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A pH-switched mesoporous nanoreactor for synergetic therapy

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Abstract

Zinc oxide nanoparticles (ZnO NPs), as a new type of pH-sensitive drug carrier, have received much attention. ZnO NPs are stable at physiological pH, but can dissolve quickly in the acidic tumor environment (pH < 6) to generate cytotoxic zinc ions and reactive oxygen species (ROS). However, the protein corona usually causes the non-specific degradation of ZnO NPs, which has limited their application considerably. Herein, a new type of pH-sensitive nanoreactor (ZnO-DOX@F-mSiO2-FA), aimed at reducing the non-specific degradation of ZnO NPs, is presented. In the acidic tumor environment (pH < 6), it can release cytotoxic zinc ions, ROS, and anticancer drugs to kill cancer cells effectively. In addition, the fluorescence emitted from fluorescein isothiocyanate (FITC)-labeled mesoporous silica (F-mSiO2) and doxorubicin (DOX) can be used to monitor the release behavior of the anticancer drug. This report provides a new method to avoid the non-specific degradation of ZnO NPs, resulting in synergetic therapy by taking advantage of ZnO NPs-induced oxidative stress and targeted drug release.

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References

  1. Petros, R. A.; DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nat. Rev. Drug Discov. 2010, 9, 615–627.

    Article  Google Scholar 

  2. Lee, J. H.; Yigit, M. V.; Mazumdar, D.; Lu, Y. Molecular diagnostic and drug delivery agents based on aptamernanomaterial conjugates. Adv. Drug Deliv. Rev. 2010, 62, 592–605.

    Article  Google Scholar 

  3. Caldorera-Moore, M. E.; Liechty, W. B.; Peppas, N. A. Responsive theranostic systems: Integration of diagnostic imaging agents and responsive controlled release drug delivery carriers. Acc. Chem. Res. 2011, 44, 1061–1070.

    Article  Google Scholar 

  4. Doane, T. L.; Burda, C. The unique role of nanoparticles in nanomedicine: Imaging, drug delivery and therapy. Chem. Soc. Rev. 2012, 41, 2885–2911.

    Article  Google Scholar 

  5. Li, Z. X.; Barnes, J. C.; Bosoy, A.; Stoddart, J. F.; Zink, J. I. Mesoporous silica nanoparticles in biomedical applications. Chem. Soc. Rev. 2012, 41, 2590–2605.

    Article  Google Scholar 

  6. Casasús, R.; Climent, E.; Marcos, M. D.; Martínez-Máñez, R.; Sancenó n, F.; Soto, J.; Amoró s, P.; Cano, J.; Ruiz, E. Dual aperture control on pH- and anion-driven supramolecular nanoscopic hybrid gate-like ensembles. J. Am. Chem. Soc. 2008, 130, 1903–1917.

    Article  Google Scholar 

  7. Aznar, E.; Marcos, M. D.; Martínez-Máñez, R.; Sancenón, F.; Soto, J.; Amorós, P.; Guillem, C. pH- and photo-switched release of guest molecules from mesoporous silica supports. J. Am. Chem. Soc. 2009, 131, 6833–6843.

    Article  Google Scholar 

  8. Ferris, D. P.; Zhao, Y.-L.; Khashab, N. M.; Khatib, H. A.; Stoddart, J. F.; Zink, J. I. Light-operated mechanized nanoparticles. J. Am. Chem. Soc. 2009, 131, 1686–1688.

    Article  Google Scholar 

  9. Chen, C. E.; Geng, J.; Pu, F.; Yang, X. J.; Ren, J. S.; Qu, X. G. Polyvalent nucleic acid/mesoporous silica nanoparticle conjugates: Dual stimuli-responsive vehicles for intracellular drug delivery. Angew. Chem., Int. Ed. 2011, 50, 882–886.

    Article  Google Scholar 

  10. Shi, P.; Li, M.; Ren, J. S.; Qu, X. G. Gold nanocage-based dual responsive “caged metal chelator” release system: Noninvasive remote control with near infrared for potential treatment of Alzheimer's disease. Adv. Funct. Mater. 2013, 23, 5412–5419.

    Article  Google Scholar 

  11. Chen, Z. W.; Li, Z. H.; Lin, Y. H.; Yin, M. L.; Ren, J. S.; Qu, X. G. Biomineralization inspired surface engineering of nanocarriers for pH-responsive, targeted drug delivery. Biomaterials 2013, 34, 1364–1371.

