344
Views
13
Downloads
18
Crossref
N/A
WoS
19
Scopus
3
CSCD
In the intrinsic pathway of apoptosis, stresses of mitochondrial reactive oxygen species (mitoROS) might be sensed as more effective signals than those in cytosol, as mitochondria are the major sources of reactive oxygen species (ROS) and pivotal components during cell apoptosis. Mitochondrial superoxide dismutase (SOD2) takes the leading role in eliminating mitoROS, and inhibition of SOD2 might induce severe disturbances overwhelming the mitochondrial oxidative equilibrium, which would elevate the intracellular oxidative stresses and drive cells to death. Herein, we report a general strategy to kill cancer cells by targeted inhibition of SOD2 using 2-methoxyestradiol (2-ME, an inhibitor for the SOD family) via a robust mitochondria-targeted mesoporous silica nanocarrier (mtMSN), with the expected elevation of mitoROS and activation of apoptosis in HeLa cells. Fe3O4@MSN was employed in the mitochondria-targeted drug delivery and selective inhibition of mitochondrial enzymes, and was shown to be stable with good biocompatibility and high loading capacity. Due to the selective inhibition of SOD2 by 2-ME/mtMSN, enhanced elevation of mitoROS (132% of that with free 2-ME) was obtained, coupled with higher efficiency in initiating cell apoptosis (395% of that with free 2-ME in 4 h). Finally, the 2-ME/mtMSN exhibited powerful efficacy in targeted killing of HeLa cells by taking advantage of both biological recognition and magnetic guiding, causing 97.0% cell death with only 2 μg/mL 2-ME/mtMSN, hinting at its great potential in cancer therapy through manipulation of the delicate mitochondrial oxidative balance.
In the intrinsic pathway of apoptosis, stresses of mitochondrial reactive oxygen species (mitoROS) might be sensed as more effective signals than those in cytosol, as mitochondria are the major sources of reactive oxygen species (ROS) and pivotal components during cell apoptosis. Mitochondrial superoxide dismutase (SOD2) takes the leading role in eliminating mitoROS, and inhibition of SOD2 might induce severe disturbances overwhelming the mitochondrial oxidative equilibrium, which would elevate the intracellular oxidative stresses and drive cells to death. Herein, we report a general strategy to kill cancer cells by targeted inhibition of SOD2 using 2-methoxyestradiol (2-ME, an inhibitor for the SOD family) via a robust mitochondria-targeted mesoporous silica nanocarrier (mtMSN), with the expected elevation of mitoROS and activation of apoptosis in HeLa cells. Fe3O4@MSN was employed in the mitochondria-targeted drug delivery and selective inhibition of mitochondrial enzymes, and was shown to be stable with good biocompatibility and high loading capacity. Due to the selective inhibition of SOD2 by 2-ME/mtMSN, enhanced elevation of mitoROS (132% of that with free 2-ME) was obtained, coupled with higher efficiency in initiating cell apoptosis (395% of that with free 2-ME in 4 h). Finally, the 2-ME/mtMSN exhibited powerful efficacy in targeted killing of HeLa cells by taking advantage of both biological recognition and magnetic guiding, causing 97.0% cell death with only 2 μg/mL 2-ME/mtMSN, hinting at its great potential in cancer therapy through manipulation of the delicate mitochondrial oxidative balance.
Sena, L. A.; Chandel, N. S. Physiological roles of mitochondrial reactive oxygen species. Mol. Cell 2012, 48, 158–167.
Yang, Y.; Song, Y.; Loscalzo, J. Regulation of the protein disulfide proteome by mitochondria in mammalian cells. Proc. Natl. Acad. Sci. USA 2007, 104, 10813–10817.
Hamanaka, R. B.; Chandel, N. S. Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes. Trends Biochem. Sci. 2010, 35, 505–513.
Simon, H. -U.; Haj-Yehia, A.; Levi-Schaffer, F. Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 2000, 5, 415–418.
Murphy, M. P. How mitochondria produce reactive oxygen species. Biochem. J. 2009, 417, 1–13.
Wang, J.; Yi, J. Cancer cell killing via ROS: To increase or decrease, that is the question. Cancer Biol. Ther. 2008, 7, 1875–1884.
