SpringerLink
Log in

Core–shell Au@MnO2 nanoparticles for enhanced radiotherapy via improving the tumor oxygenation

  • Research Article
  • Published:
Nano Research Aims and scope Submit manuscript

Abstract

Local hypoxia in solid tumors often results in resistance to radiotherapy (RT), in which oxygen is an essential element for enhancing DNA damage caused by ionizing radiation. Herein, we developed gold@manganese dioxide (Au@MnO2) core–shell nanoparticles with a polyethylene glycol (PEG) coating as a novel radiosensitizing agent to improve RT efficacy during cancer treatment. In this Au@MnO2 nanostructure, while the gold core is a well-known RT sensitizer that interacts with X-rays to produce charged particles for improved cancer killing under RT, the MnO2 shell may trigger the decomposition of endogenous H2O2 in the tumor microenvironment to generate oxygen and overcome hypoxiaassociated RT resistance. As demonstrated by both in vitro and in vivo experiments, Au@MnO2-PEG nanoparticles acted as effective radiosensitizers to remarkably enhance cancer treatment efficacy during RT. Moreover, no obvious side effects of Au@MnO2-PEG were observed in mice. Therefore, our work presents a new type of radiosensitizer with potential for enhanced RT treatment of hypoxic tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (United Kingdom)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Barker, H. E.; Paget, J. T. E.; Khan, A. A.; Harrington, K. J. The tumour microenvironment after radiotherapy: Mechanisms of resistance and recurrence. Nat. Rev. Cancer 2015, 15, 409–425.

    Article  Google Scholar 

  2. Weitzel, D. H.; Tovmasyan, A.; Ashcraft, K. A.; Rajic, Z.; Weitner, T.; Liu, C.; Li, W.; Buckley, A. F.; Prasad, M. R.; Young, K. H. et al. Radioprotection of the brain white matter by Mn(III) n-butoxyethylpyridylporphyrin-based superoxide dismutase mimic MnTnBuOE-2-PyP5+. Mol. Cancer Ther. 2015, 14, 70–79.

    Article  Google Scholar 

  3. Zhou, Y.; Hua, S.; Yu, J. H.; Dong, P.; Liu, F. J.; Hua, D. B. A strategy for effective radioprotection by chitosan-based long-circulating nanocarriers. J. Mater. Chem. B 2015, 3, 2931–2934.

    Google Scholar 

  4. Yang, X.; Yang, M. X.; Pang, B.; Vara, M.; **a, Y. N. Gold nanomaterials at work in biomedicine. Chem. Rev. 2015, 115, 10410–10488.

    Article  Google Scholar 

  5. Zhang, X.-D.; Wu, D.; Shen, X.; Chen, J.; Sun, Y.-M.; Liu, P.-X.; Liang, X.-J. Size-dependent radiosensitization of peg-coated gold nanoparticles for cancer radiation therapy. Biomaterials 2012, 33, 6408–6419.

    Article  Google Scholar 

  6. Wang, P. P.; Yu, Q. Y.; Long, Y.; Hu, S.; Zhuang, J.; Wang, X. Multivalent assembly of ultrasmall nanoparticles: One-, two-, and three-dimensional architectures of 2 nm gold nanoparticles. Nano Res. 2012, 5, 283–291.

    Article  Google Scholar 

  7. Brown, R.; Tehei, M.; Oktaria, S.; Briggs, A.; Stewart, C.; Konstantinov, K.; Rosenfeld, A.; Corde, S.; Lerch, M. High-Z nanostructured ceramics in radiotherapy: First evidence of Ta2O5-induced dose enhancement on radioresistant cancer cells in an MV photon field. Part. Part. Syst. Char. 2014, 31, 500–505.

    Article  Google Scholar 

  8. Chen, H. M.; Wang, G. D.; Chuang, Y.-J.; Zhen, Z. P.; Chen, X. Y.; Biddinger, P.; Hao, Z. L.; Liu, F.; Shen, B. Z.; Pan, Z. W. et al. Nanoscintillator-mediated X-ray inducible photodynamic therapy for in vivo cancer treatment. Nano Lett. 2015, 15, 2249–2256.

    Article  Google Scholar 

  9. Fan, W. P.; Shen, B.; Bu, W. B.; Zheng, X. P.; He, Q. J.; Cui, Z. W.; Ni, D. L.; Zhao, K. L.; Zhang, S. J.; Shi, J. L. Intranuclear biophotonics by smart design of nucleartargeting photo-/radio-sensitizers co-loaded upconversion nanoparticles. Biomaterials 2015, 69, 89–98.