    Article  Google Scholar 

  12. Chung, M. F.; Liu, H. Y.; Lin, K. J.; Chia, W. T.; Sung, H. W. A pH-responsive carrier system that generates NO bubbles to trigger drug release and reverse P-glycoprotein-mediated multidrug resistance. Angew. Chem., Int. Ed. 2015, 54, 9890–9893.

    Article  Google Scholar 

  13. Kim, B. J.; Cheong, H.; Hwang, B. H.; Cha, H. J. Musselinspired protein nanoparticles containing iron(III)-DOPA complexes for pH-responsive drug delivery. Angew. Chem., Int. Ed. 2015, 54, 7318–7322.

    Article  Google Scholar 

  14. Liu, R.; Zhang, Y.; Zhao, X.; Agarwal, A.; Mueller, L. J.; Feng, P. Y. pH-responsive nanogated ensemble based on goldcapped mesoporous silica through an acid-labile acetal linker. J. Am. Chem. Soc. 2010, 132, 1500–1501.

    Google Scholar 

  15. Xiong, H.-M.; Xu, Y.; Ren, Q.-G.; Xia, Y.-Y. Stable aqueous ZnO@polymer core-shell nanoparticles with tunable photoluminescence and their application in cell imaging. J. Am. Chem. Soc. 2008, 130, 7522–7523.

    Article  Google Scholar 

  16. Muhammad, F.; Guo, M. Y.; Guo, Y. J.; Qi, W. X.; Qu, F. Y.; Sun, F. X.; Zhao, H. J.; Zhu, G. S. Acid degradable ZnO quantum dots as a platform for targeted delivery of an anticancer drug. J. Mater. Chem. 2011, 21, 13406–13412.

    Article  Google Scholar 

  17. Muhammad, F.; Guo, M. Y.; Qi, W. X.; Sun, F. X.; Wang, A. F.; Guo, Y. J.; Zhu, G. S. pH-triggered controlled drug release from mesoporous silica nanoparticles via intracelluar dissolution of ZnO nanolids. J. Am. Chem. Soc. 2011, 133, 8778–8781.

    Google Scholar 

  18. Xiong, H. M. ZnO nanoparticles applied to bioimaging and drug delivery. Adv. Mater. 2013, 25, 5329–5335.

    Article  Google Scholar 

  19. Wang, Y. H.; Song, S. Y.; Liu, J. H.; Liu, D. P.; Zhang, H. J. ZnO-functionalized upconverting nanotheranostic agent: Multi-modality imaging-guided chemotherapy with on-demand drug release triggered by pH. Angew. Chem., Int. Ed. 2015, 54, 536–540.

    Google Scholar 

  20. Zhang, J.; Wu, D.; Li, M. F.; Feng, J. Multifunctional mesoporous silica nanoparticles based on charge-reversal plug-gate nanovalves and acid-decomposable ZnO quantum dots for intracellular drug delivery. ACS Appl. Mater. Interfaces 2015, 7, 26666–26673.

    Article  Google Scholar 

  21. Applerot, G.; Lipovsky, A.; Dror, R.; Perkas, N.; Nitzan, Y.; Lubart, R.; Gedanken, A. Enhanced antibacterial activity of nanocrystalline ZnO due to increased ROS-mediated cell injury. Adv. Funct. Mater. 2009, 19, 842–852.

    Article  Google Scholar 

  22. Xu, M. S.; Li, J.; Hanagata, N.; Su, H. X.; Chen, H. Z.; Fujita, D. Challenge to assess the toxic contribution of metal cation released from nanomaterials for nanotoxicology-the case of ZnO nanoparticle. Nanoscale 2013, 5, 4763–4769.

    Article  Google Scholar 

  23. Chen, Z. W.; Li, Z. H.; Wang, J. S.; Ju, E. G.; Zhou, L.; Ren, J. S.; Qu, X. G. A multi-synergistic platform for sequential irradiation-activated high-performance apoptotic cancer therapy. Adv. Funct. Mater. 2014, 24, 522–529.

    Article  Google Scholar 

  24. Gupta, J.; Bhargava, P.; Bahadur, D. Fluorescent ZnO for imaging and induction of DNA fragmentation and ROSmediated apoptosis in cancer cells. J. Mater. Chem. B 2015, 3, 1968–1978.

