Versatile Ligand-Exchange Method for the Synthesis of Water-Soluble

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Versatile Ligand-Exchange Method for the Synthesis of WaterSoluble Monodisperse AuAg Nanoclusters for Cancer Therapy Xiaofeng Zan, Qinzhen Li, Yiting Pan, David J. Morris, Peng Zhang, Peng Li, Haizhu Yu, and Manzhou Zhu ACS Appl. Nano Mater., Just Accepted Manuscript • DOI: 10.1021/acsanm.8b01559 • Publication Date (Web): 19 Nov 2018 Downloaded from http://pubs.acs.org on November 24, 2018

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ACS Applied Nano Materials

Versatile Ligand-Exchange Method for the Synthesis of Water-Soluble Monodisperse AuAg Nanoclusters for Cancer Therapy Xiaofeng Zan,† Qinzhen Li,† Yiting Pan,† David J. Morris,‡ Peng Zhang,‡ Peng Li,†,* Haizhu Yu,†,§,* Manzhou Zhu†,* †

Department of Chemistry and Centre for Atomic Engineering of Advanced Materials, Anhui

Province Key Laboratory of Chemistry for Inorganic/Organic Hybrid Functionalized Materials, Anhui University, Hefei, Anhui, 230601, China. ‡

Department of Chemistry, Dalhousie University, 6274 Coburg Road, Halifax, NS B3H 4J3,

Canada. §

Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking

University Shenzhen Graduate School, Shenzhen, China, 518055. KEYWORDS ligand exchange; water-soluble; AuAg nanoclusters; synthesis; monodisperse

ABSTRACT: A general-applicable two-phase ligand exchange method is developed to prepare a series of monodisperse water-soluble AuAg nanoclusters. This method relies on the ligand exchange of the water-soluble ligands (e.g., tiopronin, captopril, N-acetyl-L-cysteine, 4mercaptobenzoic acid, glutathione and mercaptosuccinic acid) with phenylacetylene and triphenylphosphine co-protected AuAg precursors. Both the polyacrylamide gel electrophoresis

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(PAGE) and transmission electron microscopy (TEM) indicate the monodispersity and ultra-small size of the prepared water-soluble metal nanoclusters. In addition, the structure has also been characterized by UV-vis absorption spectroscopy, extended X-ray absorption fine structure (EXAFS), electrospray ionization time of flight mass spectra (ESI-TOF-MS spectra) etc. The preliminary application of the as-prepared AuAg nanoclusters protected with tiopronin has been explored via the post-modification of the carboxyl groups of thiols with doxorubicin (DOX).

INTRODUCTION Water-soluble ultrasmall noble (such as Au and Ag) metal nanoparticles (NPs) with diameters below 2 nm (often called nanoclusters, i.e. NCs),1,2 in which the metal core is capped by watersoluble ligands, such as amino acids,3-5 proteins,6,7 peptides,8,9 DNA,10,11 have recently attracted increasing interests. These nanoclusters usually exhibit unique physical-chemical properties, such as superior stability, low toxicity, and high biocompatibility.12,13 Thanks to these advantages, the nanoclusters have recently been widely applied in bio-imaging,14,15 sensing,16,17 drug delivery18,19 and photothermal treatments.20,21 For example, Häkkinen and co-workers developed maleimidefunctionalized Au102 as a probe for enteroviruses echovirus 1 and coxsackievirus B3.22 Gao et al. designed an artificial peptide to coat the Au5 clusters, which was found to easily enter human nasopharyngeal cancer cell mitochondria and induce cancer apoptosis.23 Xie group used 6mercaptohexanoic acid as protecting ligand to synthesize Au25clusters, and elucidated the antimicrobial activity of this cluster to both the Gram-positive and Gram-negative bacteria.24 Despite the encouraging progress, the in-vivo applications of the metal nanoclusters are still challenging, predominantly because of the difficulty in size-control of the synthesized nanoclusters. As demonstrated by recent studies, different organs can only scavenge metal


