A Facile Ion-Doping Strategy To Regulate Tumor Microenvironments

6 days ago - Integration of multiple therapeutic/diagnostic modalities into a single system holds great promise to improve theranostic efficiency for ...
0 downloads 8 Views 935KB Size
Subscriber access provided by READING UNIV

Communication

A Facile Ion-Doping Strategy to Regulate Tumor Microenvironments for Enhanced Multimodal Tumor Theranostics Jing Bai, Xiaodan Jia, Wenyao Zhen, Wenlong Cheng, and Xiue Jiang J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11114 • Publication Date (Web): 22 Dec 2017 Downloaded from http://pubs.acs.org on December 22, 2017

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

Journal of the American Chemical Society is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

A Facile Ion-Doping Strategy to Regulate Tumor Microenvironments for Enhanced Multimodal Tumor Theranostics Jing Bai,† Xiaodan Jia,† Wenyao Zhen,†,‡ Wenlong Cheng,*,§ and Xiue Jiang*,†,‡ †

State Key Lab of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, Jilin, China ‡ §

University of Science and Technology of China, Hefei 230026, Anhui, China Department of Chemical Engineering, Monash University, Clayton, 3800, Victoria, Australia

Supporting Information Placeholder ABSTRACT: Integration of multiple therapeutic/diagnostic modalities into a single system holds great promise to improve theranostic efficiency for tumor but still remains a technical challenge. Herein, we report a new multimodal theranostic nanoconstruct based on Fe-doped polydiaminopyridine nanofusiforms, built easily and on a large scale, which can dual-regulate intracellular oxygen and glutathione levels, transport iron ions, and simultaneously be used for thermal imaging and magnetic resonance imaging. Co-loading of dihydroartemisinin and methylene blue generates a superior multifunctional theranostic agent with enhanced photo-chemotherapy efficiency and biodegradability, leading to almost complete destruction of tumors with near infrared light irradiation. This represents an attractive route to develop multimodal anticancer theranostics. Because of its versatility and complexity, cancer remains a major cause of mortality worldwide. Nanotechnology-based anticancer therapies have made a tremendous contribution to nanomedicine.1 Various types of combination therapies, including chemo/photodynamic therapy (CT/PDT),2 chemo/photothermal therapy (CT/PTT),3 photodynamic/photothermal therapy (PDT/PTT),4 and chemo/radiotherapy5 have shown outstanding antitumor effects. Various imaging agents6 such as gold nanostructure, Gd3+, and iron oxide, have also been loaded onto nanovehicles for diagnosis. Especially, nanoscale polymer-based vehicles including coordination7 and semiconducting polymers8 have been developed and used extensively for delivering imaging agents,8d gene therapeutics,8c and chemotherapeutics,7a, 7c because of their tunable physicochemical properties, good biocompatibility and biodegradability, showing great potential in accommodating multiple therapeutic/imaging agents for enhanced theranostics. Although multimodal therapies can kill cancer cells, their efficacy is still hindered by the intrinsic physiological barriers of cancer cells, including hypoxia,9 elevated H2O2, and glutathione (GSH) concentration. Hypoxia can not only decrease oxygendependent PDT efficacy but also cause drug resistance and tumor metastasis.10 Cancer cells develop an enhanced antioxidant capacity by altering the activity of reactive oxygen species (ROS) scavengers. Consequently, the ROS produced by CT and PDT can be effectively scavenged, reducing their efficiency. To solve the intrinsic inhibition, some strategies have been developed to modify the tumor microenvironment, including natural O2 transportation to tumor cells11 and preparation of O2-evolving9, 12 or GSHdepleting nanoconstructs.13 Herein, we report a simple yet efficient metal-ion doping strategy to prepare Fe-doped polydiaminopyridine nanofusiforms (FePDAP NFs) for co-loading dihydroartemisinin (DHA) and meth-

ylene blue (MB) (Figure 1A). After nanoagent uptake by cancer cells, high-level intracellular GSH will trigger Fe2+ release, and enhance the Fe-dependent cytotoxicity of DHA. The Fe-PDAP NFs with catalase-like activity can decompose H2O2 into O2, overcoming tumor hypoxia to enhance the efficiency of PDT and CT. Meanwhile, the reduced antioxidant capacity of cancer cells resulting from GSH depletion through a metal-reducing reaction further facilitates ROS generation for highly efficient PDT and CT. Additionally, Fe-PDAP NFs can be used as an magnetic resonance imaging (MRI) contrast agent and thermal imaging agent. To our knowledge, this is the first report indicating that threemodality therapy, dual-imaging function and regulation of tumor microenvironments, were integrated into one nanoconstruct for enhanced tumor theranostics.