Trachootham, D.; Alexandre, J.; Huang, P. Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nat. Rev. Drug Discov. 2009, 8, 579–591.
Watson, J. Oxidants, antioxidants and the current incurability of metastatic cancers. Open Biol. 2013, 3, 120144.
Qi, Y.; Tian, X.; Liu, J.; Han, Y.; Graham, A. M.; Simon, M. C.; Penninger, J. M.; Carmeliet, P.; Li, S. Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis. J. Cell Biol. 2012, 198, 103–114.
Scherz-Shouval, R.; Shvets, E.; Fass, E.; Shorer, H.; Gil, L.; Elazar, Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 2007, 26, 1749–1760.
Zorov, D. B.; Juhaszova, M.; Sollott, S. J. Mitochondrial ROS-induced ROS release: An update and review. BBA-Bioenergetics. 2006, 1757, 509–517.
Miwa, S.; Brand, M. D. Mitochondrial matrix reactive oxygen species production is very sensitive to mild uncoupling. Biochem. Soc. Trans. 2003, 31, 1300–1301.
Pelicano, H.; Feng, L.; Zhou, Y.; Carew, J. S.; Hileman, E. O.; Plunkett, W.; Keating, M. J.; Huang, P. Inhibition of mitochondrial respiration: A novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J. Biol. Chem. 2003, 278, 37832–37839.
Kirshner, J. R.; He, S.; Balasubramanyam, V.; Kepros, J.; Yang, C. -Y.; Zhang, M.; Du, Z.; Barsoum, J.; Bertin, J. Elesclomol induces cancer cell apoptosis through oxidative stress. Mol. Cancer Ther. 2008, 7, 2319–2327.
Bragado, P.; Armesilla, A.; Silva, A.; Porras, A. Apoptosis by cisplatin requires p53 mediated p38α MAPK activation through ROS generation. Apoptosis 2007, 12, 1733–1742.
Huang, P.; Feng, L.; Oldham, E. A.; Keating, M. J.; Plunkett, W. Superoxide dismutase as a target for the selective killing of cancer cells. Nature 2000, 407, 390–395.
Zelko, I. N.; Mariani, T. J.; Folz, R. J. Superoxide dismutase multigene family: A comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression. Free Radical Biol. Med. 2002, 33, 337–349.
Kamata, H.; Honda, S. -i.; Maeda, S.; Chang, L. F.; Hirata, H.; Karin, M. Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 2005, 120, 649–661.
Derfus, A. M.; Chan, W. C. W.; Bhatia, S. N. Intracellular delivery of quantum dots for live cell labeling and organelle tracking. Adv. Mater. 2004, 16, 961–966.
Paunesku, T.; Vogt, S.; Lai, B.; Maser, J.; Stojićević, N.; Thurn, K. T.; Osipo, C.; Liu, H.; Legnini, D.; Wang, Z. et al. Intracellular distribution of TiO2–DNA oligonucleotide nanoconjugates directed to nucleolus and mitochondria indicates sequence specificity. Nano Lett. 2007, 7, 596–601.
Marrache, S.; Dhar, S. Engineering of blended nanoparticle platform for delivery of mitochondria-acting therapeutics. Proc. Natl. Acad. Sci. USA 2012, 109, 16288–16293.
Wang, L. M.; Liu, Y.; Li, W.; Jiang, X. M.; Ji, Y. L.; Wu, X. C.; Xu, L. G.; Qiu, Y.; Zhao, K.; Wei, T. T. et al. Selective targeting of gold nanorods at the mitochondria of cancer cells: Implications for cancer therapy. Nano Lett. 2011, 11, 772–780.
Boddapati, S. V.; D'Souza, G. G. M.; Erdogan, S.; Torchilin, V. P.; Weissig, V. Organelle-targeted nanocarriers: Specific delivery of liposomal ceramide to mitochondria enhances its cytotoxicity in vitro and in vivo. Nano Lett. 2008, 8, 2559–2563.
Farokhzad, O. C.; Langer, R. L. Impact of nanotechnology on drug delivery. ACS Nano 2009, 3, 16–20.
