the nanoquencher. Although these nano-quenchers have been successfully used for fluorescent sensing, the preparation of some materials is usually fussy, and most of the materials are hardly biodegradable when applied for in vivo studies. Metal-organic frameworks (MOFs) are of structural diversity, flexible porosity, and intrinsic biodegradability.13,14 Their nanoscale structures exhibit potential advantages of rational design for biosensing probes.15-17 The methods for synthesizing NMOFs are generally categorized into four approaches: nanoscale precipitation, solvothermal, surfactant-templated, and reverse microemulsion.16 It has been reported that the nanoscale MOFs (NMOFs) probes can be used for



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direct recognition of small molecules.18-21 Recently, several NMOFs have been designed as effective fluorescence sensing platform for DNA detection. The NMOFs can be prepared by electrostatic, π-stacking, and/or hydrogen-bonding interactions with dye-labeled ss-DNA probe. Meanwhile, the fluorescence of the dye will be quenched by MOF via a photoinduced electrontransfer (PET) process.22 As have been demonstrated that H2dtoaCu22, UiO-66-NH2,23 MIL-10124 and MIL-88B25 exhibit excellent fluorescence quenching ability toward dye-labeled DNA, and thus discrimination between single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) can be easily achieved.26-28

Scheme 1. Schematic illustration of the dye-ssDNA/nano-quencher systems for fluorescent sensing of target DNA.

As the size of MOFs decrease down to nanoscale, the metal ions and organic ligands on the surface of NMOFs will not be fully coordinated, leading to the NMOFs carrying different charges.29 Such charge properties of NMOFs will certainly affect their interaction with charged dye-labelled biomolecules due to the electrostatic interactions, and in turn will affect the fluorescence quenching abilities of NMOFs toward dye-labeled biomolecules.30 The relationship


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between the fluorescence quenching and surface properties of NMOFs will finally affect the performance of the established sensing platforms, however, study on this issue has not yet been reported. Herein, nanoparticulated MIL-101(Cr) and lanthanide-based nanosheet NMOFs are designed. In order to understand the relationship between the fluorescence quenching and surface properties of NMOFs, surface charge properties of the NMOFs are adjusted by using self-assembly technique. Results show that surface properties of the NMOFs play an important role in fluorescence change of charged dye molecules in aptameric sensing. The quenched FAMlabeled ssDNA adsorbed on NMOFs via van de Waals force will be further quenched when target DNA is present as has been observed in our previous report.30 This fluorescence quenching behavior is unique for MOFs and different from that of traditional nano-quenchers (GO, CNTs, Au NPs and MoS2 nanosheets). This unique fluorescence quenching property of NMOFs offers a novel concept for construction of ratiometric fluorescence DNA biosensors. EXPERIMENTAL SECTION Synthesis of MOF nanoparticles (MIL-101). MIL-101 was synthesized according to the previous reports.31,32 Typically, Cr(NO3)3·9H2O (1.6 g, 4.0 mmol), terephthalic acid (664 mg, 4.0 mmol) and HF (0.8 mL, 4.0 mmol) were mixed with ultrapure water (20 mL), and sealed in a 30 mL vial. The mixture was reacted at 210 ºC for 8 h. The obtained green crystalline product was washed with DMF and hot ethanol. Finally, the MIL-101(Cr) nanoparticle product was dried overnight under vacuum and kept in a desiccator for further experiments. The MIL-101(Cr) nanoparticles were characterized by scanning electron microscope (SEM) and X-ray powder diffractometer (XRD).



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Preparation of PEI coated MIL-101 (PEI-MIL-101). The polyethyleneimine (PEI) coating procedure was carried out by suspending 10 mg of MIL-101 in PEI aqueous solution (10 wt%). The mixture was stirred for 20 h at room temperature. After reaction, the resulting particles (PEIMIL-101) were washed with deionized water, and resuspended in 10 mM PBS buffer (pH 7.38) for fluorescent DNA sensing experiments. Preparation of positively charged graphene (G+). Graphene (2.0 mg) and CTAB (3.0 mg) were added into 2 mL ultrapure water, and ultrasonicated for 10 min. Then, the mixture was stirred for 10 h at room temperature. The CTAB modified grapheme (G+) was collected by centrifugation and washed with water. Preparation of negatively charged graphene (G-). Graphene (2.0 mg) and SDBS (3.0 mg) were added into 2 mL ultrapure water, and ultrasonicated for 10 min. Then, the mixture was stirred for 10 h at room temperature. The SDBS modified grapheme (G-) was collected by centrifugation and washed with water. Preparation of positively charged AuNPs (AuNPs+). HAuCl4 solution (0.5 mL, 16.0 mM) was added to 20.0 mL PEI aqueous solution (5.0 mM). After adjusting the solution pH to 3.7 using HCl, the mixture was allowed to stand for 6 h at room temperature. The color of the mixture was finally changed to a red color. Preparation of negatively charged AuNPs (AuNPs-). HAuCl4 solution (20.0 mL, 0.4 mM) was heated to 100 ºC and vigorously stirred. Then, sodium citrate solution (0.3 mL, 0.2 M) was added quickly to the HAuCl4 solution. After the color of the solution was turned to dark-red, the reaction was allowed to run for additional 10 min. Finally, the solution was cooled to room temperature with continuous stirring. The product was stored in dark at 4 °C.