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nanoparticles within specific range of size.25-27 For example, nanoparticles with sizes < 5.5 nm can easily escape kidney filtration, while the large particles (> 15 nm) tend to prevent the renal excretion and accumulate in liver and spleen.28,29 Therefore, the size control plays a dominant role in the bio-functional (e.g., retention and elimination) of nanoclusters, and the synthesis of nanoclusters with monodispersity and high purity is attractive. So far, the most commonly used synthetic methods for water-soluble noble metal nanoclusters are the top-down and bottom-up methods.12,30 In the top-down approach, nanoclusters are synthesized by etching large nanoparticles with the target thiols ligands (such as amino acid,31 peptides,32 etc.). In the bottom-up approach, the metal precursors (generally metal salts or M-SR complex, while M=Au or Ag, SR=thiol) are directly reduced by reductant (e.g., NaBH4).33,34 As a novel type of top-down approach, the ligand exchange method has been recently developed. Generally, the ligand exchange method consists of two steps, the synthesis of a precursor, and the ligand exchange of the precursor with the target functional ligand.35,36 So far, the atomically precise/monodisperse nanoclusters protected by organic ligands have been widely explored, and some of their structures, such as Au49,37 Au3838 have been well characterized by single crystal Xray diffraction. Various synthetic methodologies such as one pot,39,40 etching41,42 and Brust method43,44 have been developed to prepare these atomically precise nanoclusters. Specifically, using atomically-precise/monodisperse nanoclusters as precursors, the ligand exchange method was found to be highly promising to produce monodisperse nanoclusters with high purity.12 Recently, Zheng and co-workers used the two-phase ligand exchange of the [Ag141Br12(SAdm)40]3+ (in CH2Cl2, S-Adm denotes 1-adamantanethiolate) with mercaptosuccinic acid (in water) to prepare the water-soluble NCs, and elucidated the same core structure in the precursor and the formed NCs via UV−vis spectrum analysis.45 Similarly, Tsukuda et al. obtained the water-


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soluble Au25 via the ligand exchange reactions of phosphine-stabilized Au11(PPh3)8Cl3 with glutathione (GSH).46 Herein, a two-phase ligand exchange method has been developed to prepare water-soluble AuAgNCs protected by tiopronin (Tio) via the AuxAg44-x alloy precursors. PAGE separation and TEM analysis show the ultrasmall size and monodispersity of the synthesized water-soluble AuAg NCs. Meanwhile, the structural analysis with UV-vis, FT-IR, EXAFS etc. indicate that the metal core structure of the AuxAg44-x precursor was retained after ligand exchange. In addition, with the same AuAg precursors, the two-phase ligand exchange method was widely applicable to prepare water-soluble AuAg NCs protected by captopril (Cap), N-acetyl-L-cysteine(NAC), 4mercaptobenzoic acid (MBA), GSH and mercaptosuccinic acid (MSA). Finally, the postmodification of tiopronin protected AuAg NCs with doxorubicin has been performed as a preliminary probe for the biological applications of the monodisperse NCs. EXPERIMENTAL SECTION Materials. All solvents and reagents were obtained from commercial suppliers (Shanghai Aladdin

Bio-Chem

Technology

Co.,

Ltd.)

without

further

purification,

including

tetrachloroauric(III) acid (HAuCl4•4H2O, ≥ 99.99% metals basis), triphenylphosphine ( ≥ 99.0%), methyl sulfide (98%), silver hexafluoroantimonate (98%), phenylacetylene (97%), sodium borohydride (98%), tiopronin (98%), captopril (≥ 98%), N-acetyl-L-cysteine (98%), 4methylthiobenzoic acid (90%), reduced glutathione (99%), mercaptosuccinic acid (98%), methylene chloride (≥ 99.9%), doxorubicin hydrochloride (98%) methanol (≥ 99.9%), n-hexane (≥ 98.0%) and ether absolute (99%). The deionized water (≥ 18.2 MΩ) used throughout this study was purified on a Millipore system (Millipore, USA). All glassware was thoroughly cleaned