Figure 1. (A) Synthesis schematic. (B) TEM and high-resolution (inset) and (C) AFM images of Fe-PDAP NFs. (D) FTIR spectra of DAP (a) and Fe-PDAP NFs (b). (E) XRD of PDAP NSs and Fe-PDAP NFs. (F) N1s XPS of Fe-PDAP NFs, N1: pyridinic N, N2: Fe-N, N3: pyrrolic N, and N4: graphitic N. (G) The UV-vis spectra of Fe-PDAP and Fe-PDAP/DHA/MB. Fe-PDAP NFs were synthesized on a large scale (about 2 g per batch) with a ~87% yield (Figure S1) via surfactant-free aqueous polymerization from a precursor of 2,6-diaminopyridine (DAP) using FeCl3 as an oxidant (Figure 1A) that exhibits a uniform size of 45 × 12 nm (Figure 1B and Figure S1A) and thickness of 8.5 nm (Figure 1C), demonstrating the fusiform-like two-dimensional (2D) structure because of Fe3+ as an oxidant (Figure S2). Formation of a C=N bond during polymerization causes the disap-

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

pearance of stretching vibration of the amine group14 at around 3000 cm-1 and an increase in the intensity ratio of 1640 to 1593 cm-1 (Figure 1D).15 The peak at 845 cm-1 indicates the formation of doped polymer.16 The appearance of new diffraction peaks at 32.9°, 39.4°, 42.1°, and 54.5° (Figure 1E), which are assigned to the monoclinic NH4FeCl3, confirms the coordination interactions between Fe3+ and N atoms in Fe-PDAP NFs, as suggested by the appearance of an Fe-N (N2) peak in the deconvoluted N1s spectrum (Figure 1F).17 The typical binding energy peaks of Fe2p1/2 and Fe2p3/2 demonstrate the stability of Fe3+ in the nanostructure (Figure S3), with an Fe content of 5.52 wt% measured by inductively coupled plasma (ICP). The Fe-PDAP NFs disperse well in physiological conditions with an evident Tyndall phenomenon in saline (Figure S4). DHA and MB were easily co-loaded on the FePDAP NFs through hydrophobic and π-π interactions, with loading capacities of 608.5 µg/mg and 81.6 µg/mg, respectively, which showed typical peaks at 300, 607, and 662 nm (Figure 1G) and controlled drug release under near infrared (NIR) irradiation (Figure S5).

Figure 2. (A) Fe2+ release profiles of Fe-PDAP with or without GSH. (B) H2O2-triggered O2 generation in different solutions. (C) CLSM images of RDPP in cells treated with PDAP and Fe-PDAP. Scale bars: 50 µm. (D) Photothermal curves of different concentrations of Fe-PDAP under laser irradiation. (E) Plot of R2 values vs. Fe-PDAP concentrations (in terms of Fe). Inset: T2-weighted MR images. (F) Time-dependent TEM images of Fe-PDAP suspensions. Scale bars: 200 nm. Because of the stronger affinity of Fe3+ for S oligopeptides than for N,18 GSH (200 µM) was added to an Fe-PDAP NF suspension to trigger Fe3+ release and reduction. This reduction was evaluated by phenanthroline, which can react with Fe(II) to form a complex with absorbance at 512 nm.19 Loaded iron ions (~54.3%) can be released within 24 h (Figure 2A), showing that GSH can trigger an efficient release and reduction of Fe3+. Meanwhile, reducing Fe3+ can also deplete GSH since a 25% decrease in GSH was induced in the presence of Fe-PDAP (Figure S6), compared with that in the PDAP NSs (Figure S2), suggesting the action of Fe3+ in the oxidation of GSH. Additionally, H2O2-triggered O2-production in Fe-PDAP NF solution (Figure 2B) suggests catalase-like activity of Fe-PDAP, which was confirmed in living cells using an O2 probe [Ru(dpp)3]Cl2 (RDPP), whose fluorescence can be quenched by O2 (Figure 2C). As expected, the cellular green fluorescence was quenched after treating the cells with Fe-PDAP NFs, but not in cells treated with PDAP at 24 h, although both nanomaterials could be effectively internalized by cells (Figure S7). This clearly demonstrates that Fe3+ in Fe-PDAP NFs catalyzed the H2O2triggered production of intracellular O2, overcoming tumor hypoxia. Importantly, Fe-PDAP NFs show broad NIR absorption(Figure S8), owing to the bipolaronic metal property of doped polymers.20