    Article  Google Scholar 

  10. Kwatra, D.; Venugopal, A.; Anant, S. Nanoparticles in radiation therapy: A summary of various approaches to enhance radiosensitization in cancer. Transl. Cancer Res. 2013, 2, 330–342.

    Google Scholar 

  11. Ma, M.; Huang, Y.; Chen, H. R.; Jia, X. Q.; Wang, S. G.; Wang, Z. Z.; Shi, J. L. Bi2S3-embedded mesoporous silica nanoparticles for efficient drug delivery and interstitial radiotherapy sensitization. Biomaterials 2015, 37, 447–455.

    Article  Google Scholar 

  12. Zhang, X.-D.; Luo, Z.; Chen, J.; Song, S.; Yuan, X.; Shen, X.; Wang, H.; Sun, Y.; Gao, K.; Zhang, L. et al. Ultrasmall glutathione-protected gold nanoclusters as next generation radiotherapy sensitizers with high tumor uptake and high renal clearance. Sci. Rep. 2015, 5, 8669.

    Article  Google Scholar 

  13. Zhang, X. D.; Luo, Z. T.; Chen, J.; Shen, X.; Song, S. S.; Sun, Y. M.; Fan, S. J.; Fan, F. Y.; Leong, D. T.; **e, J. P. Ultrasmall Au10-12(SG)10-12 nanomolecules for high tumor specificity and cancer radiotherapy. Adv. Mater. 2014, 26, 4565–4568.

    Article  Google Scholar 

  14. Her, S.; Jaffray, D. A.; Allen, C. Gold nanoparticles for applications in cancer radiotherapy: Mechanisms and recent advancements. Adv. Drug Deliv. Rev., in press, DOI: 10.1016/j.addr.2015.12.012.

  15. Al Zaki, A.; Joh, D.; Cheng, Z. L.; De Barros, A. L. B.; Kao, G.; Dorsey, J.; Tsourkas, A. Gold-loaded polymeric micelles for computed tomography-guided radiation therapy treatment and radiosensitization. ACS Nano 2014, 8, 104–112.

    Article  Google Scholar 

  16. Yang, Y.-S.; Carney, R. P.; Stellacci, F.; Irvine, D. J. Enhancing radiotherapy by lipid nanocapsule-mediated delivery of amphiphilic gold nanoparticles to intracellular membranes. ACS Nano 2014, 8, 8992–9002.

    Article  Google Scholar 

  17. Jain, S.; Coulter, J. A.; Butterworth, K. T.; Hounsell, A. R.; McMahon, S. J.; Hyland, W. B.; Muir, M. F.; Dickson, G. R.; Prise, K. M.; Currell, F. J. et al. Gold nanoparticle cellular uptake, toxicity and radiosensitisation in hypoxic conditions. Radiother. Oncol. 2014, 110, 342–347.

    Article  Google Scholar 

  18. Cui, L.; Tse, K.; Zahedi, P.; Harding, S. M.; Zafarana, G.; Jaffray, D. A.; Bristow, R. G.; Allen, C. Hypoxia and cellular localization influence the radiosensitizing effect of gold nanoparticles (AuNPs) in breast cancer cells. Radiat. Res. 2014, 182, 475–488.

    Article  Google Scholar 

  19. Klemm, F.; Joyce, J. A. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 2015, 25, 198–213.

    Article  Google Scholar 

  20. Siemann, D. W.; Horsman, M. R. Modulation of the tumor vasculature and oxygenation to improve therapy. Pharmacol. Ther. 2015, 153, 107–124.

    Article  Google Scholar 

  21. Lin, A.; Maity, A. Molecular pathways: A novel approach to targeting hypoxia and improving radiotherapy efficacy via reduction in oxygen demand. Clin. Cancer Res. 2015, 21, 1995–2000.

    Article  Google Scholar 

  22. Shimizu, N.; Ooka, M.; Takagi, T.; Takeda, S.; Hirota, K. Distinct DNA damage spectra induced by ionizing radiation in normoxic and hypoxic cells. Radiat. Res. 2015, 184, 442–448.

    Article  Google Scholar 

  23. Baumann, M.; Krause, M.; Overgaard, J.; Debus, J.; Bentzen, S. M.; Daartz, J.; Richter, C.; Zips, D.; Bortfeld, T. Radiation oncology in the era of precision medicine. Nat. Rev. Cancer 2016, 16, 234–249.

