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Multiscale and Multifunctional Emulsions by Host−Guest InteractionMediated Self-Assembly Songling Han,† Siyu Chen,†,‡ Lanlan Li,†,§ Jin Li,† Huijie An,† Hui Tao,† Yi Jia,† Shan Lu,† Ruibing Wang,*,§ and Jianxiang Zhang*,† †

Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China Experimental Teaching Management Center, Bin Zhou Medical University, Yantai 264000, China § State Key Laboratory of Quality Research in Chinese Medicine, and Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China ‡

S Supporting Information *

ABSTRACT: Emulsions are widely used in numerous fields. Therefore, there has been increasing interest in the development of new emulsification strategies toward emulsions with advanced functions. Herein we report the formation of diverse emulsions by host−guest interaction-mediated interfacial self-assembly under mild conditions. In this strategy, a hydrophilic diblock copolymer with one block containing β-cyclodextrin (β-CD) can assemble at the oil/water interface when its aqueous solution is mixed with an oil phase of benzyl alcohol (BA), by host−guest interactions between β-CD and BA. This results in significantly reduced interfacial tension and the formation of switchable emulsions with easily tunable droplet sizes. Furthermore, nanoemulsions with excellent stability are successfully prepared simply via vortexing. The self-assembled oil-in-water emulsions also show catastrophic phase inversion, which can generate stable bicontinuous phase and water-in-oil emulsions, thereby further extending phase structures that can be realized by this host−guest self-assembly approach. Moreover, the host−guest nanoemulsions are able to engineer different nanoparticles and microstructures as well as solubilize a diverse array of hydrophobic drugs and dramatically enhance their oral bioavailability. The host−guest self-assembly emulsification is facile, energetically friendly, and fully translatable to industry, therefore representing a conceptually creative approach toward advanced emulsions.

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sions.20−24 In all these cases, emulsions are generally stabilized with solid/soft particles or amphiphilic surfactants with matched hydrophilic−hydrophobic balance (HLB) for applications in numerous fields.7,8,12,15,25−31 Additionally, high contents of surfactants are necessary to achieve stable nanoscale emulsions.12,14,19,32,33 Consequently, the development of either conceptually or technologically creative emulsification approaches is of great importance toward advanced emulsions.34−36 Herein we demonstrate for the first time the formation of multifunctional emulsions by host−guest interaction-mediated self-assembly of a highly hydrophilic copolymer at the oil/water interface. In this case, a hydrophilic diblock copolymer with one

INTRODUCTION Different emulsions have been broadly used in materials science,1−4 colloid chemistry,5,6 biomedical engineering,7−9 in vitro biodetection,10 pharmaceutics,11−13 and cosmetic industries.14,15 Traditional techniques, such as high-shear mixing, high-pressure homogenization, and ultrasonication are frequently employed for emulsification.14 To avoid drawbacks of these high-energy methods, self-emulsification, phase inversion emulsification, and microfluidic emulsification were established as low-energy approaches. 14,16−18 However, the lower throughput and undesirable stability of the resultant emulsions largely limit practical applications of these low-energy methods.19 Recently, controlled phase separation, self-emulsification via cooling−heating cycles, and condensing water vapor onto a subcooled oil−surfactant solution have been developed as new emulsification strategies to create different emul© XXXX American Chemical Society

Received: February 5, 2018

A

DOI: 10.1021/acscentsci.8b00084 ACS Cent. Sci. XXXX, XXX, XXX−XXX

Research Article

ACS Central Science block containing β-cyclodextrin (β-CD) units serves as a polymeric host, while benzyl alcohol (BA) is used as a guest and oil phase molecule. When aqueous solution of this copolymer and BA is mixed and dispersed via vortexing or gently shaking, interfacial assembly occurs because of host− guest recognition between BA and β-CD, resulting in significantly decreased interfacial tension and the formation of emulsions with different droplet sizes. Moreover, this strategy affords nanoemulsions simply via vortexing even at very low copolymer concentrations.