Cheng, H.; Kastrup, C. J.; Ramanathan, R.; Siegwart, D. J.; Ma, M. L.; Bogatyrev, S. R.; Xu, Q. B.; Whitehead, K. A.; Langer, R.; Anderson, D. G. Nanoparticulate cellular patches for cell-mediated tumoritropic delivery. ACS Nano 2010, 4, 625–631.
Tarn, D.; Ashley, C. E.; Xue, M.; Carnes, E. C.; Zink, J. I.; Brinker, C. J. Mesoporous silica nanoparticle nanocarriers: Biofunctionality and biocompatibility. Acc. Chem. Res. 2013, 46, 792–801.
Pan, L. M.; He, Q. J.; Liu, J. N.; Chen, Y.; Ma, M.; Zhang, L. L.; Shi, J. L. Nuclear-targeted drug delivery of TAT peptide-conjugated monodisperse mesoporous silica nano-particles. J. Am. Chem. Soc. 2012, 134, 5722–5725.
Maeda, H.; Wu, J.; Sawa, T.; Matsumura, Y.; Hori, K. Tumor vascular permeability and the EPR effect in macro-molecular therapeutics: A review. J. Control. Release 2000, 65, 271–284.
Byrne, J. D.; Betancourt, T.; Brannon-Peppas, L. Active targeting schemes for nanoparticle systems in cancer therapeutics. Adv. Drug Deliver. Rev. 2008, 60, 1615–1626.
Sun, C.; Lee, J. S. H.; Zhang, M. Q. Magnetic nanoparticles in MR imaging and drug delivery. Adv. Drug Deliver. Rev. 2008, 60, 1252–1265.
Li, R. B.; Wu, R. A.; Zhao, L.; Hu, Z. Y.; Guo, S. J.; Pan, X. L.; Zou, H. F. Folate and iron difunctionalized multiwall carbon nanotubes as dual-targeted drug nanocarrier to cancer cells. Carbon 2011, 49, 1797–1805.
Masters, J. R. Hela cells 50 years on: The good, the bad and the ugly. Nat. Rev. Cancer 2002, 2, 315–319.
Tian, Y.; Yu, B. B.; Li, X.; Li, K. Facile solvothermal synthesis of monodisperse Fe3O4 nanocrystals with precise size control of one nanometre as potential MRI contrast agents. J. Mater. Chem. 2011, 21, 2476–2481.
Kim, J.; Kim, H. S.; Lee, N.; Kim, T.; Kim, H.; Yu, T.; Song, I. C.; Moon, W. K.; Hyeon, T. Multifunctional uniform nanoparticles composed of a magnetite nanocrystal core and a mesoporous silica shell for magnetic resonance and fluorescence imaging and for drug delivery. Angew. Chem. Int. Ed. 2008, 47, 8438–8441.
Slowing, I. I.; Trewyn, B. G.; Giri, S.; Lin, V. S. -Y. Mesoporous silica nanoparticles for drug delivery and biosensing applications. Adv. Funct. Mater. 2007, 17, 1225–1236.
Hakem, R.; Hakem, A.; Duncan, G. S.; Henderson, J. T.; Woo, M.; Soengas, M. S.; Elia, A.; de la Pompa, J. L.; Kagi, D.; Khoo, W. et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 1998, 94, 339–352.
Sudimack, J.; Lee, R. J. Targeted drug delivery via the folate receptor. Adv. Drug Deliver. Rev. 2000, 41, 147–162.
Veiseh, O.; Gunn, J. W.; Zhang, M. Q. Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Adv. Drug Deliver. Rev. 2010, 62, 284–304.
Yang, X. Q.; Chen, Y. H.; Yuan, R. X.; Chen, G. H.; Blanco, E.; Gao, J. M.; Shuai, X. T. Folate-encoded and Fe3O4-loaded polymeric micelles for dual targeting of cancer cells. Polymer 2008, 49, 3477–3485.
Financial support from the Creative Research Group Project of NSFC (No. 21021004), the National Natural Science Foundation of China (Nos. 21235006, 21175134, 21375125, 81161120540), the China State Key Basic Research Program Grant (No. 2012CB910601), the National Key Special Program on Infectious Diseases (No. 2012ZX10002009-011), and the Analytical Methods Innovation Program of MOST (No. 2012IM030900) are grateful acknowledged.