    Article  Google Scholar 

  24. Liu, Y. Y.; Liu, Y.; Bu, W. B.; Cheng, C.; Zuo, C. J.; **ao, Q. F.; Sun, Y.; Ni, D. L.; Zhang, C.; Liu, J. et al. Hypoxia induced by upconversion-based photodynamic therapy: Towards highly effective synergistic bioreductive therapy in tumors. Angew. Chem., Int. Ed. 2015, 54, 8105–8109.

    Article  Google Scholar 

  25. Fan, W. P.; Bu, W. B.; Zhang, Z.; Shen, B.; Zhang, H.; He, Q. J.; Ni, D. L.; Cui, Z. W.; Zhao, K. L.; Bu, J. W. et al. X-ray radiation-controlled no-release for on-demand depthindependent hypoxic radiosensitization. Angew. Chem., Int. Ed. 2015, 127, 14232–14236.

    Article  Google Scholar 

  26. Diagaradjane, P.; Shetty, A.; Wang, J. C.; Elliott, A. M.; Schwartz, J.; Shentu, S.; Park, H. C.; Deorukhkar, A.; Stafford, R. J.; Cho, S. H. et al. Modulation of in vivo tumor radiation response via gold nanoshell-mediated vascularfocused hyperthermia: Characterizing an integrated antihypoxic and localized vascular disrupting targeting strategy. Nano Lett. 2008, 8, 1492–1500.

    Article  Google Scholar 

  27. Kunjachan, S.; Detappe, A.; Kumar, R.; Ireland, T.; Cameron, L.; Biancur, D. E.; Motto-Ros, V.; Sancey, L.; Sridhar, S.; Makrigiorgos, G. M. et al. Nanoparticle mediated tumor vascular disruption: A novel strategy in radiation therapy. Nano Lett. 2015, 15, 7488–7496.

    Article  Google Scholar 

  28. Cheng, Y. H.; Cheng, H.; Jiang, C. X.; Qiu, X. F.; Wang, K. K.; Huan, W.; Yuan, A. H.; Wu, J. H.; Hu, Y. Q. Perfluorocarbon nanoparticles enhance reactive oxygen levels and tumour growth inhibition in photodynamic therapy. Nat. Commun. 2015, 6, 8785.

    Article  Google Scholar 

  29. Prasad, P.; Gordijo, C. R.; Abbasi, A. Z.; Maeda, A.; Ip, A.; Rauth, A. M.; DaCosta, R. S.; Wu, X. Y. Multifunctional albumin–MnO2 nanoparticles modulate solid tumor microenvironment by attenuating hypoxia, acidosis, vascular endothelial growth factor and enhance radiation response. ACS Nano 2014, 8, 3202–3212.

    Article  Google Scholar 

  30. Fan, H. H.; Yan, G. B.; Zhao, Z. L.; Hu, X. X.; Zhang, W. H.; Liu, H.; Fu, X. Y.; Fu, T.; Zhang, X. B.; Tan, W. H. A smart photosensitizer–manganese dioxide nanosystem for enhanced photodynamic therapy by reducing glutathione levels in cancer cells. Angew. Chem., Int. Ed. 2016, 55, 5477–5482.

    Article  Google Scholar 

  31. Song, G. S.; Liang, C.; Gong, H.; Li, M. F.; Zheng, X. C.; Cheng, L.; Yang, K.; Jiang, X. Q.; Liu, Z. Core–shell mnse@Bi2Se3 fabricated via a cation exchange method as novel nanotheranostics for multimodal imaging and synergistic thermoradiotherapy. Adv. Mater. 2015, 27, 6110–6117.

    Article  Google Scholar 

  32. Yi, X.; Yang, K.; Liang, C.; Zhong, X. Y.; Ning, P.; Song, G. S.; Wang, D. L.; Ge, C. C.; Chen, C. Y.; Chai, Z. F. et al. Imaging-guided combined photothermal and radiotherapy to treat subcutaneous and metastatic tumors using iodine-131-doped copper sulfide nanoparticles. Adv. Funct. Mater. 2015, 25, 4689–4699.

    Article  Google Scholar 

  33. Chen, H. C.; Tian, J. W.; He, W. J.; Guo, Z. J. H2O2-activatable and O2-evolving nanoparticles for highly efficient and selective photodynamic therapy against hypoxic tumor cells. J. Am. Chem. Soc. 2015, 137, 1539–1547.

    Article  Google Scholar 

  34. Chen, Y.; Ye, D. L.; Wu, M. Y.; Chen, H. R.; Zhang, L. L.; Shi, J. L.; Wang, L. Z. Break-up of two-dimensional MnO2 nanosheets promotes ultrasensitive pH-triggered theranostics of cancer. Adv. Mater. 2014, 26, 7019–7026.