host−guest interactions between PEG−PCD and BA (Figure S2c,d). Because of this inclusion complexation, interfacial tension of BA−water was considerably decreased in the presence of PEG−PCD (Figure S3a,b). Dispersion of oil and water phases was conducted by vortexing. At 5 or 10 mg mL−1 PEG−PCD, the mean size of the oil/water systems varied with the BA volume (Figure 1d), exhibiting an initial increase and subsequent decrease, followed by a relatively slight change in the examined oil fraction range. Fluorescence spectroscopy revealed the formation of relatively hydrophobic domains in aqueous solution of PEG−PCD upon the addition of various volumes of BA (Figure S3c,d). On the basis of these results, a micelle−vesicle−emulsion transition profile was proposed for this oil/water system. At the low contents of BA, its binding with the β-CD-containing block results in micelle-like aggregates.46 Further increase in BA caused a morphological transition into vesicles.47,48 Nanoemulsions are formed with additionally increased BA. Observation by transmission electron microscopy (TEM) supported this BA contentdependent structural transition (Figure 2a). At the oil/water volume ratio of 0.005:1, small nanoparticles were observed, while a vesicle-like structure was found at 0.01:1 and 0.04:1 (Figure 2a and Figure S4). The vesicles observed at high BA contents can be attributed to evaporation of BA. We also

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RESULTS AND DISCUSSION Host−guest interactions have been extremely widely employed to engineer functional materials over length scales for diverse applications.37−43 We hypothesize that emulsification will be realized when a hydrophilic copolymer in aqueous phase can interact with oil phase molecules via host−guest interactions (Figure 1a). As a proof of concept and to investigate the

Figure 1. Host−guest recognition-mediated self-assembly of emulsions. (a) Schematic of the emulsion formation by benzyl alcohol (BA) in the existence of a β-CD containing hydrophilic block copolymer PEG−PCD. (b) Physicochemical properties of PEG−PCD. (c) ITC curve (left) and thermodynamic parameters (right) showing favorable interactions between BA and PEG−PCD. (d) Changes in the average size with increase in the oil/water volume ratio at 5 or 10 mg mL−1 of PEG−PCD. Data in part d are mean ± SD (n = 3).

emulsion formation via host−guest interaction-mediated selfassembly, a hydrophilic diblock copolymer with one polyethylene glycol (PEG) block and another block bearing β-CD units (PEG−PCD) was synthesized and used (Figure S1 and Figure 1b),44 since β-CD can interact with a large number of hydrophobic compounds via host−guest recognition.45 BA was selected as a representative oil molecule, in view of its diverse applications. For example, BA is a general solvent for different materials such as waxes, shellacs, lacquers, and epoxy resins. It is also used as a bacteriostatic preservative at low concentration in intravenous formulations, topical drugs, and cosmetics. Measurement by isothermal titration calorimetry (ITC) revealed host−guest interactions between BA and β-CD, with the binding constant of 1.4 × 103 M−1 (Figure S2a,b). Likewise, thermodynamically favorable strong interactions between PEG−PCD and BA were detected (Figure 1c). 1H NMR and 1 H−1H COSY NMR spectroscopy confirmed the presence of

Figure 2. Nanoemulsions by host−guest interaction-mediated selfassembly. (a) Sketch (left) and TEM images (right) illustrating the structural transition from micelles, vesicles, and finally to o/w nanoemulsions with increased BA in aqueous solution of PEG− PCD. (b) SRFM images of different structures at varied oil/water volume ratios. (c) Representative SRFM image (left), digital photo (middle), and size distribution (right) of assembled BA/PEG−PCD nanoemulsions. (d) Size distribution profiles of BA/PEG−PCD emulsions formed in the presence of varied concentrations of PEG− PCD at the oil/water volume ratio of 0.04:1. (e) Digital photos showing the stability of BA/PEG−PCD nanoemulsions. (f) Quantified mean diameter and polydispersity index (PDI) values during longterm incubation at room temperature. The oil/water volume ratio was 0.06:1, and the PEG−PCD concentration was 5 or 10 mg mL−1. Scale bars, 500 nm (b, c). Data in part f are mean ± SD (n = 3). B