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with aqua regia (HCl: HNO3 = 3:1, v:v), rinsed with copious deionized water, and then dried in an oven prior to use. Synthesis of AuAg precursors. Ph3PAuCl47 and PhC≡CAu48-51 were prepared according to reported methods. 4.0 mL of CH2Cl2 solution containing Ph3PAuCl (24.7 mg, 0.05 mmol) was added to 2.0 mL of methanol solution of AgSbF6 (19.8 mg) under vigorous stirring, and the solution turned into a suspension immediately. After reacting for 15 min at room temperature in air in the dark, the resulting solution was centrifuged for 1 min at 10000 r/min, and the AgCl precipitate was then filtered off. The filtrate was evaporated, which was then dissolved in 15 mL CH2Cl2. After that, PhC≡CAu (29.8 mg, 0.1 mmol) was added to this solution, then a freshly prepared solution of NaBH4 (0.71 mg in 1.0 mL of ethanol) was added dropwise under vigorous stirring. The solution color changed from orange to pale brown and finally to dark brown. Then the reaction was continued for 24 h at room temperature (20 °C) in air in the dark. The mixture was evaporated to give a dark solid, which was washed with methanol (8 mL, for one time) and nhexane (8 mL, for three times). Then the solution was evaporated. Synthesis of the water-soluble AuAg NCs. To 5 mL water and 5 mL CH2Cl2 suspension of AuAg precursors (5mg), 15 mg of tiopronin was added. After being stirred for 4 h at room temperature, the CH2Cl2 layers became clear, and water solution gradually changed into brown. The phenomenon indicates that the NCs gradually transferred into the water phase. In the exchange reaction of AuAg precursors with captopril, N-acetyl-L-cysteine, 4-methylthiobenzoic acid, reduced glutathione and mercaptosuccinic acid, an equivalent amount of the other water-soluble ligands (with tiopronin) were used.


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Synthesis of the AuAg-Tio-DOX NCs.52 0.5 mg of DOX was added to 2.0 mL of water solution containing 2 mg of AuAg-Tio NCs, stirring overnight at room temperature. The excess DOX was removed by dialysis diffusion against H2O for 48 h using a dialysis membrane (Sango Biotech) with a MWCO of 10 K. The water was exchanged at 6 hour intervals during dialysis. UV-vis absorption spectra were acquired using a UV2600. TEM images were recorded by JEM2100. ESI-TOF-MS spectra were recorded on a Bruker MicroTOF-Q ESI time-of-flight system (AuAg precursors operated in positive ion mode and AuAg-Tio NCs operated in the negative ion mode). X-ray photoelectron spectroscopy (XPS) was carried out on ESCALAB 250 highperformance electron spectrometer with monochromated Al Kα radiation as the excitation source. Fourier transform infrared spectroscopy (FT-IR) was recorded on a Bruker VERTEX80 + HYPERION000. Fluorescence spectra were determined by fluorescence spectrophotometry with F-7000. Inductively coupled plasma atomic emission spectrometry (ICP-AES) was recorded on an Atomscan Advantage instrument made by Thermo Jarrell Ash Corp. Raman spectra were recorded using Confocal Laser MicroRaman Spectrometer (inVia-Reflex/inVia-Reflex), excitation wavelength was 532 nm. Zeta potential of the water-soluble AuAg NCs in water was performed on a Zetasizer ZS90 zeta potential analyzer (Malvern, at 20 °C). Nuclear magnetic resonance (NMR) analysis was measured a Bruker Advance spectrometer operating at 100 MHz for

31P,

deuterated methylene chloride was used as the solvent to dissolve AuAg precursors, and deuterium oxide was used as the solvent to dissolve AuAg-Tio NCs. Au L3-edge and Ag K-edge EXAFS data was collected from the CLS@APS (Sector 20-BM) beamline at the Advanced Photon Source (operating at 7.0 GeV) in Argonne National Labs, Chicago, IL, USA. Powdered sample of the NCs was measured in X-ray fluorescence mode simultaneously with a foil reference in transmission mode. All measurements were conducted at