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Fluorescent DNA sensing. Typically, in 400 μL PBS buffer (10 Mm, pH 7.4) with 40 nM dye-labeled P1 (FAM-P1 or TAMRA-P1), another 400 μL PBS buffer (10 Mm, pH 7.4) containing 0.4 mg·mL-1 MIL-101 (or 0.4 mg·mL-1 PEI-MIL-101, 50 μL AuNPs+ dispersion, 50 μL AuNPs- dispersion, 0.06 mg·mL-1 G+, 0.06 mg·mL-1 G-) was added and incubated for 5 min before hybridized with the target DNA T1. Then, the T1 (30 nM) was added into the mixture and hybridized with P1 for another 5 min at room temperature. The fluorescence of the mixture was then detected.

RESULTS AND DISCUSSION In our early research, a series of lanthanide-based MOF (MOF-Ln) nanosheets, synthesized from Ln(NO3)3 (Ln = La, Nd, Eu, Tb and Er respectively) and the ligand 2,2′-thiodiacetic acid, exhibited special fluorescence quenching property toward dye-labeled aptamers.30 The FAM labeled DNA exhibited different fluorescence quenching behaviors on La-MOF nanosheets and on MoS2 nanosheets, even the structures of these MOF-Ln nanosheets are similar to MoS2 nanosheets:33 the MOF-Ln nanosheets are of 2D structure stacking one or two metal planes between two negatively charged sulfur-containing planes. The FAM-labeled DNA shows different sensing processes on the platforms of MOF-Ln and MoS2 nanosheets (Figure S1). In this work, the fluorescence quenching behaviors of NMOFs (including MOF nanosheets and nanoparticles) were carried out by comparing with other nano-quenchers (graphene, CNTs, Au NPs and MoS2 nanosheets). The well-known MOF, MIL-101, was selected to investigate the fluorescence quenching behaviors affected by the surface charge properties of the NMOFs. The MIL-101 was prepared according to the previous reports (Figure S2A).31,32 The XRD pattern of



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the synthesized MIL-101crystals is in good agreement with the simulated one, showing the successful preparation of MIL-101 (Figure S2B).34 In deionized water, a positive zeta potential of +17 mV is observed for MIL-101, indicating the positive charge property on the surface of MIL-101 particles. The experiments of aptameric sensing were performed in PBS. We investigated the zeta potential of MIL-101 in PBS with different values of pH (Figure 1). We find that the MIL-101 in PBS is negatively charged in PBS. With the increase of pH value (from 5.29, 6.24, 7.38 to 8.04), more negative charges are observed. We propose that HPO42- in PBS can be adsorbed/coordinated on Cr3+ ions that are not fully coordinated. Because of steric structure of HPO42-, not all of the PO- groups can be adsorbed/coordinated on the surface Cr3+ ions. Therefore, the surface of MIL-101 carries negative charges (Figure S3). In PBS with high pH, more HPO42- groups are present, therefore, more HPO42- groups will be adsorbed/coordinated on Cr3+ ions, resulting in large zeta potential of MIL-101.

Figure 1. Zeta potentials of MIL-101 and PEI-MIL-101 in PBS with different pH values.


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Considering that the charge property of MIL-101 might have an influence on the fluorescence quenching behavior during the aptameric sensing, two fluorophores (FAM and TAMRA) with different charge groups were selected and labeled on P1 (aptamer for a Homo sapiens tumor suppressor gene), respectively (Figure S4). We find that the fluorescence quenching or recovery can be significantly affected by the charge properties (positive or negative) of the labeled fluorophores on DNA (Scheme 2).

Scheme 2. Schematic illustration of the fluorescent DNA assay with MIL-101(Cr) as a sensing platform (F.I.: means fluorescence intensity).