    Article  Google Scholar 

  25. Chen, W. H.; Luo, G. F.; Qiu, W. X.; Lei, Q.; Hong, S.; Wang, S. B.; Zheng, D. W.; Zhu, C. H.; Zeng, X.; Feng, J. et al. Programmed nanococktail for intracellular cascade reaction regulating self-synergistic tumor targeting therapy. Small 2016, 12, 733–744.

    Article  Google Scholar 

  26. Barick, K. C.; Nigam, S.; Bahadur, D. Nanoscale assembly of mesoporous ZnO: A potential drug carrier. J. Mater. Chem. 2010, 20, 6446–6452.

    Article  Google Scholar 

  27. Mitra, S.; Subia, B.; Patra, P.; Chandra, S.; Debnath, N.; Das, S.; Banerjee, R.; Kundu, S. C.; Pramanik, P.; Goswami, A. Porous ZnO nanorod for targeted delivery of doxorubicin: In vitro and in vivo response for therapeutic applications. J. Mater. Chem. 2012, 22, 24145–24154.

    Article  Google Scholar 

  28. Zhang, Z. Y.; Xu, Y. D.; Ma, Y. Y.; Qiu, L. L.; Wang, Y.; Kong, J. L.; Xiong, H. M. Biodegradable ZnO@polymer core–shell nanocarriers: pH-triggered release of doxorubicin in vitro. Angew. Chem., Int. Ed. 2013, 52, 4127–4131.

    Article  Google Scholar 

  29. Moreau, J. W.; Weber, P. K.; Martin, M. C.; Gilbert, B.; Hutcheon, I. D.; Banfield, J. F. Extracellular proteins limit the dispersal of biogenic nanoparticles. Science 2007, 316, 1600–1603.

    Article  Google Scholar 

  30. Xia, T.; Kovochich, M.; Liong, M.; Mädler, L.; Gilbert, B.; Shi, H. B.; Yeh, J. I.; Zink, J. I.; Nel, A. E. Comparison of the mechanism of toxicity of zinc oxide and cerium oxide nanoparticles based on dissolution and oxidative stress properties. ACS Nano 2008, 2, 2121–2134.

    Article  Google Scholar 

  31. Nel, A. E.; Mädler, L.; Velegol, D.; Xia, T.; Hoek, E. M. V.; Somasundaran, P.; Klaessig, F.; Castranova, V.; Thompson, M. Understanding biophysicochemical interactions at the nano-bio interface. Nat. Mater. 2009, 8, 543–557.

    Article  Google Scholar 

  32. Müller, K. H.; Kulkarni, J.; Motskin, M.; Goode, A.; Winship, P.; Skepper, J. N.; Ryan, M. P.; Porter, A. E. pH-dependent toxicity of high aspect ratio ZnO nanowires in macrophages due to intracellular dissolution. ACS Nano 2010, 4, 6767–6779.

  33. George, S.; Pokhrel, S.; Xia, T.; Gilbert, B.; Ji, Z. X.; Schowalter, M.; Rosenauer, A.; Damoiseaux, R.; Bradley, K. A.; Mä dler, L. et al. Use of a rapid cytotoxicity screening approach to engineer a safer zinc oxide nanoparticle through iron doping. ACS Nano 2010, 4, 15–29.

    Article  Google Scholar 

  34. Luo, M. D.; Shen, C. C.; Feltis, B. N.; Martin, L. L.; Hughes, A. E.; Wright, P. F. A.; Turney, T. W. Reducing ZnO nanoparticle cytotoxicity by surface modification. Nanoscale 2014, 6, 5791–5798.

    Article  Google Scholar 

  35. Zhao, Y.; Luo, Z.; Li, M. H.; Qu, Q. Y.; Ma, X.; Yu, S. H.; Zhao, Y. L. A preloaded amorphous calcium carbonate/ doxorubicin@silica nanoreactor for pH-responsive delivery of an anticancer drug. Angew. Chem., Int. Ed. 2015, 54, 919–922.

    Article  Google Scholar 

  36. Vázquez-Vázquez, C.; Vaz, B.; Giannini, V.; Pérez-Lorenzo, M.; Alvarez-Puebla, R. A.; Correa-Duarte, M. A. Nanoreactors for simultaneous remote thermal activation and optical monitoring of chemical reactions. J. Am. Chem. Soc. 2013, 135, 13616–13619.

