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.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Petros, R. A.; DeSimone, J. M. Strategies in the design of nanoparticles for therapeutic applications. Nat. Rev. Drug Discov. 2010, 9, 615–627.
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.
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.
Doane, T. L.; Burda, C. The unique role of nanoparticles in nanomedicine: Imaging, drug delivery and therapy. Chem. Soc. Rev. 2012, 41, 2885–2911.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Xiong, H. M. ZnO nanoparticles applied to bioimaging and drug delivery. Adv. Mater. 2013, 25, 5329–5335.
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.
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.
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.
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.
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.
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.
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.
Barick, K. C.; Nigam, S.; Bahadur, D. Nanoscale assembly of mesoporous ZnO: A potential drug carrier. J. Mater. Chem. 2010, 20, 6446–6452.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Hu, J.; Chen, M.; Fang, X. S.; Wu, L. M. Fabrication and application of inorganic hollow spheres. Chem. Soc. Rev. 2011, 40, 5472–5491.
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.
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.
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.
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.
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.
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.
Liu, J.; Qiao, S. Z.; Hu, Q. H.; Lu, G. Q. Magnetic nanocomposites with mesoporous structures: Synthesis and applications. Small 2011, 7, 425–443.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Narayanan, S.; Binulal, N. S.; Mony, U.; Manzoor, K.; Nair, S.; Menon, D. Folate targeted polymeric “green” nanotherapy for cancer. Nanotechnology 2010, 21, 285107.
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.
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.
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.
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).
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Rights and permissions
About this article
Cite this article
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
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12274-016-1377-2