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room temperature and ambient pressure. EXAFS data was normalizedand transformed into k- and R-space using the Athena program with conventional procedures.53 A k weighting of 3 and Rrange of 1.5-3.3 Å was used for all FT-EXAFS spectra. A k-range of 3-11.0 Å-1 was used for the Au fitting, while a k-range of 2-12.0 Å-1 was used for the Ag fitting. The EXAFS fitting was performed using the Artemis program following the standard procedure.54 Self-consistent multiple-scattering calculations were performed to obtain scattering amplitudes and phase-shift functions used for fitting various scattering paths with the Artemis program.53 Simultaneous fitting was conducted for both the Au and Ag data. The σ2 and E0 values of the Au-S, Au-Au and Au-Ag paths were correlated together, as were the E0 values of the Ag-S and Ag-Au paths in order to minimize the number of independent values to ensure reliable fitting results were obtained. PAGE experiment was carried out by using discontinuous gels (1.5 × 80 × 70 mm). The resolving and stacking gels were prepared by acrylamide monomers with the total contents of 30 and 4 wt%. The 20 μL of AuAg NCs mixed with 5 vol% glycerol were loaded into the wells of the stacking gel and electrophoresis was then run for 2 h at a constant voltage of 150 V at 4 °C. After electrophoresis, the band was cut from the gels and soaked in ultrapure water overnight at 4 °C to obtain the solution of AuAg NCs. RESULTS AND DISCUSSION All water-soluble AuAg NCs were prepared via two steps (Figure 1). First, gold and silver precursors were reduced by NaBH4 to synthesize AuAg alloy precursors. Then, ligand exchange was performed by adding the aqueous solution of the water-soluble thiols into the CH2Cl2 solution of the AuAg alloy precursors. Here, six types of thiol ligands, namely Tio, Cap, NAC, MBA, GSH and MSA were used as the water-soluble ligand. For clarity reasons, the detailed characterization


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of the AuAg alloy precursors and the Tio protected water-soluble AuAg NCs were used as an example, and the detailed characterization of all other clusters are given in supporting information. According to the recent studies, the coating of Tio on metal NCs could prevent the aggregation of NCs.55,56 In addition, the terminal carboxylic group of Tio are labile to post-modification (with peptides or DOX ect.) to achieve applications in bio-imaging and diagnosis with different biological functions (e.g., cancer treatment).57,58 In view of the promising practical applications of the Tio protected metal NCs and the necessity for monodispersity, we first prepared the Tio stabilized AuAg nanoclusters (AuAg-Tio NCs) with the aforementioned two-phase ligand exchange method.

Figure 1. Illustrative diagram for the general synthesis and the structure of the prepared watersoluble AuAg nanoclusters. As shown in Figure 2a inset, after mixing the aqueous solution of Tio with the CH2Cl2 solution of AuAg precursors for 4 hours, the lower layer (CH2Cl2 solution) gradually became clear, and the upper layer (aqueous solution) gradually changed into brown. The purity of the AuAg-Tio NCs was preliminarily verified by the PAGE separation. As shown in Figure 2b, the PAGE of AuAgTio NCs at t=2 h (at a constant voltage of 150 V) indicates a narrow size distribution. Among the several fractions, only one component is dominant, while all other fractions are almost negligible.


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Figure 2. (a) UV-vis absorption spectra of AuAg precursors and AuAg-Tio NCs (black line: CH2Cl2 solution of AuAg precursors, red line: water solutionof AuAg-Tio NCs). Inset: the digital photo of the AuAg NCs before (left) and after (right) the ligand exchange. (b) PAGE analysis on raw product of AuAg-Tio NCs. According to TEM analysis (Figure 3), the size of AuAg precursors retained after the ligand exchange, as both AuAg precursors and AuAg-Tio NCs show good dispersion and uniform size distribution, with average diameters lower than 2 nm. For AuAg precursors, the average diameter is 1.35 ± 0.18 nm, and for AuAg-Tio NCs, the average size is 1.40 ± 0.23 nm.