Figure 2A and Figure S5 show the typical fluorescence emission spectra of FAM-P1 and TAMRA-P1 in PBS with and without target DNA (T1) upon addition of MIL-101. For TAMRAP1, the fluorescence intensity decreases rapidly when MIL-101 is added into the aptamer solution. After hybridization with T1, strong fluorescence emission is recovered (Figure S5). This demonstrates that the affinity of MIL-101 toward dsDNA is weaker than ssDNA. However,



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for FAM-P1, a different fluorescence quenching behavior is observed. The fluorescence of FAM-P1 is partly quenched when it interacts with MIL-101, then it will be further quenched after hybridization with T1 (Figure 2A). We propose that the FAM-dsDNA (FAM-P1+T1) does not leave away from the MIL-101, but re-adsorbs onto the surface of MIL-101. Because the negatively charged carboxyl and phenolic hydroxyl groups on FAM can substitute the HPO42ions previously adsorbed/coordinated on the surface of MIL-101, then the FAM can interact with the surface Cr3+ ions and the FAM-dsDNA re-adsorbs onto MIL-101, resulting in further fluorescence quenching. In contrast, TAMRA-dsDNA (TAMRA-P1+T1) containing positively charged groups (quaternary ammonium groups) cannot substitute the previously adsorbed HPO42-, thus, the TAMRA-dsDNA will leave the MIL-101, and its fluorescence is recovered accordingly.

Figure 2. Fluorescence quenching properties of MIL-101 toward FAM labeled DNA. (A) Fluorescence spectra of FAM-P1 (20 nM) with T1 (30 nM) in 10 mM PBS (pH 7.38) containing 0.2 mg·mL-1 MIL-101 (F.I.: means fluorescence intensity. The excitation wavelength was 480 nm). (B) Fluorescence spectra of FAM-P1 (4


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nM) with T1 (6 nM) in 10 mM PBS (pH 7.38) containing 0.2 mg·mL-1 MIL-101. (C) Fluorescence spectra of FAM-P1with different concentrations (0.1-90 nM) with T1 (1.5 times of the concentrations of FAM-P1) in 10 mM PBS (pH 7.38) containing 0.2 mg·mL-1 MIL-101 (a), and the fluorescence spectra of residues of FAM-P1 supernatants (0.1-90 nM) after centrifugation (b). (D) Mechanism of the proposed ﬂuorescent DNA sensor by using FAM labeled aptamer based on MIL-101 platform.

The concentration ratio of MIL-101 and FAM-P1 in PBS can greatly affect the aptameric sensing progress. When the concentration of FAM-P1 is 4 nM in PBS with 0.2 mg·mL-1 MIL101, the fluorescence quenching efficiency is greater than 98 % toward FAM-P1 (Figure 2B), and in the presence of target T1, the fluorescent intensities of both FAM-P1 are not changed significantly. According to Figure 2C, the fluorescence of FAM-P1 can be completely quenched when the concentration of FAM-P1 is less than 5 nM in PBS with 0.2 mg·mL-1 MIL-101. Furthermore, when the concentration of the FAM-P1 is 5 nM-30 nM (marked in red in Figure 2C) in PBS with 0.2 mg·mL-1 MIL-101, the fluorescent intensity of the mixture of FAM-P1 and MIL-101 becomes very low due to nearly all of the FAM-P1 chains adsorbing on MIL-101. However, even when the FAM-P1 chains are previously adsorbed on MIL-101, the fluorescence of FAM-P1 is only partly quenched. A mechanism is then proposed and illustrated in Figure 2D. When less of FAM-P1 are adsorbed on the surface of MIL-101, the fluorescence of FAM-P1 will be completely quenched. With the increase of the concentration of FAM-P1, the fluorescence of FAM-P1 is partly quenched due to the steric hindrance from the high density of ssDNA chains which hampers the direct interaction between FAM and Cr ions. In the presence of target T1, the dsDNA chains will leave away from MIL-101, but the FAM groups of FAM-dsDNA can completely re-adsorb on the surface of MIL-101, which results in further fluorescence quenching. In this work, the concentration of FAM-P1 is optimized to be 20 nM in 0.2 mg·mL-1 MIL-101 and thus the fluorescence of FAM-P1 is partly quenched, which facilitates to further investigate



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the fluorescence alteration tendency (“decrease” or “increase”) of FAM-P1 in the presence of target T1 of MIL-101. Additionally, the aptameric sensing was investigated in PBS with different value of pH (Figure 3A and B). The pH value from 5.29 to 8.04 does not show obvious influence on the fluorescence intensity of TAMRA-P1 after hybridized with T1. However, it can obviously affect the fluorescence intensity of the final FAM-dsDNA (FAM-P1+T1). These results indicate that appropriate pH condition is needed for FAM-dsDNA to adsorb on the surface of MIL-101. We find that the FAM-dsDNA can better adsorb on MIL-101 in PBS with pH around 7.