To verify photothermal properties, the Fe-PDAP NF solutions were irradiated with an 808-nm laser, and the temperatures were recorded by digital thermometer and infrared thermal camera (Figure S9), which showed an obvious concentration- (Figure 2D) and laser-power-dependent increase (Figure S10), reaching 51.0°C at a concentration of 1.0 mg/mL and power density of 1.0 W cm−2. Photothermal conversion was stable (Figure S11), with an efficiency of 43.7% (Figure S12), which was higher than that of Au nanorods (22%),21 Bi2S3 (28.1%),22 and MoS2 (34.46%),23 indicating the potential of Fe-PDAP NFs as a photothermal agent. Fe-PDAP NFs also showed Fe concentration-dependent T2weighted MRI intensity (Figure 2E) with T2 relaxivities (r2) of 15.9 mM-1 s-1, showing MRI contrast ability. Importantly, the FePDAP NFs were self-biodegradable and completely fragmented in the third week, demonstrating good biocompatibility (Figure 2F).

Figure 3. (A) Concentration-dependent viabilities of FePDAP/DHA-treated cells that were pre-treated with or without BSO or NAC. (B) GSH level of cells incubated with different agents. (C) 1O2 generation evaluated by the measurement of DCFH fluorescence. (D) 1O2 generation evaluated by DPBF consumption with laser alone (a), Fe-PDAP (b), Fe-PDAP/MB (c), Fe-PDAP/MB with 100 µM (d), or 200 µM (e) H2O2 over irradiation. (E) CLSM images of DCFH in cells treated without (a) and with laser alone (b), PDAP/MB (c), PDAP/MB/DHA (d), FePDAP/MB (e), and Fe-PDAP/DHA/MB (f) for 24 h during irradiation. (F) Proposed mechanism for PDT and CT enhancement. Comparison of single or multiple modality therapeutic efficiency between Fe-PDAP- and PDAP-based nanomaterials evaluated by (G) MTT assay and (H) CLSM images. Scale bars: 50 µm. GSH-triggered Fe2+ release, O2-evolving, and GSH-depletion properties can selectively enhance Fe-dependent drug toxicity and O2-dependent ROS therapy. Therefore, we selected DHA and MB as model drugs for Fe and O2-dependent ROS therapies, respectively, to construct multiple therapeutic/diagnostic nanoplatforms for co-loading (Figure S5) and to evaluate their efficiencies separately. To evaluate the Fe-dependent therapy efficiency of FePDAP/DHA (Figure S13), HeLa cells pretreated with GSH inhibitor, buthionine sulfoximine (BSO), and the promoter, N-acetyl-Lcysteine (NAC), were incubated with Fe-PDAP/DHA. Compared to untreated cells (Figure 3A), the BSO-treated cells exhibited increased viability, whereas decreased viability was observed in NAC-treated cells. In contrast, with the same dosage, BSO, NAC and Fe-PDAP NFs (Figure S14A-C) showed negligible cytotoxicity. Pre-depletion of intracellular GSH using BSO (Figure S14D) can result in less DHA cytotoxicity because less Fe2+ is released. Meanwhile, intracellular GSH was decreased by Fe-PDAP NFs because of the reduction of Fe3+ (Figure 3B). Interestingly, GSH levels, which were even higher than the concentration of Fe3+ in