DOI: 10.1021/acscentsci.8b00084 ACS Cent. Sci. XXXX, XXX, XXX−XXX

Research Article

ACS Central Science confirmed this transition by super-resolution fluorescence microscopy (SRFM) (Figure 2b). In this case, the BA phase was doped with Nile red, a polarity-sensitive fluorescent probe that can selectively stain hydrophobic domains.49 It should be noted that the relatively large particles observed by SRFM can be attributed to the scattering effects and swelling of particles in aqueous solution. To a certain degree, both TEM and SRFM images supported the size changing profile observed in the case of increased BA volume ratios (Figure 1d). Nanoemulsions were formed when the oil/water volume ratio was higher than 0.04:1 at 10 mg mL−1 PEG−PCD. As illustrated for the sample at 0.06:1 (Figure 2c), nanoemulsions with relatively narrow size distribution were obtained. Of note, the milklike appearance should be largely attributed to the high concentration of oil droplets in the formed nanoemulsions. At a defined oil/water ratio, the size of thus assembled oil-in-water (o/w) emulsions was strongly dependent on the PEG−PCD concentration (Figure 2d), with microscale emulsions formed below 0.5 mg mL−1. It is worth noting that nanoemulsification was attained even at 0.5 mg mL−1 PEG−PCD, which is dramatically lower than that required for amphiphilic surfactants traditionally used for the preparation of nanoemulsions.14,19,32,33 At either 5 or 10 mg mL−1 PEG−PCD, the assembled nanoemulsions were stable even after ∼200 days of storage at room temperature (Figure 2e,f). Nanoemulsions thus formed were also stable against temperature fluctuation (Figure S5a−c). This is consistent with our measurements by 1H NMR spectroscopy and ITC (Figure S5d−g), which indicated the presence of host−guest interactions at 50 °C, although they were indeed impaired by temperature. Notably, whereas nanoemulsions were obtained by BA/PEG−PCD, clear phase separation appeared for BA and free β-CD (Figure S6a,b), indicating that multiple complexation and PEGylation are necessary for effective emulsification. This was substantiated by ITC data that demonstrated a higher binding constant between BA and PEG−PCD in comparison to that between BA and βCD (Figure 1c and Figure S2b). In accordance with the reversibility of host−guest interactions,50 demulsification occurred upon the addition of a competitive compound 1adamantylamine that has a higher binding constant with β-CD than BA (Figure S6c,d).45 This suggested that the assembled host−guest emulsions are switchable, which is beneficial for specific applications such as nanoparticle synthesis and emulsion polymerization.51 Of note, the formation of BA/PEG−PCD emulsions can extend the well-documented emulsification theory. According to this traditional theory,52,53 emulsifiers with HLB of 8−18 or 3.5−6 should be used to afford o/w or water-in-oil (w/o) emulsions, respectively. In the case of BA, the required HLB value is 11.4 when it is used as an oil phase,54 while PEG−PCD has a dramatically mismatched HLB value of 493, as calculated based on a previously established group contribution method.55 Despite this significant mismatch, our results demonstrated that this hydrophilic copolymer can serve as an emulsifier to generate o/w nanoemulsions. Importantly, this strategy only involves mild emulsification using particularly low copolymer concentrations. By contrast, nanoemulsions, derived from currently available techniques, are frequently produced by either high-energy or low-energy emulsification methods, in combination with the use of extremely high concentrations of surfactants and cosurfactants.14,32,33,56 In addition, catastrophic phase inversion was observed with increase in the BA volume. To clearly illustrate this process,

aqueous solution of PEG−PCD and BA doped with Nile red was gently mixed. At 10 mg mL−1 of PEG−PCD, o/w emulsions, bicontinuous phase, and w/o emulsions were found when the oil volume fraction was gradually increased from 3.8% to 83.3%, respectively (Figure 3a and Figure S7). The w/o

Figure 3. Catastrophic phase inversion and complex emulsions by host−guest recognition-mediated self-assembly of BA/PEG−PCD. (a) Fluorescence images of catastrophic phase inversion of BA/PEG− PCD emulsions at different oil volume fractions. (b) Binary phase diagram of the BA/PEG−PCD system. (c) Complex emulsions formed by BA/PEG−PCD. Scale bars, 10 μm.