    Article  Google Scholar 

  35. Song, M.; Liu, T.; Shi, C.; Zhang, X.; Chen, X. Bioconjugated manganese dioxide nanoparticles enhance chemotherapy response by priming tumor-associated macrophages toward M1-like phenotype and attenuating tumor hypoxia. ACS Nano 2016, 10, 633–647.

    Article  Google Scholar 

  36. Yuan, J.; Cen, Y.; Kong, X.-J.; Wu, S.; Liu, C.-L.; Yu, R. Q.; Chu, X. MnO2-nanosheet-modified upconversion nanosystem for sensitive turn-on fluorescence detection of H2O2 and glucose in blood. ACS Appl. Mater. Interfaces 2015, 7, 10548–10555.

    Article  Google Scholar 

  37. Fan, H. H.; Zhao, Z. L.; Yan, G. B.; Zhang, X. B.; Yang, C.; Meng, H. M.; Chen, Z.; Liu, H.; Tan, W. H. A smart dnazyme–MnO2 nanosystem for efficient gene silencing. Angew. Chem., Int. Ed. 2015, 127, 4883–4887.

    Article  Google Scholar 

  38. Zhao, Z. L.; Fan, H. H.; Zhou, G. F.; Bai, H. R.; Liang, H.; Wang, R. W.; Zhang, X. B.; Tan, W. H. Activatable fluorescence/MRI bimodal platform for tumor cell imaging via MnO2 nanosheet–aptamer nanoprobe. J. Am. Chem. Soc. 2014, 136, 11220–11223.

    Article  Google Scholar 

  39. Fan, W. P.; Bu, W. B.; Shen, B.; He, Q. J.; Cui, Z. W.; Liu, Y. Y.; Zheng, X. P.; Zhao, K. L.; Shi, J. L. Intelligent MnO2 nanosheets anchored with upconversion nanoprobes for concurrent pH-/H2O2-responsive UCL imaging and oxygenelevated synergetic therapy. Adv. Mater. 2015, 27, 4155–4161.

    Article  Google Scholar 

  40. Yang, Y.; Liu, J. J.; Sun, X. Q.; Feng, L. Z.; Zhu, W. W.; Liu, Z.; Chen, M. W. Near-infrared light-activated cancer cell targeting and drug delivery with aptamer-modified nanostructures. Nano Res. 2016, 9, 139–148.

    Article  Google Scholar 

  41. Yang, G. B.; Gong, H.; Qian, X. X.; Tan, P. L.; Li, Z. W.; Liu, T.; Liu, J. J.; Li, Y. Y.; Liu, Z. Mesoporous silica nanorods intrinsically doped with photosensitizers as a multifunctional drug carrier for combination therapy of cancer. Nano Res. 2015, 8, 751–764.

    Article  Google Scholar 

  42. Park, S.; Shim, H. W.; Lee, C. W.; Song, H. J.; Park, I. J.; Kim, J. C.; Hong, K. S.; Kim, D. W. Tailoring uniform ?-MnO2 nanosheets on highly conductive three-dimensional current collectors for high-performance supercapacitor electrodes. Nano Res. 2015, 8, 990–1004.

    Article  Google Scholar 

  43. Pan, D.; Schmieder, A. H.; Wickline, S. A.; Lanza, G. M. Manganese-based mri contrast agents: Past, present, and future. Tetrahedron 2011, 67, 8431–8444.

    Article  Google Scholar 

  44. Pan, D.; Caruthers, S. D.; Senpan, A.; Schmieder, A. H.; Wickline, S. A.; Lanza, G. M. Revisiting an old friend: Manganese-based MRI contrast agents. Wiley Interdiscip. Rev.: Nanomed. Nanobiotechnol. 2011, 3, 162–173.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. School of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, 215123, China

    Xuan Yi, Lei Chen, **aoyan Zhong, Roulin Gao, Yitao Qian, Fan Wu, Zhifang Chai & Kai Yang

  2. Institute of Functional Nano & Soft Materials (FUNSOM), Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou, 215123, China

    Guosheng Song & Zhuang Liu

Authors
  1. Xuan Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. **aoyan Zhong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roulin Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yitao Qian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fan Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Guosheng Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhifang Chai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhuang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Kai Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kai Yang.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yi, X., Chen, L., Zhong, X. et al. Core–shell Au@MnO2 nanoparticles for enhanced radiotherapy via improving the tumor oxygenation. Nano Res. 9, 3267–3278 (2016). https://doi.org/10.1007/s12274-016-1205-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12274-016-1205-8

Keywords

Search

Navigation