    Article  Google Scholar 

  37. Huang, Y. Y.; Lin, Y. H.; Ran, X.; Ren, J. S.; Qu, X. G. Self-assembly and compartmentalization of nanozymes in mesoporous silica-based nanoreactors. Chem.—Eur. J. 2016, 22, 5705–5711.

    Article  Google Scholar 

  38. Min, Q. B.; Wu, R. A.; Zhao, L.; Qin, H. Q.; Ye, M. L.; Zhu, J. J.; Zou, H. F. Size-selective proteolysis on mesoporous silica-based trypsin nanoreactor for low-MW proteome analysis. Chem. Commun. 010, 46, 6144–6146.

  39. Hu, J.; Chen, M.; Fang, X. S.; Wu, L. M. Fabrication and application of inorganic hollow spheres. Chem. Soc. Rev. 2011, 40, 5472–5491.

    Article  Google Scholar 

  40. Choi, E.; Kwak, M.; Jang, B.; Piao, Y. Z. Highly monodisperse rattle-structured nanomaterials with gold nanorod coremesoporous silica shell as drug delivery vehicles and nanoreactors. Nanoscale 2013, 5, 151–154.

    Article  Google Scholar 

  41. Kim, S. M.; Jeon, M.; Kim, K. W.; Park, J.; Lee, I. S. Postsynthetic functionalization of a hollow silica nanoreactor with manganese oxide-immobilized metal nanocrystals inside the cavity. J. Am. Chem. Soc. 2013, 135, 15714–15717.

    Article  Google Scholar 

  42. Xu, H. J.; Zhang, H. J.; Wang, D. H.; Wu, L.; Liu, X. W.; Jiao, Z. A facile route for rapid synthesis of hollow mesoporous silica nanoparticles as pH-responsive delivery carrier. J. Colloid Interface Sci. 2015, 451, 101–107.

    Article  Google Scholar 

  43. Guerrero-Martínez, A.; Pérez-Juste, J.; Liz-Marzán, L. M. Recent progress on silica coating of nanoparticles and related nanomaterials. Adv. Mater. 2010, 22, 1182–1195.

    Article  Google Scholar 

  44. Zhai, J.; Tao, X.; Pu, Y.; Zeng, X.-F.; Chen, J.-F. Core/shell structured ZnO/SiO2 nanoparticles: Preparation, characterization and photocatalytic property. Appl. Surf. Sci. 2010, 257, 393–397.

    Article  Google Scholar 

  45. Zhao, Y.; Lin, L. N.; Lu, Y.; Chen, S. F.; Dong, L.; Yu, S. H. Templating synthesis of preloaded doxorubicin in hollow mesoporous silica nanospheres for biomedical applications. Adv. Mater. 2010, 22, 5255–5259.

    Article  Google Scholar 

  46. Liu, J.; Qiao, S. Z.; Hu, Q. H.; Lu, G. Q. Magnetic nanocomposites with mesoporous structures: Synthesis and applications. Small 2011, 7, 425–443.

    Article  Google Scholar 

  47. Liu, J.; Bu, J. W.; Bu, W. B.; Zhang, S. J.; Pan, L. M.; Fan, W. P.; Chen, F.; Zhou, L. P.; Peng, W. J.; Zhao, K. L. et al. Real-time in vivo quantitative monitoring of drug release by dual-mode magnetic resonance and upconverted luminescence imaging. Angew. Chem., Int. Ed. 2014, 53, 4551–4555.

    Article  Google Scholar 

  48. Fan, W. P.; Shen, B.; Bu, W. B.; Chen, F.; Zhao, K. L.; Zhang, S. J.; Zhou, L. P.; Peng, W. J.; Xiao, Q. F.; Xing, H. Y. et al. Rattle-structured multifunctional nanotheranostics for synergetic chemo-/radiotherapy and simultaneous magnetic/ luminescent dual-mode imaging. J. Am. Chem. Soc. 2013, 135, 6494–6503.

    Article  Google Scholar 

  49. Yoon, T. J.; Kim, J. S.; Kim, B. G.; Yu, K. N.; Cho, M. H.; Lee, J. K. Multifunctional nanoparticles possessing a “magnetic motor effect” for drug or gene delivery. Angew. Chem., Int. Ed. 2005, 44, 1068–1071.

