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Manganese as a Catalytic Mediator for Photooxidation and Breaking the pH Limitation of Nanozymes Jinyi Zhang, Shihong Wu, Xiaomei Lu, Peng Wu, and Juewen Liu Nano Lett., Just Accepted Manuscript • DOI: 10.1021/acs.nanolett.9b00725 • Publication Date (Web): 09 Apr 2019 Downloaded from http://pubs.acs.org on April 9, 2019

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Manganese as a Catalytic Mediator for Photo-oxidation and Breaking the pH Limitation of Nanozymes

Jinyi Zhang,† Shihong Wu,‡ Xiaomei Lu,‡ Peng Wu*,‡ and Juewen Liu*,†

† Department

of Chemistry, Waterloo Institute for Nanotechnology, Waterloo, Ontario,

Canada N2L 3G1 ‡ Analytical

& Testing Center, College of Chemistry, State Key Laboratory of Hydraulics and

Mountain River Engineering, Sichuan University, Chengdu 610064 (China) E-mail: [email protected], [email protected] Phone number: 134-3816-3640, 519-888-4567

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ABSTRACT A long-standing challenge in nanozyme catalysis is low activity at physiological pH, especially for oxidase and peroxidase mimicking nanozymes. We herein communicate that Mn(II) can promote catalysis at neutral pH for carbon dots (C-dots) as a photo-oxidase nanozyme. The C-dots produce singlet oxygen upon light irradiation for oxidizing Mn(II) to Mn(III), which is confirmed by a suite of spectroscopic evidence. The in situ produced Mn(III) acts as a mediator, analogous to mediators in electrochemistry to enhance electron transfer. None of the other divalent metal ions show such an effect, allowing selective detection of Mn(II) down to 5 nM. EDTA further enhances the activity by stabilizing the highly

active

Mn(III),

producing

an

intense

blue

color

by

oxidizing

3,3’,5,5’-tetramethylbenzidine (TMB) in just 10 sec. Finally, this reaction was used to evaluate antioxidants. With this method, more analytical and biomedical applications of nanozymes can be exploited at neutral pH and it may inspire other strategies to overcome the pH limitation in nanozyme catalysis.

KEYWORDS: catalysis, antioxidation, carbon dots, nanozymes, biosensors

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Recently, nanomaterial-based enzyme mimics (nanozymes) have attracted enormous interest due to their lower cost and higher stability compared to natural enzymes,1-4 leading to a diverse range of applications from biosensing, imaging to tissue engineering and therapeutics. By definition, nanozymes should work efficiently in physiological conditions, but this is not always the case. For example, most oxidase and peroxidase mimicking nanozymes use chromogenic

3,3’,5,5’-tetramethylbenzidine

(TMB)

and

(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) as substrates,1,

2, 5, 6

2,

2’-azino-bis

but they cannot be

oxidized efficiently at neutral pH (e.g. pH 7), thus restricting biological applications of nanozymes. To better mimic enzymes, efforts have been made to enhance nanozyme activity at neutral pH but with limited success.7 For example, NiO nanoparticles were reported as an oxidase mimic to oxidize Amplex red (but not TMB or ABTS) at neutral pH.8 Oxidation by oxidase-mimicking CeO2 nanozyme at neutral pH was either very slow,9 or quickly inactivated in 1 min.2 A peroxidase mimic, Cu2+-modified graphene oxide, can oxidize NADH at neutral pH, but it had no activity with TMB or ABTS.10 Although Co3O4/H2O2 can oxidize TMB at neutral pH, this reaction was slow as well.11 The above examples used chemical reagents to activate oxygen or H2O2, and an alternative route is to use light.12-14 Graphene quantum dot (GQD)12 and carbon dots (C-dots)14 have a high yield of singlet oxygen (1O2) and they have been widely studied as photo-oxidase nanozymes. However, effective photo-oxidation of TMB still requires a low pH. On the other hand, horseradish peroxidase (HRP) works efficiently at neutral pH. Therefore, new strategies are needed to break the pH limitation of nanozymes. -3-


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In electrochemistry, mediators such as Fe(CN)63-/Fe(CN)64- can significantly enhance the efficiency of electron transfer since they are very stable and can be added at high concentrations. We want to develop an analogous system for nanozymes to break the pH limitation. Mn(III) has been shown to oxidize organic contaminants with extraordinarily high rates.15-17 Ligand-stabilized Mn(III) was recognized as an important redox-active intermediate in the Mn biogeochemical cycling.18 Herein, we communicate that in situ produced Mn(III) can drastically enhance the photo-oxidase activity of nanozymes for many substrates in neutral pH.

