Facile Coordination-Precipitation Route to Insoluble Metal Roussin's

Oct 10, 2017 - ... and Cancer Center, Collaborative Innovation Center for Biotherapy, West ... Key Technology Engineering Laboratory for Medical Ultra...
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Facile Coordination-Precipitation Route to Insoluble Metal Roussin’s Black Salts for NIR-Responsive Release of NO for Anti-Metastasis Lijuan Chen,† Qianjun He,*,‡ Minyi Lei,† Liwei Xiong,§ Kun Shi,† Liwei Tan,† Zhaokui Jin,‡ Tianfu Wang,‡ and Zhiyong Qian*,† †

State Key Laboratory of Biotherapy and Cancer Center, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. China ‡ National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen 518060, Guangdong P. R. China § Hubei Key Laboratory of Plasma Chemistry and Advanced Materials, Wuhan Institute of Technology, Wuhan 430073, China S Supporting Information *

ABSTRACT: A facile and general coordination-precipitation method is developed to synthesize insoluble metal Roussin’s black salts (Me-RBSs) as a new type of NIR-responsive NORMs. The weak-field ligand coordination of metal+−RBS− brings a NIR absorption effect of Me-RBSs, and further gives rise to the NIR adsorption-dependent NIR-responsive NO release profile. Intratumoral NIR-responsive release of NO effectively inhibits the growth and metastasis of the metastatic breast cancer. Aqueous insolubility of Me-RBSs ensures lower cytotoxicity and higher thermostability compared with traditional soluble RBSs. This work establishes a new class of NIRsensitive NO donors, and may spark new inspiration for designing intelligent gas-releasing molecules. KEYWORDS: controlled release, gas therapy, NO donor, Roussin’s black salts, antimetastasis, near infrared light, NO-releasing molecules

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and nitroimines, are only sensitive to UV and visible light rather than near-infrared (NIR) light.14−16 By comparison, NIR light has a relatively higher depth of tissue penetration and remarkably lower phototoxicity. At present, NIR responsiveness is mainly achieved by energy transfer between UV-responsive NORMs and NIR absorbers, such as graphene oxide nanosheet (GON), upconversion nanoparticle (UCNP), two-photon chromophore.17−20 However, such composite systems have relatively low energy transfer efficiencies and reduced NOloading capacities compared with individual NORMs. The inherent NIR-responsiveness of NORMs is preferable to the absorber-assisted NIR-responsiveness for controlled release of therapeutic NO, but the direct molecular design and synthesis of NORMs for inherent NIR-responsive behavior is still challenging. In this work, a facile coordination-precipitation route (Figure 1A) is developed to synthesize insoluble metal RBSs (abbreviated as Me-RBSs) as a new kind of NIR-responsive NORMs. The as-synthesized Me-RBSs exhibit distinct NIR

itric oxide (NO), a liposoluble gas, plays an important role as a messenger molecule in cerebrovascular system, immune system, nervous system, reproductive system, and cancer.1−3 Especially in the field of cancer therapy, NO gas works with tumor cells in a concentration-dependent manner. Too low concentration (pM to nM) of NO will promote tumor cell growth, but relatively high concentration of NO can remarkably inhibit tumor occurrence and development by an “anti-Warburg effect”,4,5 whereas too high a concentration of NO in the blood (>15% methemoglobin, or >1 mM NO) could have a potential risk of NO poisoning.6 Therefore, it is vitally important to control the safe concentration of NO in the blood and effective concentration in the lesion. The administration of stimuli-responsive NO-releasing molecules (NORMs) to realize the controlled release of NO is one of most promising solutions.7,8 Existing NORMs are either spontaneous to release NO under physiological conditions or sensitive to light, heat, thiols, oxidants, NO synthases (NOSs), etc.9−13 Among these stimulus resources, light is most facilely available and controllable, including sustainability, interruptability and renewability. However, most of light-responsive NORMs, such as Roussin’s black salts (RBS), bis-N-nitroso compounds (BNNs) © XXXX American Chemical Society