ACS Paragon Plus Environment

Page 2 of 5

Page 3 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society Fe-PDAP/DHA, further decreased by Fe-PDAP/DHA, suggesting a possible cycling reaction between Fe3+ and Fe2+ resulting from GSH oxidation and DHA reduction (Figure 3F). As GSH is an ROS scavenger, GSH depletion can directly enhance the amount of ROS. MB was chosen as a model and loaded onto the surface of Fe-PDAP NFs (Fe-PDAP/MB) and PDAP (PDAP/MB) (Figure S15), and the production of ROS with GSH was evaluated using an ROS probe (Figure 3C). During irradiation, the 1O2 produced by PDAP/MB was completely scavenged by GSH, whereas 1O2 produced by Fe-PDAP/MB was scavenged to a lesser extent and even much less scavenged for 1O2 produced by Fe-PDAP/DHA/MB, suggesting that the reduced ROS scavenger capacity resulting from GSH oxidation could be intensified by the introduction of DHA, greatly enhancing the production of ROS. Furthermore, the O2-evolving properties of Fe-PDAP NFs can enhance ROS production of delivered photosensitizer.12a Indeed, the addition of H2O2 to Fe-PDAP/MB resulted in enhanced 1 O2 generation (Figure S16 and Figure 3D), demonstrating their ability to enhance 1O2 production. ROS levels enhanced by O2-evolving and GSH-depleting FePDAP NFs were confirmed in living cells using the ROS probe 2,7-dichlorofluorescein diacetate (DCFH-DA) (Figure 3E). Compared to the cells treated with PDAP-based agents, the FePDAP/MB-treated cells show brighter fluorescence, suggesting an enhanced ROS level because of the synergy between Fe3+-induced O2 evolution and GSH depletion. Notably, the brightest fluorescence is observed in the Fe-PDAP/DHA/MB-treated cells, suggesting the highest ROS level. The synergy of CT and PDT and/or more GSH depletion resulting from the introduction of DHA (Figure 3E) can reduce mitochondrial membrane potential (Figure S17). Consequently, both MB and DHA delivered by Fe-PDAP NFs that were internalized by clathrin-mediated endocytosis (Figure S18) showed greater anticancer efficiency than those delivered by Fe-free PDAP as determined by MTT assay (Figure 3G) and calcine AM and propidium iodide (PI) co-staining assay (Figure 3H). Notably, when the cells were treated with FePDAP/DHA/MB after 808/650-nm laser irradiation, almost all cells were damaged, as determined by MTT assay (83%, Figure 3G) and the production of strong red fluorescence signals (Figure 3H), which showed an enhanced synergetic PDT/CT/PTT therapeutic efficiency resulting from the Fe2+-transportation, O2evolution, and GSH-consumption capabilities of Fe-PDAP NFs.

Fe-PDAP NFs showed a long blood circulation half-life of 5.6 ± 1.5 h (Figure S19A). The Fe content in each organ dropped continually and nearly disappeared by the fourth day post-injection (Figure S19B). Nearly all the injected Fe-PDAP NFs were excreted via feces and urine after seven days post-injection (Figure S19C). The tumor temperature increased to 52.4°C with 10 min of irradiation, demonstrating the potential of in vivo PTT with FePDAP NFs (Figure 4B). Tumor inhibition efficacy of the agent was evaluated by in vivo treatment of tumor-bearing mice (Figure 4C–E) that were randomly divided into several groups: saline (control), Fe-PDAP/MB + 650 nm laser (PDT), Fe-PDAP/DHA (CT), Fe-PDAP/MB + 808 nm laser (PTT), Fe-PDAP/DHA/MB + 650 nm laser (PDT/CT), and Fe-PDAP/DHA/MB + 650/808 nm laser (PDT/CT/PTT). No significant body weight change was observed in the treatment groups, indicating the low systemic toxicity of the agent (Figure S20). Compared to the control group and single-mode treatment (PDT, CT, and PTT) groups, the dual-mode treatment (PDT/CT) groups showed significant tumor inhibition; however, dual-mode treatment was still less efficient than triple-mode treatment (PDT/CT/PTT), which almost eliminated tumors without any relapse. The introduction of PTT into PDT/CT treatment not only ablated tumor by hyperthermia but also triggered the release of DHA and MB, further improving photo-chemotherapy efficiency. Moreover, the histological analysis of tumors revealed that most tumor cells were damaged by the three-mode treatment (Figure S21A). The ability of Fe-PDAP NFs to overcome tumor hypoxia was demonstrated by hypoxia-inducible factor (HIF-1α) staining assay (Figure S21B). No significant pathological changes were noted between control group and the treatment group in the main organs (Figure S22). Importantly, blood chemistry, complete blood panel, and histological analyses of healthy mice did not reveal significant abnormalities (Figure S23–25), confirming the good biocompatibility of the nanoconstructs. Thus, we developed a novel PDT/CT/PTT synergistic tumor therapy agent based on Fe-PDAP NFs co-loaded with DHA and MB. This novel nanoconstruct cleaved H2O2 to generate O2, overcoming tumor hypoxia and enhancing PDT efficiency. The nanoconstruct interacted with GSH to release Fe2+ and increase the cytotoxicity of DHA and simultaneously decreased intracellular GSH levels, further enhancing PDT and CT efficiency. Furthermore, the nanoconstructs can be monitored with in vivo thermal imaging and MRI owing to the absorption of NIR light and the presence of Fe3+. The dual imaging-guided three-mode therapy and dual regulation of tumor microenvironments open new avenues for next-generation tumor theranostics.