Figure 1. (A) Photographs of TMB (0.8 mM) oxidation by C-dots (5 μg/mL) in the presence or absence of Mn(II) (1 mM) and EDTA (1 mM) with light (365 nm, 10 sec) at different pH. A no light control is also presented. (B) Absorption spectra of oxidized TMB at different conditions at pH 7. (C) Enhanced TMB oxidation as a function of Mn(II) concentration with 30 μg/mL C-dots and 20 sec reaction time (Inset: the low concentration region showing a linear response). (D) Among the tested metals (1 mM each), without or with 1 mM EDTA, only Mn(II) enhanced oxidation. (E) Schematic illustration of Mn(II) enhancing the photo-oxidase activity of C-dots at neutral pH. The reaction of TMB oxidiation is also shown.

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Mn(II) promotes TMB oxidation at neutral pH. We first illuminated our C-dots with 356 nm light to generate singlet oxygen (1O2).14 The characterization of our C-dots by UV-vis, fluorescence and XPS spectroscopy, and TEM is shown in Figure S1. With just the C-dots and light, a typical pH-dependent activity trend for TMB oxidation was observed as expected (Figure 1A, top row, Figure S2), where the blue oxidation product was produced only at pH below 5.2, 14, 19-21 Without the C-dots, light irradiation alone cannot oxidize TMB (Figure S3). The electron paramagnetic resonance (EPR) spectra of the 1O2 generated by the C-dots suggested that the faster oxidation of TMB at lower pH was not due to the production of more 1O2 at this condition (Figure S4). It should be related to the chemistry of TMB, since it is known for difficult to oxidize at neutral pH.22 The migration distance of 1O2 in solution is very short (< 200 nm), which can be estimated from its short phosphorescence lifetime (~400 ns).23 Deactivation of 1O2 to the ground triplet state emits phosphorescence, and 1O2 has to encounter the substrate and complete the reaction before its deactivation. If this short lifetime or migration distance is the problem, it might be solved by adding a mediator that can diffuse for a longer time. Mediators such as Fe(CN)63-/Fe(CN)64- are frequently used in electrochemistry due to their high stability and high added concentration, significantly enhancing the efficiency of electron transfer. We wanted to use such a design principle here, and Mn(II)/Mn(III) was chosen due to the strong oxidation power of Mn(III).16, 24, 25 Interestingly, adding Mn(II) to our C-dots significantly enhanced oxidation of TMB (Figure 1A, middle row). In particular, the absorbance at pH 7.4 reached 50% of that at pH 4 (see Figure S5 for quantification). The UV-vis spectra of the reaction products in Figure 1A at pH 7 are shown in Figure 1B. A -5-


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strong absorption peak at 652 nm was responsible for the observed blue color of the TMB oxidation product. To test if this observation is unique to Mn(II), we tried 11 common metal ions. Only Mn(II) showed such an enhancement (Figure 1D, and see Figure S6 for spectra), although some other metals can also form 2+/3+ redox pairs, such as Fe and Co. The redox potentials of Fe(II)/Fe(III), Mn(II)/Mn(III), and Co(II)/Co(III) are 0.77 V, 1.54 V, and 1.81 V respectively. Although Co(III) is a stronger oxidizer, it might be unstable or not generated. For example, due to the high redox potentials of Co(II)/Co(III), 1O2 may not be able to oxidize Co(II) to Co(III). The absorption spectrum of Co(II) did not change significantly in the presence of C-dots and EDTA with light (Figure S7). Alternatively, Co(III) could be less stable than Mn(III), and thus the generated Co(III) disappeared rapidly.

Since the main focus of this study catalysis, we turned our attention to understand the reaction mechanism. We compared the activity of several oxidase and peroxidase nanozymes along with horse radish peroxidase (HRP) at pH 4 and pH 7 (Table 1). Our C-dot/Mn(II) system was activated by light, the peroxidase systems used H2O2, while the oxidase nanozymes used no light or H2O2. To reach an absorbance of 1, the other nanozymes required 15 min or more at pH 4, consistent with the literature,2

1, 11, 20, 26, 27

while the C-dot/Mn(II)

took only 10 sec. In addition, the activity of the C-dot/Mn(II) at pH 7 reached 75% of that at pH 4, representing the smallest pH influence. These properties compared favorably even with HRP. Besides, the kinetic parameters of C-dots/Mn2+ (Figure 2) and HRP/H2O2 (Figure S8) at pH 4 and 7 were measured at various concentrations of TMB. The smaller Km and higher Vmax of the C-dots/Mn2+ at lower pH is consistent with its better catalytic efficiency. -6-