Received: August 1, 2017 Accepted: October 9, 2017

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DOI: 10.1021/acsami.7b11325 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

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peak. The red shift of the NIR absorption from the Cu center (810 to 910 nm) should be due to the replace of the midfield H2O ligand by the weak-field RBS− ligand.23 Because the UVresponsiveness of RBS is well-known to derive from its absorption property in the UV zone,24,25 it is deduced that CuRBS will be sensitive to NIR light for NO release, which is also indeed confirmed as following in this work. Furthermore, the structure of Cu-RBS was confirmed by characterization with elemental analysis, FT-IR, TG and XRD. The elemental analysis result indicates that the molar rate of Cu:Fe:S is about 1:8:6. Therefore, we preliminarily infer the molecular formula of Cu-RBS to be Cu(RBS) 2 (Cu[Fe4S3(NO)7]2). From FTIR spectra (Figure 2B), the single nitrosyl peak of RBS at about 1740 cm−1 splits into two ones after complexation with Cu2+, indicating the creation of two different chemical environments of nitrosyl induced by the coordination of Cu and RBS−. From TG data (Figure S3), CuRBS exhibits a RBS-similar cascade of endothermic change (Figure S3B) and mass loss (Figure S3A) at 150−500 °C, because of the thermal decomposition release of seven nitrosyl groups, which suggests that seven nitrosyl groups were maintained in the formation of Cu-RBS as shown in the green zone. The endothermic change and mass loss below 90 °C correspond to the removal of water because no NO release from Cu-RBS is detected below 90 °C (the gray zone in Figure S2B). Above 90 °C, the mass loss of Cu-RBS is obviously lower than of RBS, possibly owing to the replacement of the NH4+ group of RBS by Cu2+ because the thermal decomposition of NH4+ will lead to the release of NH3 and H2S gases, as suggested by the green arrows in Figure S3B. Moreover, from XRD data (Figure 2C), by comparison of crystal structures of RBS, CuSO4, and Cu-RBS, it can be found that Cu-RBS is the product of reaction between RBS and CuSO4. From the present crystal database, the crystal phase of Cu-RBS cannot be searched out according to its three strongest peaks, indicating that it might be a new material. Indeed, the insoluble Me-RBSs including Cu-RBS have not been reported before as far as we know. Unfortunately, it is quite hard to obtain a high-quality Cu-RBS crystal so that we cannot solve its crystal structure at present. Nevertheless, from present characterization results, we can still draw the conclusion that Cu-RBS is indeed the stoichiometric coordination complexation product of Cu2+ and RBS−. Moreover, it has been found that Cu-RBS has a considerably poor solubility in water, which is expected to favor enhancing the thermal stability of RBS, lowering its cytotoxicity and endowing it stable light-responsiveness. Because of a high solubility in water (936.5 μg/mL, 1.6 mM ionic concentration), RBS exhibits high cytotoxicity (Figure S4) and hemolysis (Figure S5) derived from highly released RBS−, and high unstability in the ambient condition (Figure S6). By comparison, the aqueous solubility of Cu-RBS is only 2.8 μg/ mL (4.8 μM ionic concentration), which is much lower than that of RBS. Cu-RBS also has relatively lower cytotoxicity to normal cells (Figure S4) and invisible hemolysis (Figure S5) than RBS, especially at high concentrations, which should be attributed to its insolubility and low ion leakage. Furthermore, the insolubility of Cu-RBS enables its stable absorption of NIR light in water in favor of stable NIR-responsive NO release (Figure 3). On the basis of the above-mentioned NIR absorption feature, the responsiveness of Cu-RBS to different power densities of 808 nm NIR light for NO release was further investigated. As

Figure 1. Schematic illustration of the coordination-precipitation process of (A) Me-RBS and (B) NIR-responsive release of NO.

