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.

  • Article
  • Published:

Breaking the depth dependency of phototherapy with Cerenkov radiation and low-radiance-responsive nanophotosensitizers

Nature Nanotechnology volume 10, pages 370–379 (2015)Cite this article

Subjects

Abstract

The combination of light and photosensitizers for phototherapeutic interventions, such as photodynamic therapy, has transformed medicine and biology. However, the shallow penetration of light into tissues and the reliance on tissue oxygenation to generate cytotoxic radicals have limited the method to superficial or endoscope-accessible lesions. Here we report a way to overcome these limitations by using Cerenkov radiation from radionuclides to activate an oxygen-independent nanophotosensitizer, titanium dioxide (TiO2). We show that the administration of transferrin-coated TiO2 nanoparticles and clinically used radionuclides in mice and colocalization in tumours results in either complete tumour remission or an increase in their median survival. Histological analysis of tumour sections showed the selective destruction of cancerous cells and high numbers of tumour-infiltrating lymphocytes, which suggests that both free radicals and the activation of the immune system mediated the destruction. Our results offer a way to harness low-radiance-sensitive nanophotosensitizers to achieve depth-independent Cerenkov-radiation-mediated therapy.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Titanium dioxide and Tc photoagents for CRIT.
Figure 2: Cellular uptake of NPS.
Figure 3: In vitro assessment of CRIT.
Figure 4: CRIT through an intratumoural administration of TiO2 and 64Cu (TiO2+64Cu).
Figure 5: In vivo biodistribution of NPS.
Figure 6: Evaluation of CRIT through systemically administered photoagents and FDG.

Similar content being viewed by others

References

  1. Ethirajan, M., Chen, Y., Joshi, P. & Pandey, R. K. The role of porphyrin chemistry in tumor imaging and photodynamic therapy. Chem. Soc. Rev. 40, 340–362 (2011).

    Article  CAS  Google Scholar 

  2. Spring, B. Q. et al. Selective treatment and monitoring of disseminated cancer micrometastases in vivo using dual-function, activatable immunoconjugates. Proc. Natl Acad. Sci. USA 111, E993–E492 (2014).

    Article  Google Scholar 

  3. Jelley, J. V. Cerenkov radiation and its applications. Br. J. Appl. Phys. 6, 227–232 (1955).

    Article  Google Scholar 

  4. Robertson, R. et al. Optical imaging of Cerenkov light generation from positron-emitting radiotracers. Phys. Med. Biol. 54, N355 (2009).

    Article  CAS  Google Scholar 

  5. Cherry, S. & Dahlbom, M. in PET (ed. Phelps, M.) 1–117 (Springer, 2006).

    Book  Google Scholar 

  6. Liu, H. et al. Molecular optical imaging with radioactive probes. PLoS ONE 5, e9470 (2010).

    Article  Google Scholar 

  7. Spinelli, A. E. et al. Multispectral Cerenkov luminescence tomography for small animal optical imaging. Opt. Express 19, 12605–12618 (2011).

    Article  CAS  Google Scholar 

  8. Kotagiri, N., Niedzwiedzki, D. M., Ohara, K. & Achilefu, S. Activatable probes based on distance-dependent luminescence associated with Cerenkov radiation. Angew. Chem. Int. Ed. 52, 7756–7760 (2013).

    Article  CAS  Google Scholar 

  9. Sun, X. et al. Self-illuminating 64Cu-doped CdSe/ZnS nanocrystals for in vivo tumor imaging. J. Am. Chem. Soc. 136, 1706–1709 (2014).

    Article  CAS  Google Scholar 

  10. Axelsson, J., Davis, S. C., Gladstone, D. J. & Pogue, B. W. Cerenkov emission induced by external beam radiation stimulates molecular fluorescence. Med. Phys. 38, 4127–4132 (2011).