ASSOCIATED CONTENT Supporting Information Experimental details, photothermal conversion efficiency calculations, DHA and MB loading amounts, and Supplementary Figures S1–S25. Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author Figure 4. In vivo MRI (A) and thermal imaging (B) of tumorbearing mice at 24 h postinjection of saline and Fe-PDAP NFs. Representative photographs (C), relative tumor volume (D), and mean tumor weights (E) from different groups of tumor-bearing mice after treatment. The ability of Fe-PDAP NFs to accumulate in tumors was validated by T2-weighted MRI. Tumors presented an obvious dark signal at 24 h post-injection of Fe-PDAP NFs compared to that of control group (Figure 4A), suggesting the potential for in vivo MRI use. Although the amount of Fe-PDAP NFs in tumors was less than that accumulated in livers and spleens (Figure S19B),

*[email protected]; *[email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT This work was financially supported by the National Natural Science Foundation of China (21505130, 21675149, and 21705146), the Key Research Program of Frontier Sciences, CAS (QYZDYSSW-SLH019), the Science and Technology Development Program of Jilin Province (20170414037GH), and the K.C. Wong Education Foundation.

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

REFERENCES (1) (a) Wu, M. X.; Yang, Y. W. Adv. Mater. 2017, 29, 1606134; (b) Chen, Y. L.; Chang, M. C.; Cheng, W. F. Cancer Lett. 2017, 400, 282-292; (c) Sun, Z.; Xie, H.; Tang, S.; Yu, X.; Guo, Z.; Shao, J.; Zhang, H.; Huang, H.; Wang, H. Angew. Chem. Int. Ed. 2015, 54, 11526-11530. (2) Wang, Y.; Wei, G.; Zhang, X.; Xu, F.; Xiong, X.; Zhou, S. Adv. Mater. 2017, 29, 1605357. (3) Zhang, L.; Chen, Y.; Li, Z.; Li, L.; Saint-Cricq, P.; Li, C.; Lin, J.; Wang, C.; Su, Z.; Zink, J. I. Angew. Chem. Int. Ed. 2016, 55, 2118-2121. (4) Tang, Q.; Xiao, W.; Huang, C.; Si, W.; Shao, J.; Huang, W.; Chen, P.; Zhang, Q.; Dong, X. Chem. Mater. 2017, 29, 5216-5224. (5) Zhang, R.; Song, X.; Liang, C.; Yi, X.; Song, G.; Chao, Y.; Yang, Y.; Yang, K.; Feng, L.; Liu, Z. Biomaterials 2017, 138, 13-21. (6) Gharatape, A.; Salehi, R. Eur. J. Med. Chem. 2017, 138, 221-233. (7) (a) Liu, D.; Poon, C.; Lu, K.; He, C.; Lin, W. Nat. Commun. 2014, 5, 4182; (b) Liu, F.; He, X.; Chen, H.; Zhang, J.; Zhang, H.; Wang, Z. Nat. Commun. 