absorption and NIR-responsive NO release behaviors owing to the coordination between metal and the weak-field RBS− ligand (Figure 1B). By comparison to highly soluble RBS, Me-RBSs are much more stable and insoluble in water, ensuring stable light responsiveness and low toxicity. The developed coordination-precipitation route is high-speed, high-efficiency, and general to a wide range of metals for the formation of MeRBSs. Herein Cu-RBS as a typical example of Me-RBS is introduced intensively. As shown in Figure S1, Cu(RBS)2 (abbreviated as Cu-RBS) was synthesized by a facile coordination-precipitation strategy which was generally applied to the synthesis of various MeRBSs, especially the coordination complexes of transition metals and RBS. The soluble RBS (molecular formula NH4[Fe4S3(NO)7]·H2O), which was prepared according to an improved method,21 was completely dissolved in deionized water, demonstrating a clear brown solution. The fresh RBS solution was mixed with an excessive blue solution of CuSO4. Several seconds or minutes later, a kind of black precipitate was visibly formed. After static incubation for 3 h, the precipitation process almost ended, and then the black Cu-RBS precipitate was collected and washed several times with water to remove residual ions (yield = 90.4%). It is worth noting that the RBS− anion has a strong metal-coordination capability owing to a high proportion of the nitrosyl ligand. Therefore, the formation of the Me-RBS precipitates should be attributed to the electrostatic attraction and coordination complexation between metal+ and RBS−. The precipitated Cu-RBS is visibly flocculent by naked-eye observation because of its insolubility in water, and from SEM image (Figure S2), the Cu-RBS precipitate seems to be large aggregates on the micrometer scale. From absorption spectra of reactants and product (Figure 2A), the absorption of RBS is mainly located in the UV−vis zone rather than in the NIR one, whereas CuSO4 has a strong NIR absorption peak centered at 810 nm because of the formation of [Cu(H2O)4]2+ complex.22 It is exciting to discover that the reaction product Cu-RBS also possesses a strong NIR absorption peak centered at about 910 nm besides a broad UV

Figure 2. Structure characterization of reactants and product by (A) absorption, (B) FTIR, and (C) XRD spectra. B

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including Cu2+, Fe2+, Pb2+, Co2+, and Al3+, could form insoluble Me-RBS precipitates with RBS faster or more slowly. These Me-RBSs also exhibit clear NIR-responsive NO release profiles and NIR absorption capabilities (Figure 3C). It is interesting that higher 808 nm absorbance (Figure 3D), faster NIRresponsive NO release (Figure 3C), indicating that the NIRresponsive release behavior of Me-RBS is highly dependent on its NIR-absorption capability. In contrast, neither Au-RBS nor Pt-RBS can release NO gas under the irradiation of NIR light and also have very weak or almost no NIR absorption. NIR absorption/responsiveness of Me-RBSs (except for Au-RBS and Pt-RBS) should result from the stable coordination complexation between metal and RBS as indicated by the reservation of nitrosyl group (Figure S7), whereas no NIR absorption/responsiveness of Au-RBS and Pt-RBS might be due to losses of nitrosyl ligand and RBS structure (Figure S7), which could be destroyed by too high acidity of metal precursors HAuCl4 and H2PtCl6. Therefore, suitable metal precursors, which can coordinate with nitrosyl and also do not destruct RBS−, should be selected for synthesis of NIRresponsive Me-RBSs. Furthermore, we investigated the anticancer application of Cu-RBS as NIR-responsive NO donor. First, Cu-RBS plus NIR irradiation can lead to distinct in vitro cytotoxicity against 4T1 cells in a concentration-dependent way (Figure S8), because of intracellular NIR-responsive release of NO (Figure S9). Further, the 4T1-LUC orthotopic primary mice model was used to evaluate the anticancer and antimetastasis effects of the NIR-activated Cu-RBS.28−30 From Figure 4A, neither NIR irradiation only (808 nm laser, 1 W/cm2, 10 min × 3 times) nor injection of Cu-RBS only (200 mg/kg) remarkably inhibited the fast growth of the 4T1-LUC primary tumor compared with injection of PBS as blank control, however the combination of Cu-RBS injection and NIR irradiation markedly inhibited the growth of tumor, which could result from the anticancer effect of NO repeatedly released from Cu-RBS under the NIR irradiation (Figure 3) since there is no visible photothermal effect (Figure S10) of Cu-RBS. After therapy for 23 days, the ex vivo data show significant difference in tumor size and tumor weight among four experiment groups (Figure 4B and Figure S11), further visualizing the tumor inhibition effect of Cu-RBS plus NIR. Besides, tumor bioluminescence technology was also used to track the growth of tumors, and bioluminescence results (Figure S12) also suggested the clear tumor-inhibition effect of the NIR-activated Cu-RBS, but not on three control groups (PBS, NIR, Cu-RBS). Moreover, it could also be found that the first three-day irradiation of NIR light toward Cu-RBS can maintain good therapy efficacy within following 2 weeks (Figure 4A). It seems that later tumor growth (17−23 day) might need more NO therapy by further NIR irradiation, which had not been carried out unfortunately in this work. The optimization of NIR irradiation dosage (power, duration, and frequency) needs more research for ideal long-term therapy efficacy in the future. Additionally, there is no remarkable change and difference in body weight among four experiment groups (Figure S13), and no tissue toxicity to major organs (heart, liver, spleen, and kidney) is visible (Figure S14), suggesting no obvious systematic toxicity of Cu-RBS. The antimetastasis effect of NIR-activated Cu-RBS was further investigated by bioluminescence imaging, Masson and H&E staining analyses of pulmonary metastasis in the 4T1LUC tumor-bearing BALB/c mice model. From Figure 4C, large pieces of tumor cell tissues (bioluminescence, yellow

