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Photosensitiser functionalised luminescent upconverting nanoparticles for efficient photodynamic therapy of breast cancer cells

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Abstract

Photodynamic therapy (PDT) is a well-established treatment of cancer in which cell toxic reactive oxygen species, including singlet oxygen (1O2), are produced by a photosensitiser drug following irradiation of a specific wavelength. Visible light is commonly used as the excitation source in PDT, although these wavelengths do have limited tissue penetration. In this research, upconverting nanoparticles (UCNPs) functionalised with the photosensitiser Rose Bengal (RB) have been designed and synthesised for PDT of breast cancer cells. The use of UCNPs shifts the required excitation wavelength for the production of 1O2 to near infrared light (NIR) thus allowing deeper tissue penetration. The system was designed to maximise the production of 1O2 via efficient Förster resonance energy transfer (FRET) from the UCNPs to the photosensitiser. Highly luminescent NaYF4:Yb,Er,Gd@NaYF4 core-shell UCNPs were synthesised that exhibited two main anti-Stokes emission bands at 541 and 652 nm following 980 nm irradiation. RB was chosen as the photosensitiser since its absorption band overlaps with the green emission of the UCNPs. To achieve efficient energy transfer from the nanoparticles to the photosensitiser, the functionalised UCNPs included a short L-lysine linker to attach the RB to the nanocore yielding RB-lysine functionalised UCNPs. The efficient FRET from the UCNPs to the RB was confirmed by luminescence lifetime measurements. The light emitted by the UCNPs at 541 nm, following excitation at 980 nm, generates the 1O2via the RB. Multi-photon and confocal laser scanning microscopies confirmed the internalisation of the RB-lysine-UCNPs by SK-BR-3 breast cancer cells. Cell viability studies revealed that the RB-lysine-UCNPs induced low dark toxicity in cells prior to PDT treatment. Importantly, following irradiation at 980 nm, high levels of cell death were observed in cells loaded with the RB-lysine-UCNPs. Cell death following PDT treatment was also confirmed using propidium iodide and confocal microscopy. The high drug loading capacity (160 RB/nanoparticle) of the UCNPs, the efficient FRET from the UCNPs to the photosensitiser, the high level of accumulation inside the cells and their PDT cell kill suggest that the RB-lysine-UCNPs are promising for NIR PDT and hence suitable for the treatment of deep-lying cancer tumours.

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Acknowledgements

The authors would like to thank Dr Paul Thomas (School of Biological Sciences, University of East Anglia) for his help with the multi-photon microscopy and Dr Christoph Fenzl (Institute of Analytical Chemistry, University of Regensburg) for his help with the TEM measurements. The authors are grateful for the financial support from the School of Chemistry, University of East Anglia, for PGC and MJM. DAR wishes to thank the Big C cancer charity (Grant # 10-20R) for financial support. Financial support from the European Union COST Action CM1403: “The European upconversion network -from the design of photon-upconverting nanomaterials to biomedical applications” is gratefully acknowledged.

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Authors and Affiliations

  1. Institute of Analytical Chemistry, Chemo- and Biosensors, University of Regensburg, 93040, Regensburg, Germany

    Markus Buchner, Verena Muhr, Anna Kröninger, Antje J. Baeumner & Thomas Hirsch

  2. School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, Norfolk, NR4 7TJ, UK

    Paula García Calavia, David A. Russell & Maria J. Marin

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  1. Markus Buchner
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  2. Paula García Calavia
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Correspondence to Thomas Hirsch or Maria J. Marin.

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Buchner, M., Calavia, P.G., Muhr, V. et al. Photosensitiser functionalised luminescent upconverting nanoparticles for efficient photodynamic therapy of breast cancer cells. Photochem Photobiol Sci 18, 98–109 (2019). https://doi.org/10.1039/c8pp00354h

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  • DOI: https://doi.org/10.1039/c8pp00354h

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