    Article  CAS  Google Scholar 

  11. Spinelli, A. E. et al. First human Cerenkography. J. Biomed. Opt. 18, 20502 (2013).

    Article  Google Scholar 

  12. Thorek, D. L., Ogirala, A., Beattie, B. J. & Grimm, J. Quantitative imaging of disease signatures through radioactive decay signal conversion. Nature Med. 19, 1345–1350 (2013).

    Article  CAS  Google Scholar 

  13. Linsebigler, A., Lu, G. & Yates, J. Photocatalysis on TiOn surfaces: principles, mechanisms, and selected results. Chem. Rev. 95, 735–758 (1995).

    Article  CAS  Google Scholar 

  14. Schwarz, P. F. et al. A new method to determine the generation of hydroxyl radicals in illuminated TiO2 suspensions. J. Phys. Chem. B 101, 7127–7134 (1997).

    Article  CAS  Google Scholar 

  15. Boehm, H. P. Acidic and basic properties of hydroxylated metal oxide surfaces. Discuss. Faraday Soc. 52, 264–275 (1971).

    Article  Google Scholar 

  16. Mitchell, G. S., Gill, R. K., Boucher, D. L., Li, C. & Cherry, S. R. In vivo Cerenkov luminescence imaging: a new tool for molecular imaging. Philos. Trans. A 369, 4605–4619 (2011).

    Article  CAS  Google Scholar 

  17. Huang, W., Lei, M., Huang, H., Chen, J. & Chen, H. Effect of polyethylene glycol on hydrophilic TiO2 films: porosity-driven superhydrophilicity. Surf. Coat. Technol. 204, 3954–3961 (2010).

    Article  CAS  Google Scholar 

  18. Gatter, K. C., Brown, G., Trowbridge, I. S., Woolston, R. E. & Mason, D. Y. Transferrin receptors in human tissues: their distribution and possible clinical relevance. J. Clin. Pathol. 36, 539–545 (1983).

    Article  CAS  Google Scholar 

  19. Ji, Z. et al. Dispersion and stability optimization of TiO2 nanoparticles in cell culture media. Environ. Sci. Technol. 44, 7309–7314 (2010).

    Article  CAS  Google Scholar 

  20. Bowman, D. C. The amazingly versatile titanocene derivatives. J. Chem. Educ. 83, 735 (2006).

    Article  CAS  Google Scholar 

  21. Clearfield, A., Warner, D. K., Saldarriaga-Molina, C. H., Ropal, R. & Bernal, I. Structural studies of (π-C5H5)2MX2 complexes and their derivatives. The structure of bis(π-cyclopentadienyl)titanium dichloride. Can. J. Chem. 53, 1622–1629 (1975).

    Article  CAS  Google Scholar 

  22. Lümmen, G., Sperling, H., Luboldt, H., Otto, T. & Rübben, H. Phase II trial of titanocene dichloride in advanced renal-cell carcinoma. Cancer Chemother. Pharmacol. 42, 415–417 (1998).

    Article  Google Scholar 

  23. Kröger, N., Kleeberg, U. R., Mross, K., Edler, L. & Hossfeld, D. K. Phase II clinical trial of titanocene dichloride in patients with metastatic breast cancer. Oncol. Res. Treat. 23, 60–62 (2000).

    Article  Google Scholar 

  24. Davidenko, N., Garcia, O. & Sastre, R. The efficiency of titanocene as photoinitiator in the polymerization of dental formulations. J. Biomater. Sci. Polym. Ed. 14, 733–746 (2003).

    Article  CAS  Google Scholar 

  25. Tehfe, M-A., Lalevée, J., Morlet-Savary, F., Graff, B. & Fouassier, J-P. On the use of bis(cyclopentadienyl)titanium(IV) dichloride in visible-light-induced ring-opening photopolymerization. Macromolecules 45, 356–361 (2011).

    Article  Google Scholar 

  26. Brindley, P. B., Davies, A. G. & Hawari, J. A. A. An ESR study of the photolysis of dicyclopentadienyltitanium dichloride. J. Organomet. Chem. 250, 247–256 (1983).