Figure 3. (A) Responsiveness of Cu-RBS to NIR light (808 nm) for NO release, (B) NIR controllability of Cu-RBS for NO release CuRBS, (C) NIR light-responsive NO release behaviors of Me-RBS complexes, which are highly related to (D) their NIR absorption properties.

shown in Figure 3A, Cu-RBS can indeed sustainably release NO gas under the irradiation of NIR light as expected, and the release rate increases with the increase in power density of NIR light but gradually decreases over NIR irradiation time. By comparison, RBS has not released NO gas for a long enough time even at the highest power density of NIR irradiation, because of the shortage of NIR absorption behavior. It is very clear that the quickly responsive NO release from Cu-RBS in the beginning of NIR irradiation enables the NO concentration to rapidly achieve an effective drug concentration (μM level) for cancer therapy, and then a sustained release favors the maintenance of drug concentration within an effective and safe range. Besides high responsiveness, high controllability for gas release is considerably important to realizing on-demand gas administration.26,27 Therefore, the NIR controllability of CuRBS for NO release was also investigated, as shown in Figure 3B. When NIR light was switched on, the release of NO was initiated. Once NIR light was switched off, the release of NO stopped almost completely. The multiple repeats of switching on/off NIR light could also renew/suspend NO release well in spite of decreased release rate with the increase of NIR irradiation time. This indicates that Cu-RBS indeed has a high NIR controllability for NO release. Therefore, the NO-released concentration can be well-controlled on demand through controlling the switching and power of NIR light, which is of great significance to manipulating the drug concentration within the therapeutic window and also reducing the risk of NO poisoning and promoting tumor cell growth. To test the universality of the developed coordinationprecipitation strategy for synthesis of NIR-responsive Me-RBSs, several common metal salts were used to synthesize corresponding Me-RBS with RBS, and the spectrum properties and NIR-responsiveness behaviors of Me-RBSs were investigated and compared. As expected, a range of metal ions, C

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Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsami.7b11325. Experimental part, TG and DSC patterns, cytotoxicity data, hemolysis data, stability data, FTIR spectra, digital and bioluminescence imaging of tumor mice, tumor weight, and H&E staining of various organs (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Qianjun He: 0000-0003-0689-8838 Zhiyong Qian: 0000-0003-2992-6424 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We greatly appreciate the help of Dr. Zhenyong Man from SIC CAS in analysis of crystal structure. We thank the financial support from National Natural Science Foundation of China (Grants 31525009, 81601605, 81501572, 51402220), Sichuan Innovative Research Team Program for Young Scientists (2016TD0004), Shenzhen Basic Research Program (JCYJ20170302151858466), Natural Science Foundation of SZU (827-000143), Shenzhen Peacock Plan (KQTD2016053112051497), the Fundamental Research Funds for the Shenzhen University, China (2016076), State Key Laboratory of Advanced Technology for Materials Synthesis and Processing, and Wuhan University of Technology (2017-KF-6).