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Table 1. Oxidation of TMB (652 nm) at acidic and neutral pH by various nanozymes and by HRP. Nanozymes

pH 4.0

Km

Vmax

pH 7.0

Km

Vmax

Abs, time

(mM)

(mM/s)

Abs, time

(mM)

(mM/s)

1.9×10-3

0.84, 0.4 min

7.0×10-4

0.05, 60 min

6.3×10-5

0.03, 60 min

-

0.01, 60 min

3.4×10-5

0.01, 60 min

1.9×10-5

0.06, 60 min

0.079

C-dots + Mn2+

1.12, 0.2 min

CeO2

0.62, 30 min

CeO2 + F-

1.36, 30 min

CoO

0.12, 30 min

Fe3O4 + H2O2

0.23, 30 min

Co3O4 + H2O2

0.15, 30 min

AuNPs + H2O2

0.17, 30 min

0.134

-

GO + H2O2

1.13, 15 min

0.024

HRP + H2O2

1.33, 5 min

3.8 0.14 0.098 0.063

0.051

0.105

1.5×10-3

A7.0/A4.0 75%

-

-

-

-

-

-

-

-

-

-

0.04, 60 min

-

-

24%

-

0.15, 30 min

-

-

13%

1.1×10-4

0.60, 10 min

8.0×10-5

45%

0.176

8% 2% 8% 4% 41%

Reaction conditions: C-dots (5 μg/mL) + Mn2+ (1 mM) with 356 nm light irradiation; CeO2 (100 μg/mL); CeO2 (20 μg/mL) + F- (1 mM); CoO, Fe3O4, Co3O4, GO (100 μg/mL); AuNP (40 μg/mL), and HRP (1 nM) for oxidizing TMB (0.8 mM). H2O2 was 1 mM if added. Kinetic parameters of C-dots + Mn2+ and HRP + H2O2 are from Figure 2 and Figure S8, and the rest are from the literature.1, 2, 11, 20, 26 The TEM micrographs of the nanozymes are shown in Figure S9.

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Figure 2. (A) Evaluation of the enzyme-like activity of C-dots/Mn(II) at pH 4 and 7. (A), (C) the oxidation kinetics of TMB in the presence of different concentrations of TMB; (B), (D) the corresponding Lineweaver-Burk plot. The reactions were performed with 5 μg/mL C-dots, 1 mM Mn(II) with 365 nm light irradiation at 1 sec pulses.

Mn(III) is responsible for oxidation. We have assumed the in situ produced Mn(III) to be responsible for enhanced oxidation at neutral pH, and some evidence is presented here. Aqueous Mn(III) is unstable but, it can be stabilized by ligands such as EDTA.28,

29

Interestingly, when EDTA was added, TMB oxidation was even more efficient both in acid and neutral media (Figure 1A, row 3, see Figure S5 for quantification). The color change occurred in just 10 sec. To our knowledge, this is the most efficient TMB oxidation by nanozyme at neutral pH.

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The Mn(III)/EDTA complex has an absorption peak within 400-600 nm.30 When we mixed the C-dots with Mn(II) and EDTA, no absorbance was observed in this region (Figure 3A, red spectrum). After illumination with 365 nm light, a peak emerged (blue spectrum), while no peak was observed when EDTA was omitted after illumination (black spectrum). If the C-dots were omitted, no peak was observed after illumination either regardless of EDTA (pink and green spectra). This strongly supports the generation of Mn(III)-EDTA complex.30 We then used this peak to study the stability of the Mn(III)/EDTA complex. After the initial illumination, we turned off the light. This peak was quite stable and decreased only 8.9% after 12 min (Figure 3B), but it disappeared immediately with the addition of ascorbic acid (AA), a reducing agent. The high stability of Mn(III)/EDTA allowed us to separate illumination from oxidation. For example, when TMB was added 10 min after turning off light, oxidation still occurred instantaneously (Figure 3B, inset). However, without EDTA or light, this delayed oxidation did not occur.

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Figure 3. (A) The UV-vis absorption spectra of 1 mM Mn(II) in the presence and absence of 5 µg/mL C-dots, 1 mM EDTA and light. (B) The stability of Mn(III)/EDTA in the absence and after addition of AA at pH 7.0. Inset: TMB treated by the three complexes in (A). (C) TMB (1 mM) oxidation by various illumination time periods (365 nm) with C-dots (20 μg/mL), Mn(II) (25 μM) and EDTA (50 μM) at pH 7.0. (D) The fluorescence of the C-dots unaffected by Mn(II). (E) 1O2 phosphorescence spectra induced by the C-dots collected in a CD3CN−D2O mixed solvent (v/v = 15/1) in the presence and absence of Mn(II) and EDTA. (F) Photographs of TMB oxidized by HRP and Fe3O4 with H2O2.