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Figure 3. TEM images of AuAg NCs before and after ligand exchange with Tio. (a) AuAg precursors and (b) AuAg-Tio NCs. Insets: the histograms of core sizes. According to UV-vis absorption spectra characterizations before (in CH2Cl2 solution) and after ligand exchange (in aqueous solution), AuAg precursors exhibit four characteristic peaks at 352, 450, 492 and 634 nm (Figure 2a). Interestingly, the absorption spectra of the AuAg precursors (black line in Figure 2a) are highly close to those of Au24Ag20 NCs recently reported by Zheng et al.59 in both the appearance and the position of characteristic peaks (352 vs 351 nm; 450 vs 447 nm; 492 vs 491 nm and 634 vs 639 nm). As the UV-vis spectra is highly sensitive to the structure of the NCs, the tiny shifts (< 5 nm) of characteristic peaks mentioned above indicates that the two clusters might share the same metal framework, both of which consist of 44 metal atoms. Meanwhile, the absorption spectra of the water-soluble AuAg-Tio NCs (with three prominent peaks at 366, 487 and 632 nm) were similar to those of the AuAg precursor, and thus we anticipated that the ligand exchange did not perturb the metal core structure. This proposal is further verified by ESI-TOF-MS analysis (vide infra). According to the recent studies on absorption spectra of metal nanoclusters, the band centered at ∼634 nm could be assigned to the metal-metal transition.60 Due to the scarce contribution of the ligand shell, this peak was retained after the ligand exchange. Meanwhile, the


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peaks at 450 and 492 nm of the AuAg precursors correspond to the ligand to metal electronic transition, while the broadened peak at 487 nm in the water-soluble AuAg-Tio NCs could be caused by both the changed ligand type and the solvent effect.60,61 The high-energy peaks at 352 nm for the AuAg precursors and 366 nm for the AuAg-Tio NCs might mainly correspond to the charge transitions between the overlapped π electrons on the alkyne group or the carbonyl groups in the ligand shell. Similar absorption peaks have also been observed in the polymethyl vinyl etheralt-maleic acid protected Ag NCs.62 According to the ICP-AES analysis, the Au: Ag atomic ratio in AuAg-Tio NCs is 1.1:1. The atomic ratio of Au: Ag agrees with the XPS measurement. XPS analysis also demonstrated the change in the electronic state of Au and Ag atoms after the ligand exchange. As shown in Figure 4a and 4b, before ligand exchange, the Au 4f2/7 peak of the Au-Ag precursors is slightly higher than the Au(0) peak (84.70 eV vs 84.0 eV), and the Ag 3d5/2 peak at 368.40 eV is slightly higher than the Ag(0) peak (368.0 eV). The results reveal the oxidation state of Au and reduction state of Ag in the AuAg precursors, which correlate with the recently reported anti-galvanic reduction in Au-Ag alloy nanoclusters.63-65 After the ligand exchange, the Au 4f2/7 and Ag 3d5/2 peaks shifted to 84.35 eV and 368.15 eV, respectively. Despite the maintained oxidation state of Au and the reduction state of Ag, the shift of the peaks demonstrated the slight reduction of Au and the oxidation of Ag during the ligand exchange. Similar observation was also reported before,66 and the reason was supposed to relate to the distinct electronic effect before and after the ligand exchange (alkynes vs thiolates). Meanwhile, the coating of Tio in AuAg-Tio NCs was evidenced by S 2p peak at 162.25 eV (Figure S1).


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Figure 4. XPS spectra of (a) Au 4f and (b) Ag 3d in the AuAg precursors and the water-soluble AuAg-Tio NCs. In addition, according to the ESI-TOF-MS analysis (Figure 5), the AuAg precursors mainly compose of AuxAg44-x(Ph ≡ C)m(PPh3)nClp (Figure 5a: Au24Ag20(PhC ≡ C)15(PPh3)3Cl8, Au22Ag22(PhC≡C)18(PPh3)3Cl5 and Au19Ag25(PhC≡C)18(PPh3)4Cl5-), and the main components of AuAg-Tio NCs are AuxAg44-x(Tio)wClz (Figure 5b: Au18Ag26(Tio)18Cl8, Au19Ag21(Tio)18Cl8, Au20Ag24(C5H8NO3S)18Cl8, Au18Ag26(C5H8NO3S)20Cl6 etc.). The isotopic peaks of the target composition showed excellent consistency with the theoretical one (see Table S1 for the details). In addition, the Raman (Figure S2), P 2p XPS (Figure S3) and

31P

NMR (Figure S4) spectra

verified that the alkyne and phosphine ligands were completely removed after the ligand exchange.