Figure 4. Anticancer and antimetastasis effects of NIR-activated CuRBS on the 4T1-LUC tumor-bearing BALB/c orthotopic primary mice model: (A) the changes of tumor volume with time (*P < 0.05, **P < 0.01) after intratumoral injection with PBS as blank control, NIR, Cu-RBS (200 mg/kg) and Cu-RBS+NIR (1 W/cm2, 10 min/ time, 1 time/day, first 3 days); (B) the weight and digital photographs of ex vivo tumors after therapy for 23 days; (C) the bioluminescence, Masson and H&E staining images of ex vivo lung tissues after therapy for 23 days. In C, the yellow and green circles indicate the zones of tumor cells and tumor hyperplasia/nodules, respectively.

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circles in Masson images) and hyperplasia/nodules (green circles in H&E images) are clearly visible in three control groups (PBS, NIR, Cu-RBS), but these cannot be found out in the therapy group of Cu-RBS+NIR. Instead, the whole structure of lung from the Cu-RBS+NIR group is considerably intact, clear, and appears to be no inflammation. This suggests that the NIR-activated Cu-RBS has effectively inhibited the pulmonary metastasis of the 4T1-LUC primary tumor model after therapy for 23 days. In brief, Cu-RBS as a new NIRactivated NO donor demonstrates the significant anticancer and antimetastasis effects, exhibiting a good application potential for controlled gas therapy of cancer. In summary, we have developed a facile coordinationprecipitation strategy to synthesize a new kind of NIRresponsive NORMs Me-RBSs, which generally have a NIR absorption property. The synthesized Me-RBSs exhibit NIR absorption-dependent NIR-responsive NO release behaviors. Aqueous insolubility of Me-RBSs ensures stable lightresponsiveness, low cytotoxicity, and high thermostability. The NIR-activated Cu-RBS has the significant anticancer and antimetastasis effects on the pulmonary metastasis of the 4T1LUC primary tumor model. This work establishes a new category of NIR-responsive NORMs, and may spark new inspiration for designing intelligent, safe, and high-efficacy gasreleasing molecules.

REFERENCES

(1) Carpenter, A. W.; Schoenfisch, M. H. Nitric Oxide Release: Part II. Therapeutic Applications. Chem. Soc. Rev. 2012, 41, 3742−3752. (2) Mishra, B. B; Rathinam, V. A. K.; Martens, G. W.; Martinot, A. J.; Kornfeld, H.; Fitzgerald, K. A.; Sassetti, C. M. Nitric Oxide Controls the Immunopathology of Tuberculosis by Inhibiting NLRP3 Inflammasome−Dependent Processing of IL-1βChristian Bogdan. Nat. Immunol. 2013, 14, 52−60. (3) Murad, F. Discovery of Some of the Biological Effects of Nitric Oxide and Its Role in Cell Signaling (Nobel Lecture). Angew. Chem., Int. Ed. 1999, 38, 1856−1868. (4) Xu, W.; Liu, L.; Loizidou, M.; Ahmed, M.; Charles, I. G. The Role of Nitric Oxide in Cancer. Cell Res. 2002, 12, 311−320. (5) Ridnour, L. A.; Thomas, D. D.; Donzelli, S.; Espey, M. G.; Roberts, D. D.; Wink, D. A.; Isenberg, J. S. The Biphasic Nature of Nitric Oxide Responses in Tumor Biology. Antioxid. Redox Signaling 2006, 8, 1329−1337. (6) Sullivan, J. B.; Krieger, G. B.; Thomas, R. J. Methemoglobinforming chemicals. In Hazardaous Materials Toxicology: Clinical Principles of Environmental Health; Williams & Wilkins: Philadelphia, PA, 1992, (7) Kim, J.; Saravanakumar, G.; Choi, H. W.; Park, D.; Kim, W. J. A Platform for Nitric Oxide Delivery. J. Mater. Chem. B 2014, 2, 341− 356. (8) Fan, W.; Lu, N.; Huang, P.; Liu, Y.; Yang, Z.; Wang, S.; Yu, G.; Liu, Y.; Hu, J.; He, Q.; Qu, J.; Wang, T.; Chen, X. Glucose-Responsive Sequential Generation of Hydrogen Peroxide and Nitric Oxide for Synergistic Cancer Starving-Like/Gas Therapy. Angew. Chem., Int. Ed. 2017, 56, 1229. D