To test whether Mn(II) can be cycled, we used only 25 μM Mn(II) (lower than the concentration of TMB, 1 mM, Figure 3C). With continuous illumination, a steady growth of -10-


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the color was observed. After 1 min, each Mn(II) converted more than 2 TMB molecules (Figure 3C, εoxTMB = 39000 M-1cm-1), confirming its role as a catalytic mediator. Based on this, we drew the scheme of the reaction in Figure 1E. After confirming the role of in situ generated Mn(III) and its stability, we then investigated its production. The C-dots acted as a photosensitizer, but its fluorescence at 440 nm was not quenched by Mn(II) (Figure 3D; see Figure S10 for unchanged lifetime). Thus the enhanced oxidation was likely to be independent of photophysical processes of the C-dots, and we turned our attention to photochemical processes.

Figure 4. (A) The UV-vis spectra of ABTS (0.5 mM) and (B) fluorescence spectra of AR (10 μM) at pH 7 in different conditions. Insets are their photographs. (C) The structures of photosensitizers. (D) The absorbance of oxidized TMB by in the presence of PB (1 μM) and RB (1 μM) with light illumination (2 min) under different conditions in 50 mM acetic buffer (pH 7.0). Illumination wavelength: 365 nm for C-dots; 520 nm for PB and RB.

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Mn(II) can be oxidized to Mn(III) by dissolved oxygen, but the reaction rate is extremely slow.24 Given the strict requirement of light, the 1O2 generated by the C-dots might be responsible for oxidation of Mn(II).14, 31 Indeed, we confirmed the presence of 1O2 from its phosphorescence emission at 1275 nm (Figure 3E).32,

33

Adding Mn(II) decreased the

phosphorescence by about 40%, while with EDTA, the phosphorescence completely disappeared. As a further control to understand the effect of light, we found that Mn(II) did not enhance peroxidation of TMB by using either HRP or Fe3O4 (as a HRP mimic) without light at neutral pH (Figure 3F). Therefore, the role of Mn(II) was not to produce peroxide species, but to produce Mn(III). Taken together, all the evidence pointed to Mn(II) being oxidized to Mn(III) by 1O2 to achieve its role as a catalytic mediator. In situ production of Mn(III) has been reported in a few systems, for example, by using electrochemistry,34,

35

organic synthesis,36-38 and reducing manganese oxidants.15,

16

Compared to the previous work, our photochemical method has many advantages such as the use of abundant and green dioxygen for oxidation, and only requiring a brief light illumination with cost-effective C-dots. Most labs can use this method. The requirement of light could be a limitation, and this strategy may not be applicable to nanozymes without photosensitization activities. Nevertheless, the understanding on role of in situ produced Mn(III) is important for rational improving of other nanozymes. To test the generality of this reaction, we studied a few more substrates.2, 39, 40 While it was difficult for free C-dots to oxidize ABTS even at acidic pH (Figure S11A), the reaction occurred with Mn(II) and EDTA added (Figure 4A). Similarly, Mn(II) also enhanced -12-


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oxidation of AR (Figure 4B), dopamine (Figure S11B), and nicotinamide adenine dinucleotide (NADH) at neutral pH (Figure S11C). Other photosensitizers can also be promoted by adding Mn(II). The above studies used C-dots as a photosensitizer for producing 1O2. If our proposed mechanism is true, other photosensitizers might achieve the same goal. Therefore, two molecular photosensitizers, phloxine B (PB) and rose bengal (RB) were tested (Figure 4C). PB and RB possess four bromine or iodine atoms on the xanthene ring and these heavy atoms favor intersystem crossing (ISC) to activate the triplet state, which further transfers energy to oxygen to generate 1O2.13,

41

With PB and RB, we also observed enhanced oxidation of TMB in the

presence of Mn(II) at neutral pH, while the dyes did not oxidize TMB with light alone (Figure 4D). Similarly, EDTA further accelerated these reactions. At the same concentration (5 μg/mL) and light irradiation time (10 s, 365 nm for C-dot, 520 nm for RB and PB), the C-dots were 2-fold faster than the two molecular photosensitizers (Figure S12). At the same time, being a nanomaterial, the C-dots can be easily modified for various analytical and biomedical applications.