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Figure 5. ESI-TOF-MS analysis of (a) AuAg precursors in CH2Cl2 (positive ion mode) and (b) AuAg-Tio NCs in aqueous solution (negative ion mode). According to the EXAFS analysis of AuAg-Tio NCs (Table 1 and Figure S5), the coordination number (CN) of Au-S is significantly lower than that of Ag-S (0.8 vs 2.6), and thus the S atoms predominantly bond to Ag atoms. Meanwhile, the high Au-Au CN values indicate that many Au atoms are located close together in the NCs, with a few Ag atoms nearby (evidenced by the high Ag-Au but low Au-Ag CN values). The Ag-Ag path is negligible from the Ag data, and thus was not included in Table 1. All these results indicate that Au atoms locate in the core of AuAg-Tio NCs, while Ag atoms mainly locate on the exterior motifs.


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Table 1. Structural parameters of AuAg-Tio NCs extracted from the EXAFS fitting (s02=0.81). Bond

CN

R (Å)

σ2 (Å) x10-3

E0 (eV)

R factor

Au-S

0.8 (3)

2.26 (3)

14 (5)

0 (4)

0.025

Au-Au

6 (4)

2.73 (5)

14 (5)

0 (4)

0.025

Au-Ag

1 (1)

2.79 (1)

14 (5)

0 (4)

0.025

Ag-S

2.6 (6)

2.47 (1)

15 (3)

-6.1 (8)

0.025

Ag-Au

2.6 (6)

2.79 (1)

19 (2)

-6.1 (8)

0.025

R is interatomic distance; σ2 is Debye-Waller factor (a measure of thermal and static disorder in absorber-scatterer distances); E0 is edge-energy shift (the difference between the zero kinetic energy value of the sample and that of the theoretical model). In FT-IR analysis of AuAg-Tio NCs (Figure 6), free tiopronin was tested as a reference, which shows characteristic S-H peaks at ~2528.8 cm-1. Such peaks disappeared in the FT-IR spectrum of AuAg-Tio NCs, indicating the coating of tiopronin on AuAg-Tio NCs. Meanwhile, the C ≡ C stretching band at 2060 cm-1 (slightly redshift compared to the 2108cm-1 peak of free acetylene, Figure S6) in the FT-IR spectra of AuAg precursors (Figure 6b, black line) is invisible in the FTIR spectrum of AuAg-Tio NCs, implying the removal of the acetylene ligand during the ligand exchange.


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Figure 6. FT-IR spectra of (a) tiopronin (black line) and AuAg-Tio NCs (red line). The -SH stretching frequency is marked. (b) AuAg precursors (black line) and AuAg-Tio NCs (red line). The aforementioned characterizations (with UV-vis, MALDI-MS, TEM etc.) elucidate the sizemaintained ligand exchange from AuAg precursor to AuAg-Tio NCs. It is noteworthy that the two-phase ligand exchange method is generally applicable to the formation of other water-soluble nanoclusters with the same core structure but different protecting ligands (the specific AuAg precursors, i.e. AuxAg44-x, was used in all the concerned two-phase ligand exchange in this study). For example, Cap, NAC, MBA, GSH and MSA all undergo the exchange reactions with the aforementioned AuAg precursors smoothly. The PAGE separation for all these water-soluble AuAgNCs showed narrow size distribution (Figure 7) and one predominant fraction, the amount of which was significantly higher than all other species. The UV-vis spectra of all the water-soluble AuAg NCs are similar (Figure 8), all of which showed characteristic peaks at around 366, 487 and 632 nm (similar to the UV-vis spectra of AuAg-Tio NCs). In addition, the TEM analysis (Figure 9) showed consistent size-distribution, and the average diameters of Cap, NAC, MBA, GSH and MSA capped AuAg NCs are 1.42±0.28 nm, 1.53±0.30 nm, 1.53±0.30 nm, 1.36±0.20 nm and 1.38±0.24 nm, respectively. In addition, Raman spectra, FT-IR and XPS of all these water-soluble


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NCs and the free water-soluble ligand were tested (Figures S2 and Figures S7-S8). The free ligands all showed characteristic S-H peaks (at around 2550 cm-1) on FT-IR, which were completely disappeared after ligand exchange. The results indicate the coating of water-soluble ligand on AuAg-Tio NCs. Meanwhile, the C≡C stretching band at 2060 cm-1 on Raman spectra of the AuAg precursors disappeared after ligand exchange, indicating the complete removal of alkyne ligands in all these cases (Figure S2). XPS spectra of Au 4f and Ag 3d in different of water-soluble AuAg NCs are also similar (Figure S8).

