Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

In vivo photodynamic therapy using upconversion nanoparticles as remote-controlled nanotransducers

Nature Medicine volume 18, pages 1580–1585 (2012)Cite this article

Subjects

Abstract

Conventional photodynamic therapy (PDT) is limited by the penetration depth of visible light needed for its activation. Here we used mesoporous-silica–coated upconversion fluorescent nanoparticles (UCNs) as a nanotransducer to convert deeply penetrating near-infrared light to visible wavelengths and a carrier of photosensitizers. We also used the multicolor-emission capability of the UCNs at a single excitation wavelength for simultaneous activation of two photosensitizers for enhanced PDT. We showed a greater PDT efficacy with the dual-photosensitizer approach compared to approaches using a single photosensitizer, as determined by enhanced generation of singlet oxygen and reduced cell viability. In vivo studies also showed tumor growth inhibition in PDT-treated mice by direct injection of UCNs into melanoma tumors or intravenous injection of UCNs conjugated with a tumor-targeting agent into tumor-bearing mice. As the first demonstration, to the best of our knowledge, of the photosensitizer-loaded UCN as an in vivo–targeted PDT agent, this finding may serve as a platform for future noninvasive deep-cancer therapy.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Mesoporous-silica–coated NaYF4:Yb,Er UCN as an agent of PDT.
Figure 2: Dual photosensitizer approach with single-wavelength activation using UCNs for enhanced PDT.
Figure 3: In vivo PDT of injected tumor cells prelabeled with UCN.
Figure 4: In vivo PDT of a subcutaneous tumor model injected with UCNs.
Figure 5: Targeted in vivo PDT of a subcutaneous tumor model injected with FA-PEG-UCNs.

References

  1. Prasad, P.N. Introduction to Biophotonics (John Wiley & Sons, New York, 2003).

  2. Konan, Y.N., Gurny, R. & Allemann, E. State of the art in the delivery of photosensitizers for photodynamic therapy. J. Photochem. Photobiol. B 66, 89–106 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Frangioni, J.V. In vivo near-infrared fluorescence imaging. Curr. Opin. Chem. Biol. 7, 626–634 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Auzel, F. Upconversion and anti-stokes processes with f and d ions in solids. Chem. Rev. 104, 139–173 (2004).

    Article  CAS  PubMed  Google Scholar 

  5. Heer, S., Kompe, K., Gudel, H.U. & Haase, M. Highly efficient multicolour upconversion emission in transparent colloids of lanthanide-doped NaYF4 nanocrystals. Adv. Mater. (Deerfield Beach Fla.) 16, 2102–2105 (2004).

    Article  CAS  Google Scholar 

  6. Guo, H. & Qiao, Y.M. Preparation, characterization, and strong upconversion of monodisperse Y2O3:Er3+,Yb3+ microspheres. Opt. Mater. 31, 583–589 (2009).

    Article  CAS  Google Scholar 

  7. Li, Z.Q. & Zhang, Y. Monodisperse silica-coated polyvinylpyrrolidone/NaYF4 nanocrystals with multicolor upconversion fluorescence emission. Angew. Chem. Int. Ed. 45, 7732–7735 (2006).

    Article  CAS  Google Scholar 

  8. Chatterjee, D.K., Rufaihah, A.J. & Zhang, Y. Upconversion fluorescence imaging of cells and small animals using lanthanide doped nanocrystals. Biomaterials 29, 937–943 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Chatterjee, D.K. & Zhang, Y. Upconverting nanoparticles as nanotransducers for photodynamic therapy in cancer cells. Nanomedicine 3, 73–82 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. Qian, H.S., Guo, H., Ho, P., Mahendran, R. & Zhang, Y. Mesoporous-silica–coated up-conversion fluorescent nanoparticles for photodynamic therapy. Small 5, 2285–2290 (2009).

    Article  CAS  PubMed  Google Scholar 

  11. Idris, N.M. et al. Tracking transplanted cells in live animal using upconversion fluorescent nanoparticles. Biomaterials 30, 5104–5113 (2009).

    Article  CAS  PubMed  Google Scholar 

  12. Guo, H., Qian, H., Idris, N.M. & Zhang, Y. Singlet oxygen-induced apoptosis of cancer cells using upconversion fluorescent nanoparticles as a carrier of photosensitizer. Nanomedicine 6, 486–495 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Zhang, P., Steelant, W., Kumar, M. & Scholfield, M. Versatile photosensitizers for photodynamic therapy at infrared excitation. J. Am. Chem. Soc. 129, 4526–4527 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xiong, L. et al. High contrast upconversion luminescence targeted imaging in vivo using peptide-labeled nanophosphors. Anal. Chem. 81, 8687–8694 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Xiong, L.Q. et al. Synthesis, characterization, and in vivo targeted imaging of amine-functionalized rare-earth up-converting nanophosphors. Biomaterials 30, 5592–5600 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Nyk, M., Kumar, R., Ohulchanskyy, T.Y., Bergey, E.J. & Prasad, P.N. High contrast in vitro and in vivo photoluminescence bioimaging using near infrared to near infrared up-conversion in TM3+ and Yb3+ doped fluoride nanophosphors. Nano Lett. 8, 3834–3838 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cheng, L.A., Yang, K., Shao, M.W., Lee, S.T. & Liu, Z.A. Multicolor in vivo imaging of upconversion nanopaticles with emissions tuned by luminescence resonance energy transfer. J. Phys. Chem. C 115, 2686–2692 (2011).