emulsions formed by phase inversion were stable upon longterm incubation. This catastrophic phase inversion was also observed at 5 and 20 mg mL−1 of PEG−PCD (Figure S8). By microscopic observation of the inversion processes at different PEG−PCD concentrations, a binary phase diagram was established, suggesting that low PEG−PCD concentrations afford a broad oil fraction window for the formation of bicontinuous phase (Figure 3b). Previously, this oil phase content-dependent catastrophic phase inversion and bicontinuous liquids were found for emulsions stabilized by colloidal particles.28,57−59 By contrast, inversion does not occur or appreciable coalescence appears during phase inversion for emulsions stabilized by only one pure surfactant or surfactant/ cosurfactant systems, respectively.57,60 Our results for the first time demonstrated that the emulsion transition and stable bicontinuous emulsions can be attained using a hydrophilic block copolymer. Additionally, complex emulsions, such as water-in-oil-in-water (w/o/w) and oil-in-water-in-oil (o/w/o) emulsions were realized using PEG−PCD (Figure 3c). It has been extensively documented that emulsions should be stabilized by amphiphilic molecules or solid particles.53,56,60−63 Our findings demonstrated that different types of emulsions can be achieved by host−guest interaction-mediated interfacial assembly, when an affinity copolymer in the water phase can interact with oil molecules via inclusion complexation. Subsequently, we investigated applications of the assembled host−guest emulsions. By nanoemulsification of BA/PEG− PCD, with the oil phase containing hydrophobic polymers, nanoparticles based on biodegradable polyesters such as poly(εcaprolactone) (PCL) were fabricated after the oil phase was removed by evaporation (Figure 4a). Likewise, nanoparticles or microspheres derived from poly(D,L-lactide) (PLA) were C

DOI: 10.1021/acscentsci.8b00084 ACS Cent. Sci. XXXX, XXX, XXX−XXX

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ACS Central Science

Figure 4. Engineering of polymeric nanoparticles and microstructures via self-assembled host−guest emulsions. TEM micrographs of (a) poly(εcaprolactone) (PCL) nanoparticles and (b) poly(D,L-lactide) (PLA) nanoparticles or microspheres derived from assembled BA/PEG−PCD o/w emulsions. (c) SEM image of a microporous pattern based on BA/PEG−PCD o/w emulsions. SEM images showing ordered honeycomb microporous structure of either (d) polyester or (e) N-substituted polyacrylamides. PLGA5050 and PLGA7525 represent poly(lactide-co-glycolide) with a monomer ratio of 50:50 or 75:25, respectively. PNPAm, poly(N-phenylacrylamide); PNtBAm, poly(N-tert-butylacrylamide).

successfully produced using assembled BA/PEG−PCD o/w emulsions with varied oil phase fractions (Figure 4b). On the other hand, hexagonal patterns were formed on freshly cleaved mica after evaporation of the oil phase of BA/PEG−PCD o/w emulsions (Figure 4c). When different polymers including biodegradable poly(lactide-co-glycolide) (PLGA) and PLA as well as N-substituted polyacrylamides were dissolved in the oil phase, ordered honeycomb microporous polymer structures were observed (Figure 4d,e). In contrast, only particles were found when the BA solutions containing these polymers were coated on mica (Figure S9). Whereas hierarchically ordered porous polymer superstructures are generally constructed by self-assembly of amphiphilic or rod−coil copolymers under controlled conditions,64,65 our findings substantiated that they can also be obtained by the assembled BA/PEG−PCD emulsions, with their compositions easily regulatable by polymers dissolved in the oil phase. In addition, the assembled nanoemulsions can be used for drug delivery. We found that a diverse array of hydrophobic drugs with different chemical structures can be solubilized in the oil phase of BA/PEG−PCD o/w nanoemulsions (Figure S10). By encapsulation into the assembled o/w nanoemulsions, area under the plasma concentration−time curve (AUC) of an anti-inflammatory drug indomethacin was significantly increased after oral administration (Figure 5a), when compared with the drug suspension in saline. Also, BA/PEG−PCD o/w nanoemulsions remarkably enhanced the oral bioavailability of an anticancer drug paclitaxel delivered via the oral route (Figure 5b). Preliminary in vivo evaluations in mice were performed to investigate the safety profile of assembled BA/PEG−PCD nanoemulsions after oral administration at 33 mL kg−1, which was 10-fold higher than that used for drug delivery studies. At day 14 after treatment, mice administered with either nanoemulsions or saline displayed comparable body weight and organ index (Figure S11a,b). Likewise, no significant changes were found for typical hematological parameters, including white blood cell, red blood cell, platelet, and