Figure 7. PAGE analysis of (a) AuAg-Cap NCs; (b) AuAg-NAC NCs; (c) AuAg-MBA NCs; (d) AuAg-GSH NCs and (e) AuAg-MSA NCs.


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Figure 8. UV-vis absorption spectra of the water-soluble AuAg NCs after ligand exchange, and insets: digital photos of AuAg NCs precursors (1) and after ligand exchange with Tio (2); Cap (3); NAC (4); MBA (5); GSH (6) and MSA (7).


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Figure 9. TEM images of the water-soluble AuAg NCs. (a) AuAg-Cap NCs; (b) AuAg-NAC NCs; (c) AuAg-MBA NCs; (d) AuAg-GSH NCs and (e) AuAg-MSA NCs; (f) Average size of nanoclusters protected with different ligands. With the monodisperse water-soluble metal NCs in hand, we finally attempted to testify their practical applications via the post-modification of AuAg-Tio NCs with DOX, an anticancer drug for a wide range of malignancies. AuAg-Tio-DOX NCs was prepared according to reported methods.52 After mixing DOX with the hydrous solution of AuAg-Tio NCs overnight at room temperature, excess DOX was removed by dialysis diffusion method. As shown in Figure 10a, both the changes in the distribution of the fractions on PAGE separation and the luminescence test (upon exposure to UV light) show the coating of DOX on AuAg-Tio NCs. According to fluorescence spectra (Figure 10b), AuAg-Tio-DOX NCs shows intense fluorescence, with the emission maximum appearing at about 595 nm. Comparing the UV-vis spectra of AuAg-Tio NCs and AuAg-Tio-DOX NCs, we found that DOX makes little influence on the UV-vis spectra of AuAg-Tio NCs (Figure S9). Zeta potential was tested after ligand exchange, the value of AuAgTio-DOX NCs is significantly less negative (-16.5 mV vs -34.9 mV, AuAg-Tio NCs). In addition,


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the fluorescence and excitation spectra of AuAg-Tio-DOX NCs highly resembled that of the free DOX (Figure S10). As the AuAg-Tio NCs exhibit no luminescence, we suggest that the luminescence of AuAg-Tio-DOX originated from the coated DOX. According to the recent studies, the AuAg-Tio-DOX NCs could show highly-promising applications in anti-cancer diagnosis.67,15 To this end, the prepared AuAg-Tio-DOX NCs in this study might be used as the multifunctional cancer therapy platform with both imaging and therapy activity, and the biocompatibility was expected to be superior to the reported NCs due to the ultrasmall size and the monodispersity. The related work is current underway in our lab.

Figure 10. (a) PAGE analysis on AuAg-Tio NCs (in H2O) and AuAg-Tio-DOX NCs (in H2O); (b) Emission spectra of AuAg-Tio NCs and AuAg-Tio-DOX NCs. Insets: digital photos of AuAgTio NCs and AuAg-Tio-DOX NCs upon excitation at 365 nm. CONCLUSIONS We developed a two-phase ligand exchange method to synthesize a series of water-soluble nanoclusters with high monodispersity. This method relies on the synthesis of AuAg alloy