DOI: 10.1021/acsami.7b11325 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX

Letter

ACS Applied Materials & Interfaces (9) Sortino, S. Light-Controlled Nitric Oxide Delivering Molecular Assemblies. Chem. Soc. Rev. 2010, 39, 2903−2913. (10) Diring, S.; Wang, D. O.; Kim, C.; Kondo, M.; Chen, Y.; Kitagawa, S.; Kamei, K.; Furukawa, S. Localized Cell Stimulation by Nitric Oxide Using a Photoactive Porous Coordination Polymer Platform. Nat. Commun. 2013, 4, 2684. (11) Neuman, D.; Ostrowski, A. D.; Absalonson, R. O.; Strouse, G. F.; Ford, P. C. Photosensitized NO Release from Water-Soluble Nanoparticle Assemblies. J. Am. Chem. Soc. 2007, 129, 4146−4147. (12) Neuman, D.; Ostrowski, A. D.; Mikhailovsky, A. A.; Absalonson, R. O.; Strouse, G. F.; Ford, P. C. Quantum Dot Fluorescence QuenchingPathways with Cr(III) Complexes. Photosensitized NO Production from Trans-Cr(cyclam)(ONO)2+. J. Am. Chem. Soc. 2008, 130, 168−175. (13) Tan, L.; Wan, A.; Zhu, X.; Li, H. Visible Light-Triggered Nitric Oxide Release from Near-Infrared Fluorescent Nanospheric Vehicles. Analyst 2014, 139, 3398−3406. (14) Mitchell-Koch, J. T.; Reed, T. M.; Borovik, A. S. Light-Activated Transfer of Nitric Oxide from a Porous Material. Angew. Chem., Int. Ed. 2004, 43, 2806−2809. (15) Fan, J.; He, Q.; Liu, Y.; Zhang, F.; Yang, X.; Wang, Z.; Lu, N.; Fan, W.; Lin, L.; Niu, G.; He, N.; Song, J.; Chen, X. Light-Responsive Biodegradable Nanomedicine Overcomes Multidrug Resistance via NO-Enhanced Chemosensitization. ACS Appl. Mater. Interfaces 2016, 8, 13804−13811. (16) Bourassa, J.; DeGraff, W.; Kudo, S.; Wink, D. A.; Mitchell, J. B.; Ford, P. C. Photochemistry of Roussin’s Red Salt, Na2[Fe2S2(NO)4], and of Roussin’s Black Salt, NH4[Fe4S3(NO)7]. In Situ Nitric Oxide Generation to Sensitize γ-Radiation Induced Cell Death. J. Am. Chem. Soc. 1997, 119, 2853−2860. (17) Fan, J.; He, N.; He, Q.; Liu, Y.; Ma, Y.; Fu, X.; Liu, Y.; Huang, P.; Chen, X. A Novel Self-Assembled Sandwich Nanomedicine for NIR-Responsive Release of NO. Nanoscale 2015, 7, 20055−20062. (18) Zhang, X.; Tian, G.; Yin, W.; Wang, L.; Zheng, X.; Yan, L.; Li, J.; Su, H.; Chen, C.; Gu, Z.; Zhao, Y. Controllable Generation of Nitric Oxide by Near-Infrared Sensitized Upconversion Nanoparticles for Tumor Therapy. Adv. Funct. Mater. 