Figure 5. Assembled BA/PEG−PCD o/w nanoemulsions for drug delivery. (a, b) Plasma drug concentrations at defined time points (left) and AUC (right) after oral administration of nanoemulsions containing (a) an anti-inflammatory drug indomethacin or (b) an anticancer drug paclitaxel. Data are mean ± SD (n = 6); *p < 0.05.

hemoglobin (Figure S11c−f). In comparison to saline-treated mice, the nanoemulsion group did not show significantly increased levels of biochemical markers of alanine aminotransferase, aspartate aminotransferase, urea, and creatinine (Figure S11g,h), which are relevant to hepatic and kidney functions, respectively. Moreover, quantification of the typical lipids (including total cholesterol, triglyceride, high-density lipoprotein, and low-density lipoprotein) showed no significant differences in the examined two groups (Figure S11i). Analysis of hematoxylin and eosin-stained sections indicated that treatment with assembled BA/PEG−PCD nanoemulsions did not cause discernible injuries in main organs such as heart, liver, spleen, lung, and kidneys (Figure S12). Whereas further longD

DOI: 10.1021/acscentsci.8b00084 ACS Cent. Sci. XXXX, XXX, XXX−XXX

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(6) Salis, A.; Ninham, B. W. Models and mechanisms of Hofmeister effects in electrolyte solutions, and colloid and protein systems revisited. Chem. Soc. Rev. 2014, 43, 7358−7377. (7) Pontani, L. L.; Jorjadze, I.; Viasnoff, V.; Brujic, J. Biomimetic emulsions reveal the effect of mechanical forces on cell−cell adhesion. Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 9839−9844. (8) Kislukhin, A. A.; Xu, H.; Adams, S. R.; Narsinh, K. H.; Tsien, R. Y.; Ahrens, E. T. Paramagnetic fluorinated nanoemulsions for sensitive cellular fluorine-19 magnetic resonance imaging. Nat. Mater. 2016, 15, 662−668. (9) Weiss, M.; Frohnmayer, J. P.; Benk, L. T.; Haller, B.; Janiesch, J.W.; Heitkamp, T.; Börsch, M.; Lira, R. B.; Dimova, R.; Lipowsky, R.; Bodenschatz, E.; Baret, J. C.; Vidakovic-Koch, T.; Sundmacher, K.; Platzman, I.; Spatz, J. P. Sequential bottom-up assembly of mechanically stabilized synthetic cells by microfluidics. Nat. Mater. 2018, 17, 89−96. (10) Zhang, Q.; Savagatrup, S.; Kaplonek, P.; Seeberger, P. H.; Swager, T. M. Janus emulsions for the detection of bacteria. ACS Cent. Sci. 2017, 3, 309−313. (11) Singh, Y.; Meher, J. G.; Raval, K.; Khan, F. A.; Chaurasia, M.; Jain, N. K.; Chourasia, M. K. Nanoemulsion: concepts, development and applications in drug delivery. J. Controlled Release 2017, 252, 28− 49. (12) Lawrence, M. J.; Rees, G. D. Microemulsion-based media as novel drug delivery systems. Adv. Drug Delivery Rev. 2012, 64, 175− 193. (13) Zhao, C. X. Multiphase flow microfluidics for the production of single or multiple emulsions for drug delivery. Adv. Drug Delivery Rev. 2013, 65, 1420−1446. (14) Fryd, M. M.; Mason, T. G. Advanced nanoemulsions. Annu. Rev. Phys. Chem. 2012, 63, 493−518. (15) Patravale, V. B.; Mandawgade, S. D. Novel cosmetic delivery systems: an application update. Int. J. Cosmet. Sci. 2008, 30, 19−33. (16) Perazzo, A.; Preziosi, V.; Guido, S. Phase inversion emulsification: Current understanding and applications. Adv. Colloid Interface Sci. 2015, 222, 581−599. (17) Shah, R. K.; Shum, H. C.; Rowat, A. C.; Lee, D.; Agresti, J. J.; Utada, A. S.; Chu, L.