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precursors co-protected by alkyne and phosphine ligands, from which the two-phase ligand exchange could be easily carried out. This method is applicable to various water-soluble ligands, such as tiopronin, captopril, N-acetyl-L-cysteine, 4-mercaptobenzoic acid, glutathione and mercaptosuccinic acid. These water-soluble AuAg NCs have advantages inthe ultrasmall size (< 2 nm) and high monodispersityas elucidated by PAGE and TEM etc. This study provides a straightforward method to prepare the ultra-small, water-soluble metal nanoclusters with high monodispersity, and will hopefully motivate the future design and practical applications of watersoluble metal nanoclusters with various functionality. ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website. ESI of experiment and simulation AuAg precursors and water-soluble AuAg-Tio NCs (Table S1.); XPS spectra of S 2p in AuAg-Tio NCs (Figure S1); Raman spectra of phenylacetylene, AuAg precursors and all water-soluble AuAg NCs (Figure S2); XPS spectra of P 2p in AuAg precursors and all water-soluble AuAg NCs (Figure S3); 31P NMR spectra of the AuAg precursors and the water-soluble AuAg-Tio NCs (Figure S4); Experimental EXAFS and best fit of AuxAg44-x (Figure S5); FT-IR spectra of the AuAg precursors and PhC≡CH (Figure S6); FTIR of all free water-soluble ligands and all water-soluble AuAg NCs (Figure S7); XPS spectra of Au 4f and Ag 3d in the AuAg precursor and and all water-soluble AuAg NCs (except AuAg-Tio NCs) (Figure S8); UV-vis absorption spectra of free DOX, AuAg-Tio NCs and AuAg-Tio-Dox NCs (Figure S9); Emission spectra of AuAg-Tio NCs, free DOX and AuAg-Tio-DOX NCs and excitation spectra of free DOX and AuAg-Tio-DOX NCs (Figure S10) (PDF)


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AUTHOR INFORMATION Corresponding Author *E-mail:[email protected] (P. L.) *E-mail: [email protected] (H.Y.). *E-mail: [email protected] (M.Z.). ORCID Peng Li: 0000-0002-0574-3044 Peng Zhang: 0000-0003-3603-0175 Haizhu Yu: 0000-0003-3010-1331 Manzhou Zhu: 0000-0002-3068-7160 Notes The authors declare no competing financial interest. ACKNOWLEDGMENT We acknowledge financial support from the National Natural Science Foundation of China (21631001, 21672001, 21571001, 21372006, U1532141 and 11374013), the Ministry of Education, and the Education Department of Anhui Province. P. Z. thanks the financial support from NSERC Canada. This research used resources of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, and was supported by the U.S. DOE under Contract No. DE-AC0206CH11357, and the Canadian Light Source and its funding partners. Synchrotron technical


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support from Dr. Zou Finfrock at the CLS@APS Sector 20-BM beamline is gratefully acknowledged. ABBREVIATIONS NP, nanoparticle; NC, nanocluster; GSH, glutathione; Tio,tiopronin; Cap, captopril; NAC, Nacetyl-L-cysteine; MBA, 4-mercaptobenzoic acid; MSA, mercaptosuccinic acid; DOX, doxorubicin; TEM, transmission electron microscopy; ESI-TOF-MS spectra, electrospray ionization time of flight mass spectra; XPS, X-ray photoelectron spectroscopy; FT-IR, Fourier transform infrared spectroscopy; ICP-AES, inductively coupled plasma atomic emission spectrometry; EXAFS, extended X-ray absorption fine structure; PAGE, polyacrylamide gel electrophoresis; S-Adm, 1-adamantanethiolate; M-SR, Au-thiol or Ag-thiol; AuAg-Tio NCs, tiopronin stabilized AuAg nanoclusters; AuAg-Cap NCs, captopril stabilized AuAg nanoclusters; AuAg-NAC NCs, N-acetyl-L-cysteine stabilized AuAg nanoclusters; AuAg-MBA NCs, 4mercaptobenzoic acid stabilized AuAg nanoclusters; AuAg-GSH NCs, glutathione stabilized AuAg nanoclusters; AuAg-MSA NCs, mercaptosuccinic acid stabilized AuAg nanoclusters. REFERENCES (1) Jin, R.; Zeng, C.; Zhou, M.; Chen, Y. Atomically Precise Colloidal Metal Nanoclusters and Nanoparticles: Fundamentals and Opportunities. Chem. Rev. 2016, 116, 10346-10413. (2) Nasaruddin, R.; Chen, T.; Yan, N.; Xie, J. Roles of Thiolate Ligands in the Synthesis, Properties and Catalytic Application of Gold Nanoclusters. Coord. Chem. Rev. 2018, 368, 60-79. (3) Yang, X.; Luo, Y.; Zhuo, Y.; Feng, Y.; Zhu, S. Novel Synthesis of Gold Nanoclusters Templated with L-Tyrosine for Selective Analyzing Tyrosinase. Anal. Chim. Acta 2014, 840, 8792.


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SYNOPSIS


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Versatile Ligand-Exchange Method for the Synthesis of Water-Soluble

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