    Article  CAS  Google Scholar 

  27. Qian, Z. M., Li, H., Sun, H. & Ho, K. Targeted drug delivery via the transferrin receptor-mediated endocytosis pathway. Pharmacol. Rev. 54, 561–587 (2002).

    Article  CAS  Google Scholar 

  28. Tijana, R., Nada, M. D., Adam, E. & Elena, R. in Handbook of Nanophysics 1–28 (CRC Press, 2010).

    Google Scholar 

  29. Paunesku, T. et al. Biology of TiO2-oligonucleotide nanocomposites. Nature Mater. 2, 343–346 (2003).

    Article  CAS  Google Scholar 

  30. Zhao, J. et al. Titanium dioxide (TiO2) nanoparticles induce JB6 cell apoptosis through activation of the caspase-8/Bid and mitochondrial pathways. J. Toxicol. Environ. Health A 72, 1141–1149 (2009).

    Article  CAS  Google Scholar 

  31. O'Connor, K. et al. Novel titanocene anti-cancer drugs and their effect on apoptosis and the apoptotic pathway in prostate cancer cells. Apoptosis 11, 1205–1214 (2006).

    Article  CAS  Google Scholar 

  32. Kelloff, G. J. et al. Progress and promise of FDG-PET imaging for cancer patient management and oncologic drug development. Clin. Cancer Res. 11, 2785–2808 (2005).

    Article  CAS  Google Scholar 

  33. Heyne, B., Maurel, V. & Scaiano, J. C. Mechanism of action of sensors for reactive oxygen species based on fluorescein–phenol coupling: the case of 2-[6-(4′-hydroxy)phenoxy-3H-xanthen-3-on-9-yl]benzoic acid. Org. Biomol. Chem. 4, 802–807 (2006).

    Article  CAS  Google Scholar 

  34. Rozhkova, E. A. et al. A high-performance nanobio photocatalyst for targeted brain cancer therapy. Nano Lett. 9, 3337–3342 (2009).

    Article  CAS  Google Scholar 

  35. Misra, R. M., Bajaj, M. S. & Kale, V. P. Vasculogenic mimicry of HT1080 tumour cells in vivo: critical role of HIF-1α-neuropilin-1 axis. PLoS ONE 7, 21 (2012).

    Google Scholar 

  36. Dautry-Varsat, A., Ciechanover, A. & Lodish, H. F. pH and the recycling of transferrin during receptor-mediated endocytosis. Proc. Natl Acad. Sci. USA 80, 2258–2262 (1983).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Funding for this project was, in part, by grants from the US National Institutes of Health (NCI R01 CA171651 and P50 CA094056, NIBIB R01 EB008111 and R01 EB021048, and SIG S10 RR031625) and the National Science Foundation (CCF 0963742). We thank T. Voller and P. Eisenbeis for generously providing 64Cu, V. Sharma for technetium-99 m, W. Beatty and S. Greco for analysing histology sections, P. Gibbons, H. Wynder and J. Elsner for assistance with TEM imaging, and staff of the Siteman Cancer Center Small Animal microPET Facility for imaging with FDG-PET.

Author information

Authors and Affiliations

  1. Department of Radiology, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Nalinikanth Kotagiri, Gail P. Sudlow, Walter J. Akers & Samuel Achilefu

Authors
  1. Nalinikanth Kotagiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gail P. Sudlow
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Walter J. Akers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Samuel Achilefu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

N.K. and S.A. conceived and designed the experiments, analysed the data and wrote manuscript. N.K. performed most of the experiments. W.J.A. assisted in the animal study design and analysis and contributed to editing the final manuscript. G.P.S. assisted in cell studies, animal handling, histological section preparation and editing the final manuscript.

Corresponding author

Correspondence to Samuel Achilefu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information

Supplementary information (PDF 542 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kotagiri, N., Sudlow, G., Akers, W. et al. Breaking the depth dependency of phototherapy with Cerenkov radiation and low-radiance-responsive nanophotosensitizers. Nature Nanotech 10, 370–379 (2015). https://doi.org/10.1038/nnano.2015.17

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2015.17

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research