Highly sensitive detection of Mn(II). Given the excellent specificity for Mn(II), we then tested the concentration of Mn(II) required for the reaction. With more Mn(II) added, more TMB was oxidized (Figure 1C). Therefore, this system might be useful as a highly sensitive sensor for Mn(II). From this color change and by measuring the 652 nm peak intensity, Mn(II) was detected down to 5 nM based on the 3/slope calculation (see Figure S13 for optimization), where  is the standard deviation of background variation. Compared with

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previously reported assays (Table S1), this system is among the most sensitive colorimetric detection method for Mn(II).

Evaluation of antioxidants. Given the importance of the photochemical process for 1O2 production, molecules that can intervene these processes, such as antioxidants, might inhibit the reaction. Antioxidants can prevent damages to cellular components caused by reactive oxygen species (ROS),42, 43 and they can also treat patients with oxidative stress.44 Herein, AA, glutathione (GSH), glutamine (Gln), and cysteine (Cys) were tested for their antioxidation activities. Indeed, they strongly inhibited the oxidation of TMB (Figure 5). At the same time, they significantly reduced the phosphorescence of 1O2 (Figure S14), indicating they captured 1O2. In contrast, several other amino acids and glucose had little effect, and these molecules are not known for anti-oxidation activity (Figure 5).

Figure 5. Anti-oxidation tests based on C-dots/Mn(II) and TMB at pH 4 and pH 7. 120 μM of each of AA, Gln, GSH, and Cys was used. Buffer: acetic buffer: pH 4.0 and 7.0 (50 mM), 1 mM Mn(II) with 1 mM EDTA.

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Anti-oxidation was observed at both neutral and acidic pH, but some differences were noticed. Consistent with the literature, AA almost fully inhibited oxidation of TMB both at pH 4.0 and 7.0 (Figure S15A).45, 46 Interestingly, the lower concentration of GSH, Gln, and Cys had stronger antioxidant activity than AA at neutral pH (Figure S15B). These differences are likely a reflection of their pH-dependent reducing ability. In addition, since TMB is difficult to oxidize at neutral pH, the oxidation activity of nanozymes is more easily inhibited at neutral pH than at acidic pH. For example, the sensitivity to GSH was increased several times at pH 7.0 (Figure S16). Compared to some literature reported strategies of detecting antioxidants, including spectroscopy,47 photo-electrochemistry,48 and nanozymes,11,

49

our

method is simpler and faster (Table S2). In the cellular environment, many antioxidants are present. Our system evaluates the total anti-oxidation activity, while some other probes are available for detecting specific molecules such as GSH.50, 51 Both types of information are important and they are complementary to each other.

CONCLUSIONS In summary, we have made a few interesting and important observations in this study. First, Mn(II) can significantly enhance oxidation of a diverse range of substrates in the presence of 1O

2

produced via photosensitization. This can be used for highly sensitive and selective

detection of Mn(II). In addition, we have developed an Mn-mediated general oxidation method for nanozymes that can produce 1O2 to work at physiological pH, a solution for a long-standing problem in the nanozyme field. Our system can also enhance oxidation of a broad range of substrates and it would be useful for analytical and environmental -15-


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applications. Finally, this system can be used to evaluate antioxidants. The neutral reaction condition will stimulate further nanozyme studies for biological systems.

ASSOCIATED CONTENT Supporting Information Available: The Supporting Information is available free of charge on the ACS Publications website. This file includes materials, experimental methods, Table S1, S2 and Figure S1 to S16 for additional spectroscopy data and control experiments (PDF).

AUTHOR INFORMATION Corresponding Author Peng Wu and Juewen Liu E-mail: [email protected], [email protected]

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS Funding for this work was from the Natural Sciences and Engineering Research Council of Canada (NSERC), and the National Natural Science Foundation of China (21522505).

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(50) Niu, L.-Y.; Guan, Y.-S.; Chen, Y.-Z.; Wu, L.-Z.; Tung, C.-H.; Yang, Q.-Z. Bodipy-Based Ratiometric Fluorescent Sensor for Highly Selective Detection of Glutathione over Cysteine and Homocysteine. J. Am. Chem. Soc. 2012, 134, 18928–18931. (51) Yin, J.; Kwon, Y.; Kim, D.; Lee, D.; Kim, G.; Hu, Y.; Ryu, J.-H.; Yoon, J. Cyanine-Based Fluorescent Probe for Highly Selective Detection of Glutathione in Cell Cultures and Live Mouse Tissues. J. Am. Chem. Soc. 2014, 136, 5351–5358.

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