2015, 6, 8003; (c) Rieter, W. J.; Pott, K. M.; Taylor, K. M. L.; Lin, W. J. Am. Chem. Soc. 2008, 130, 11584-11585. (8) (a) Zhu, H.; Fang, Y.; Miao, Q.; Qi, X.; Ding, D.; Chen, P.; Pu, K. ACS Nano 2017, 11, 8998-9009; (b) Jiang, Y.; Cui, D.; Fang, Y.; Zhen, X.; Upputuri, P. K.; Pramanik, M.; Ding, D.; Pu, K. Biomaterials 2017, 145, 168-177; (c) Lyu, Y.; Cui, D.; Sun, H.; Miao, Y.; Duan, H.; Pu, K. Angew. Chem. 2017, 129, 9283-9287; (d) Lyu, Y.; Fang, Y.; Miao, Q.; Zhen, X.; Ding, D.; Pu, K. ACS Nano 2016, 10, 4472-4481. (9) Zheng, D. W.; Li, B.; Li, C. X.; Fan, J. X.; Lei, Q.; Li, C.; Xu, Z. S.; Zhang, X. Z. ACS Nano 2016, 10, 8715-8722. (10) Schito, L.; Semenza, G. L. Trends in Cancer 2016, 2, 758-770. (11) Wang, P.; Li, X.; Yao, C.; Wang, W.; Zhao, M.; El-Toni, A. M.; Zhang, F. Biomaterials 2017, 125, 90-100. (12) (a) Kim, J.; Cho, H. R.; Jeon, H.; Kim, D.; Song, C.; Lee, N.; Choi, S. H.; Hyeon, T. J. Am. Chem. Soc. 2017, 139, 10992-10995; (b) Chen, H.; Tian, J.; He, W.; Guo, Z. J. Am. Chem. Soc. 2015, 137, 1539-1547. (13) Ju, E.; Dong, K.; Chen, Z.; Liu, Z.; Liu, C.; Huang, Y.; Wang, Z.; Pu, F.; Ren, J.; Qu, X. Angew. Chem. Int. Ed. 2016, 55, 11467-11471. (14) Alghanmi, R. M.; Habeeb, M. M. J. Mol. Liq. 2013, 181, 20-28. (15) Li, X. G.; Huang, M. R.; Duan, W.; Yang, Y. L. Chem. Rev. 2002, 102, 2925-3030. (16) Li, Y.; Li, G.; Peng, H.; Qin, Y.; Chen, K. Synth. Met. 2013, 164, 4246. (17) Li, J.; Ghoshal, S.; Liang, W.; Sougrati, M. T.; Jaouen, F.; Halevi, B.; McKinney, S.; McCool, G.; Ma, C. R.; Yuan, X. X.; Ma, Z. F.; Mukerjee, S.; Jia, Q. Energy Environ. Sci. 2016, 9, 2418-2432. (18) Zhao, C.; Wang, K.; Cai, Q.; Tu, H.; Pan, L.; Yu, L. Prep. Biochem. Biotechnol. 2017, 47, 835-840. (19) Shen, Y.; Posavec, L.; Bolisetty, S.; Hilty, F. M.; Nyström, G.; Kohlbrecher, J.; Hilbe, M.; Rossi, A.; Baumgartner, J.; Zimmermann, M. B.; Mezzenga, R. Nat. Nanotechnol. 2017, 12, 642-647. (20) Bjorklund, R. B.; Liedberg, B. J. Chem. Soc., Chem. Commun. 1986, 1293-1295. (21) Liu, Y.; Ai, K.; Liu, J.; Deng, M.; He, Y.; Lu, L. Adv. Mater. 2013, 25, 1353-1359. (22) Liu, J.; Zheng, X.; Yan, L.; Zhou, L.; Tian, G.; Yin, W.; Wang, L.; Liu, Y.; Hu, Z.; Gu, Z.; Chen, C.; Zhao, Y. ACS Nano 2015, 9, 696-707. (23) Tan, L.; Wang, S.; Xu, K.; Liu, T.; Liang, P.; Niu, M.; Fu, C.; Shao, H.; Yu, J.; Ma, T.; Ren, X.; Li, H.; Dou, J.; Ren, J.; Meng, X. Small 2016, 12, 2046-2055.

ACS Paragon Plus Environment

Page 4 of 5

Page 5 of 5 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

For Table of Contents Only

5 ACS Paragon Plus Environment