-Y.; Kim, J. W.; Fernandez-Nieves, A.; Martinez, C. J.; Weitz, D. A. Designer emulsions using microfluidics. Mater. Today 2008, 11, 18−27. (18) Kohli, K.; Chopra, S.; Dhar, D.; Arora, S.; Khar, R. K. Selfemulsifying drug delivery systems: an approach to enhance oral bioavailability. Drug Discovery Today 2010, 15, 958−965. (19) Gupta, A.; Eral, H. B.; Hatton, T. A.; Doyle, P. S. Nanoemulsions: formation, properties and applications. Soft Matter 2016, 12, 2826−2841. (20) Song, Y.; Shum, H. C. Monodisperse w/w/w double emulsion induced by phase separation. Langmuir 2012, 28, 12054−12059. (21) Haase, M. F.; Brujic, J. Tailoring of high-order multiple emulsions by the liquid-liquid phase separation of ternary mixtures. Angew. Chem., Int. Ed. 2014, 53, 11793−11797. (22) Zarzar, L. D.; Sresht, V.; Sletten, E. M.; Kalow, J. A.; Blankschtein, D.; Swager, T. M. Dynamically reconfigurable complex emulsions via tunable interfacial tensions. Nature 2015, 518, 520. (23) Choi, C. H.; Weitz, D. A.; Lee, C. S. One step formation of controllable complex emulsions: from functional particles to simultaneous encapsulation of hydrophilic and hydrophobic agents into desired position. Adv. Mater. 2013, 25, 2535−2535. (24) Tcholakova, S.; Valkova, Z.; Cholakova, D.; Vinarov, Z.; Lesov, I.; Denkov, N.; Smoukov, S. K. Efficient self-emulsification via coolingheating cycles. Nat. Commun. 2017, 8, 15012. (25) Engelis, N. G.; Anastasaki, A.; Nurumbetov, G.; Truong, N. P.; Nikolaou, V.; Shegiwal, A.; Whittaker, M. R.; Davis, T. P.; Haddleton, D. M. Sequence-controlled methacrylic multiblock copolymers via sulfur-free RAFT emulsion polymerization. Nat. Chem. 2017, 9, 171− 178. (26) Guzey, D.; McClements, D. J. Formation, stability and properties of multilayer emulsions for application in the food industry. Adv. Colloid Interface Sci. 2006, 128, 227−248.

term treatment should be carried out for safety studies, these data suggested that BA/PEG−PCD nanoemulsions may serve as a safe nanovehicle for oral drug delivery.

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CONCLUSIONS In summary, we demonstrate that diverse emulsions can be formed by host−guest interaction-mediated self-assembly of a hydrophilic guest copolymer at the oil/water interface. In this strategy, one block of the guest diblock copolymer can interact with oil molecules via host−guest interactions. This innovative emulsification offers a facile, mild, and low-energy strategy toward multifunctional emulsions with different microstructures and over length scales. The catastrophic phase inversion performance further extends the range of phase structures than can be realized by host−guest self-assembled emulsions. Furthermore, the reversibility of host−guest interactions affords switchable capacity to these diverse emulsions. These favorable properties facilitate their wide applications in the engineering of functional materials as well as for the development of cosmetic and biomedical products.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acscentsci.8b00084. Details of materials and methods, characterization of polymers and emulsions, and additional data and images (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Ruibing Wang: 0000-0001-9489-4241 Jianxiang Zhang: 0000-0002-0984-2947 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This study was supported by the National Natural Science Foundation of China (No. 81471774), Graduate Student Research Innovation Project of Chongqing (to L.L.L.), and Science and Technology Development Fund, Macau SAR (FDCT Grant No.: FDCT/030/2017/A1).

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DOI: 10.1021/acscentsci.8b00084 ACS Cent. Sci. XXXX, XXX, XXX−XXX