    Article  CAS  Google Scholar 

  18. Wang, C., Cheng, L.A. & Liu, Z.A. Drug delivery with upconversion nanoparticles for multi-functional targeted cancer cell imaging and therapy. Biomaterials 32, 1110–1120 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Li, Z.Q., Zhang, Y. & Jiang, S. Multicolor core/shell-structured upconversion fluorescent nanoparticles. Adv. Mater. (Deerfield Beach Fla.) 20, 4765–4769 (2008).

    Article  CAS  Google Scholar 

  20. Wang, M. et al. NIR-responsive silica-coated NaYbF4:Er/Tm/Ho upconversion fluorescent nanoparticles with tunable emission colors and their applications in immunolabeling and fluorescent imaging of cancer cells. J. Phys. Chem. C 113, 19021–19027 (2009).

    Article  CAS  Google Scholar 

  21. Kuznetsova, N.A. et al. New reagents for determination of the quantum efficiency of singlet oxygen generation in aqueous media. Russ. J. Gen. Chem. 71, 36–41 (2001).

    Article  CAS  Google Scholar 

  22. Joensen, J. et al. The thermal effects of therapeutic lasers with 810 and 904 nm wavelengths on human skin. Photomed. Laser Surg. 29, 145–153 (2011).

    Article  PubMed  Google Scholar 

  23. Laser Institute of America. American National Standard for Safe Use of Lasers. in ANSI Z136.1–2000 (Laser Institute of America, Orlando, Florida, 2000).

  24. Mohapatra, S., Mallick, S.K., Maiti, T.K., Ghosh, S.K. & Pramanik, P. Synthesis of highly stable folic acid conjugated magnetite nanoparticles for targeting cancer cells. Nanotechnology 18, 385102 (2007).

    Article  Google Scholar 

  25. Li, X. et al. In vitro and in vivo evaluation of folate receptor-targeting amphiphilic copolymer-modified liposomes loaded with docetaxel. Int. J. Nanomedicine 6, 1167–1184 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Gao, D., Agayan, R.R., Xu, H., Philbert, M.A. & Kopelman, R. Nanoparticles for two-photon photodynamic therapy in living cells. Nano Lett. 6, 2383–2386 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kim, S., Ohulchanskyy, T.Y., Pudavar, H.E., Pandey, R.K. & Prasad, P.N. Organically modified silica nanoparticles co-encapsulating photosensitizing drug and aggregation-enhanced two-photon absorbing fluorescent dye aggregates for two-photon photodynamic therapy. J. Am. Chem. Soc. 129, 2669–2675 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Z.Q. Li, A. Priyam and C.X. Li (Department of Bioengineering, Faculty of Engineering, National University of Singapore) for synthesis of the nanoparticles and S. Rajan for technical support in preparing the schematic illustration. We also acknowledge financial support from the Agency for Science, Technology and Research (A*STAR) Biomedical Research Council (grants R-397-000-062-305 and R-397-000-119-305) and National University of Singapore.

Author information

Authors and Affiliations

  1. Department of Bioengineering, Faculty of Engineering, National University of Singapore, Singapore

    Niagara Muhammad Idris, Muthu Kumara Gnanasammandhan & Yong Zhang

  2. Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore

    Jing Zhang & Paul C Ho

  3. Department of Surgery, Faculty of Medicine, National University of Singapore, Singapore

    Ratha Mahendran

  4. Nanoscience and Nanotechnology Initiative, National University of Singapore, Singapore

    Yong Zhang

  5. National University of Singapore (NUS) Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore

    Yong Zhang

Authors
  1. Niagara Muhammad Idris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Muthu Kumara Gnanasammandhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Paul C Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ratha Mahendran
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N.M.I. and Y.Z. conceived of and designed the experiments, analyzed the data and wrote the paper. N.M.I. performed most of the experiments, and M.K.G. performed the targeted PDT experiments. J.Z., P.C.H. and R.M. contributed to the data analyses and discussion.

Corresponding author

Correspondence to Yong Zhang.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 and Supplementary Methods (PDF 339 kb)

Supplementary Video 1

Rotation of a volume rendered z-stacks of the green upconversion fluorescence of a suspended UCN-labeled cell. (MOV 2161 kb)

Supplementary Video 2

Rotation of a volume rendered z-stacks of the DAPI-stained nucleus of a suspended UCN-labeled cell. (MOV 519 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Idris, N., Gnanasammandhan, M., Zhang, J. et al. In vivo photodynamic therapy using upconversion nanoparticles as remote-controlled nanotransducers. Nat Med 18, 1580–1585 (2012). https://doi.org/10.1038/nm.2933

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2933

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing