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Blood-vessel closure using photosensitizers engineered for two-photon excitation

Abstract

The spatial control of optical absorption provided by two-photon excitation has led to tremendous advances in microscopy1 and microfabrication2. Medical applications of two-photon excitation in photodynamic therapy3,4 have been widely suggested5,6,7,8,9,10,11,12,13,14,15,16,17,18, but thus far have been rendered impractical by the low two-photon cross-sections of photosensitizer drugs (which are compounds taken up by living tissues that become toxic on absorption of light). The invention of efficient two-photon activated drugs will allow precise three-dimensional manipulation of treatment volumes, providing a level of targeting unattainable with current therapeutic techniques. Here we present a new family of photodynamic therapy drugs designed for efficient two-photon excitation and use one of them to demonstrate selective closure of blood vessels through two-photon excitation photodynamic therapy in vivo. These conjugated porphyrin dimers have two-photon cross-sections that are more than two orders of magnitude greater than those of standard clinical photosensitizers17. This is the first demonstration of in vivo photodynamic therapy using a photosensitizer engineered for efficient two-photon excitation.

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Figure 1: Structures and absorption spectra of conjugated porphyrin dimers 1–5, and the clinical photosensitizer verteporfin, 6.
Figure 2: In vitro photodynamic therapy.
Figure 3: Fluorescence from photosensitizer 1 in vivo.
Figure 4: In vivo two-photon blood-vessel closure with photosensitizer 1.

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Acknowledgements

We thank M.K. Akens, T.D. McKee and K. Patel for assistance with tail vein injections, J. Jonkman and G. Netchev for microscopy assistance, the EPSRC (Engineering and Physical Sciences Research Council) Mass Spectrometry Service (Swansea) for mass spectra and Thorlabs for support with OCT imaging. This work was supported by grants from EPSRC (to H.L.A. and D.P.), the Canadian Institute for Photonic Innovations (to B.C.W.), Wenner-Gren Foundation (to E.D.) and the European Commission (Marie Curie Fellowship to M.B., MEIT-CT-2006-041522).

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H.A.C., E.D. and M.B. synthesized the porphyrin dimers. H.A.C. and E.D. screened the compounds in vitro. M.D. and A.R. measured the two-photon absorption spectra. M.K.K. measured singlet oxygen yields. E.H.M. and M.K. implanted the window chambers. A.M. imaged vessels by OCT, M.K. by stereomicroscopy and H.A.C. by hyperspectral and laser scanning techniques. All authors discussed the results and contributed to the manuscript.

Corresponding authors

Correspondence to Brian C. Wilson or Harry L. Anderson.

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Blood vessel closure using photosensitisers designed for two–photon excitation (PDF 2712 kb)

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Collins, H., Khurana, M., Moriyama, E. et al. Blood-vessel closure using photosensitizers engineered for two-photon excitation. Nature Photon 2, 420–424 (2008). https://doi.org/10.1038/nphoton.2008.100

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