2015, 25, 3049−3055. (19) Garcia, J. V.; Yang, J.; Shen, D.; Yao, C.; Li, X.; Wang, R.; Stucky, G. D.; Zhao, D.; Ford, P. C.; Zhang, F. NIR-Triggered Release of Caged Nitric Oxide using Upconverting Nanostructured Materials. Small 2012, 8, 3800−3805. (20) Wecksler, S.; Mikhailovsky, A.; Ford, P. C. Photochemical Production of Nitric Oxide via Two-Photon Excitation with NIR Light. J. Am. Chem. Soc. 2004, 126, 13566−13567. (21) Brauer, G. Handbook of Preparative Inorganic Chemistry, 2nd ed.; Academic Press: New York, 1963; pp 1763−1764. (22) Ballhausen, C. J. Studies of Absorption Spectra. II. Theory of Copper (II) Spectra. Kgl. Danske Videnskab. Selskab. Mater. Fys. Medd. 1954, 29, 3−18. (23) Baker, A. T. The Ligand Field Spectra of Copper (II) Complexes. J. Chem. Educ. 1998, 75, 98. (24) Jaworska, M.; Stasicka, Z. Structure and UV−vis Spectroscopy of Roussin Black Salt [Fe4S3(NO)7]−. J. Mol. Struct. 2006, 785, 68−75. (25) Chmura, A.; Szacilowski, K.; Stasicka, Z. The Role of Photoinduced Electron Transfer Processes in Photodegradation of the [Fe4(μ3-S)3(NO)7]−Cluster. Nitric Oxide 2006, 15, 370−379. (26) Fan, W.; Bu, W.; Zhang, Z.; Shen, B.; Zhang, H.; He, Q.; Ni, D.; Cui, Z.; Zhao, K.; Bu, J.; Du, J.; Liu, J.; Shi, J. X-ray RadiationControlled NO-Release for On-Demand Depth Independent Hypoxic Radiosensitization. Angew. Chem., Int. Ed. 2015, 54, 14026−14030. (27) He, Q.; Kiesewetter, D. O.; Qu, Y.; Fu, X.; Fan, J.; Huang, P.; Liu, Y.; Zhu, G.; Liu, Y.; Qian, Z.; Chen, X. NIR-Responsive OnDemand Release of CO from Metal Carbonyl-Caged Graphene Oxide Nanomedicine. Adv. Mater. 2015, 27, 6741−6746. (28) Qu, Y.; Chu, B. Y.; Peng, J. R.; Liao, J. F.; Qi, T. T.; Shi, K.; Zhang, X. N.; Wei, Y. Q.; Qian, Z. Y. A Biodegradable ThermoResponsive Hybrid Hydrogel: Therapeutic Applications in Preventing the Post-Operative Recurrence of Breast Cancer. NPG Asia Mater. 2015, 7, e207.

(29) Longo, J. P. F; Muehlmann, L. A.; Miranda-Vilela, A. L.; Portilho, F. A.; de Souza, L. R.; Silva, J. R.; Lacava, Z. G.M.; Bocca, A. L.; Chaves, S. B.; Azevedo, R. B. Prevention of Distant Lung Metastasis after PhotoDynamic Therapy Application in a Breast Cancer Tumor Model. J. Biomed. Nanotechnol. 2016, 12, 689−699. (30) Jiang, L.; Li, L.; He, B.; Pan, D. Y.; Luo, K.; Yi, Q. Y.; Gu, Z. W. Anti-Cancer Efficacy of Paclitaxel Loaded in pH Triggered Liposomes. J. Biomed. Nanotechnol. 2016, 12, 79−90.

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DOI: 10.1021/acsami.7b11325 ACS Appl. Mater. Interfaces XXXX, XXX, XXX−XXX