    Article  Google Scholar 

  50. Liong, M.; Lu, J.; Kovochich, M.; Xia, T.; Ruehm, S. G.; Nel, A. E.; Tamanoi, F.; Zink, J. I. Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. ACS Nano 2008, 2, 889–896.

    Article  Google Scholar 

  51. Shi, P.; Liu, Z.; Dong, K.; Ju, E. G.; Ren, J. S.; Du, Y. D.; Li, Z. Q.; Qu, X. G. A smart “sense-act-treat” system: Combining a ratiometric pH sensor with a near infrared therapeutic gold nanocage. Adv. Mater. 2014, 26, 6635–6641.

    Article  Google Scholar 

  52. Chen, T. T.; Hu, Y. H.; Cen, Y.; Chu, X.; Lu, Y. A dualemission fluorescent nanocomplex of gold-cluster-decorated silica particles for live cell imaging of highly reactive oxygen species. J. Am. Chem. Soc. 2013, 135, 11595–11602.

    Article  Google Scholar 

  53. Xue, X. D.; Zhao, Y. Y.; Dai, L. R.; Zhang, X.; Hao, X. H.; Zhang, C. Q.; Huo, S. D.; Liu, J.; Liu, C.; Kumar, A. et al. Spatiotemporal drug release visualized through a drug delivery system with tunable aggregation-induced emission. Adv. Mater. 2014, 26, 712–717.

    Article  Google Scholar 

  54. Yan, Z. Q.; Shi, P.; Ren, J. S.; Qu, X. G. A “sense-andtreat” hydrogel used for treatment of bacterial infection on the solid matrix. Small 2015, 11, 5540–5544.

    Article  Google Scholar 

  55. Deng, X. Y.; Luan, Q. X.; Chen, W. T.; Wang, Y. L.; Wu, M. H.; Zhang, H. J.; Jiao, Z. Nanosized zinc oxide particles induce neural stem cell apoptosis. Nanotechnology 2009, 20, 115101.

    Article  Google Scholar 

  56. Narayanan, S.; Binulal, N. S.; Mony, U.; Manzoor, K.; Nair, S.; Menon, D. Folate targeted polymeric “green” nanotherapy for cancer. Nanotechnology 2010, 21, 285107.

    Article  Google Scholar 

  57. Li, Z. H.; Dong, K.; Huang, S.; Ju, E. G.; Liu, Z.; Yin, M. L.; Ren, J. S.; Qu, X. G. A smart nanoassembly for multistage targeted drug delivery and magnetic resonance imaging. Adv. Funct. Mater. 2014, 24, 3612–3620.

    Article  Google Scholar 

  58. Conte, C.; Ungaro, F.; Maglio, G.; Tirino, P.; Siracusano, G.; Sciortino, M. T.; Leone, N.; Palma, G.; Barbieri, A.; Arra, C. et al. Biodegradable core–shell nanoassemblies for the delivery of docetaxel and Zn(II)-phthalocyanine inspired by combination therapy for cancer. J. Control. Release 2013, 167, 40–52.

    Article  Google Scholar 

  59. Miao, W. J.; Shim, G.; Lee, S.; Lee, S.; Choe, Y. S.; Oh, Y. K. Safety and tumor tissue accumulation of pegylated graphene oxide nanosheets for co-delivery of anticancer drug and photosensitizer. Biomaterials 2013, 34, 3402–3410.

    Article  Google Scholar 

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Acknowledgements

This work was supported by the National Basic Research Program of China (No. 2012CB720602) and the National Natural Science Foundation of China (Nos. 21210002, 21431007, and 21533008).

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Authors and Affiliations

  1. Laboratory of Chemical Biology and State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China

    Zhengqing Yan, Andong Zhao, Xinping Liu, Jinsong Ren & Xiaogang Qu

  2. University of Chinese Academy of Sciences, Beijing, 100039, China

    Zhengqing Yan, Andong Zhao & Xinping Liu

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  1. Zhengqing Yan
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  2. Andong Zhao
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  3. Xinping Liu
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  4. Jinsong Ren
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  5. Xiaogang Qu
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Correspondence to Xiaogang Qu.

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Yan, Z., Zhao, A., Liu, X. et al. A pH-switched mesoporous nanoreactor for synergetic therapy. Nano Res. 10, 1651–1661 (2017). https://doi.org/10.1007/s12274-016-1377-2

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