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