Figure 3. MIL-101 and PEI-MIL-101 for aptameric sensing. (A and B) peak fluorescence intensity of TAMRA-P1 (20 nM, A) or FAM-P1 (20 nM, B) with and without T1 (30 nM) in 0.2 mg·mL-1 MIL-101 (suspended in 10 mM PBS with different pH values). (C) FT-IR spectra of MIL-101 and PEI-MIL-101. (D) Fluorescence spectra of FAM-P1 (18 nM) (B1) with T1 (25 nM) in 10 mM PBS (pH 7.38) containing 0.2 mg·mL-1 PEI-MIL-101 (The excitation wavelength was 480 nm).


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For better understanding the influence of surface charge property of MIL-101 on the fluorescence quenching behaviors, PEI was used to modify the surface of MIL-101. FT-IR spectra of the MIL-101 and PEI-MIL-101 show the characteristic absorption bands of PEI (3420 cm-1 for N-H stretch and 1106 cm-1 for C-N stretch), confirming the modification of PEI on the surface of MIL-101 (Figure 3C). The zeta potential of the prepared PEI-MIL-101 in PBS (pH 7.38, Figure 1) is +16.90 mV, which demonstrates that the surface charge property is reversed due to the generated quaternary ammonium groups in PEI layer in PBS. The fluorescence quenching property of PEI-MIL-101 toward FAM-P1 was investigated. As shown in Figure 3D, the fluorescence intensity of FAM is recovered when T1 is added into the mixture of FAM-P1 and PEI-MIL-101. This indicates that the surface charge property of MIL101 can considerably affect its fluorescence quenching behavior. The surface grafted PEI layer can block the interaction between FAM groups labeled on DNA and the Cr3+ ions that are not fully coordinated in MIL-101. Therefore, the final product FAM-dsDNA will leave away from PEI-MIL-101, but not re-adsorbs on MIL-101 (Figure S6). However, for TAMRA-labeled DNA sensing, the PEI layer has negligible influence on the progress of fluorescence quenching and recovery compared with the unmodified MIL-101 (Figure S7). Other traditional nano-quenchers (such as graphene, AuNPs and CNTs, Figure S8) with positively or negatively charged surfaces were also employed to investigate their fluorescence quenching properties toward FAM labeled DNA.35-37 As shown in Figure S9A, the zeta potentials of the prepared G+, G-, AuNPs+ and AuNPs- are +31.3 mV, -26.6 mV, 18.1 mV and 21.3 mV, respectively. The surface charge property of CNT-NH2 can be modulated by the pH value of PBS. In PBS with pH 5.29, the zeta potential of CNT-NH2 is 12.5 mV, while in PBS with pH 8.04, the zeta potential changes to 24.5 mV. For better monitoring the fluorescence



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quenching progresses of these nano-quenchers toward FAM labeled DNA, the concentration ratio of nano-quenchers to dye-ssDNA was optimized in order to have partly quenching of the fluorescence of FAM-P1 on nano-quenchers. In the presence of target T1, the fluorescence of FAM-ssDNA on all of these nano-quenchers can be recovered, but is not further quenched as that for NMOFs (Figure S9B). These results show that NMOFs exhibit unique fluorescence quenching property toward FAM labeled DNA. We propose that the unique fluorescence quenching property toward FAM labeled DNA was caused by the metal ions on the surface of NMOFS. For example, the positive zeta potential of +17 mV for MIL-101 in pure water implies that the metal ions on the surface of MIL-101 ware not yet fully coordinated, and will have stronger coordination interaction with the negatively charged carboxyl and phenolic hydroxyl groups on FAM than with TAMRA containing a positive quaternary ammonium (Scheme 3).

Scheme 3. Scheme of the strong coordination interaction between the metal ions on the surface of NMOFs and FAM labeled on dsDNA.


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CONCLUSION In summary, we have revealed that the surface charge property of NMOFs (including MOF nanosheets and nanoparticles) exhibits an impotent role in fluorescent aptameric sensing when using NMOFs as the sensing platform. During DNA sensing, the negatively charged fluorophore (FAM) labeled DNA experiences a fluorescence intensity “decrease followed by decrease” process, which is different from that of the traditional nano-quenchers. The fluorescence quenching behavior can be reversed by changing the negative or positive charge property of NMOFs (MIL-101). We believe that this study provides a new concept in terms of fluorescence quenching properties of NMOFs in the context of DNA detection.

ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website. Materials and reagents, apparatus and measurements, SEM image of MIL-101, XRD pattern of MIL-101, structures of the labeled fluorophores (FAM and TAMRA) on P1, fluorescence spectra of TAMRA labeled DNA, TEM images and schematic representations of G+, G-, AuNPs+, AuNPs- and CNTs.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] (X.-H. X.). * E-mail: [email protected] (Y. D.)



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Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by the grants from the National Natural Science Foundation of China (21327902, 21635004, 21627806, 21705165).

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Graphic abstract 881x685mm (72 x 72 DPI)

ACS Paragon Plus Environment

Insight into the Unique Fluorescence Quenching Property of Metal

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