Photodynamic therapy by in situ nonlinear photon conversion

Abstract

In photodynamic therapy, light is absorbed by a therapy agent (photosensitizer) to generate reactive oxygen, which then locally kills diseased cells. Here, we report a new form of photodynamic therapy in which nonlinear optical interactions of near-infrared laser radiation with a biological medium in situ produce light that falls within the absorption band of the photosensitizer. The use of near-infrared radiation, followed by upconversion to visible or ultraviolet light, provides deep tissue penetration, thus overcoming a major hurdle in treatment. By modelling and experiment, we demonstrate activation of a known photosensitizer, chlorin e6, by in situ nonlinear optical upconversion of near-infrared laser radiation using second-harmonic generation in collagen and four-wave mixing, including coherent anti-Stokes Raman scattering, produced by cellular biomolecules. The introduction of coherent anti-Stokes Raman scattering/four-wave mixing to photodynamic therapy in vitro increases the efficiency by a factor of two compared to two-photon photodynamic therapy alone, while second-harmonic generation provides a fivefold increase.

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Figure 1: Nonlinear optical mechanisms for PDT.
Figure 2: Experimental design for nonlinear excitation of PDT.
Figure 3: Contributions of CARS/FWM and SHG nonlinear optical conversions to chlorin e6 excitation.
Figure 4: Cellular phototoxicity in response to nonlinear optical PDT excitation by CARS/FWM/TPA and TPA modes for different numbers of laser scans.
Figure 5: Cellular phototoxicity in response to nonlinear optical PDT excitation by SHG/TPA and TPA modes for different numbers of laser scans.

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Acknowledgements

This work was supported in part by a grant from the Air Force Office of Scientific Research (grants no. 1096313-1-58130 and no. FA95500610398). J.Q. acknowledges support from the National Natural Science Foundation of China (61378091) and the National Basic Research Program of China (grant no. 2012CB825802).

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A.V.K. provided technical and conceptual support and edited the manuscript. A.P. performed experiments, analysed data and wrote the manuscript. A.N.K. designed and performed experiments, analysed data and edited the manuscript. A.B. performed theoretical modelling and wrote the theoretical analysis. T.Y.O. designed experiments, analysed the data and wrote the manuscript. J.Q. performed experiments and edited the manuscript. P.N.P. supervised the analysis and edited the manuscript.

Corresponding authors

Correspondence to J. Qu or P. N. Prasad.

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The authors declare no competing financial interests.

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Kachynski, A., Pliss, A., Kuzmin, A. et al. Photodynamic therapy by in situ nonlinear photon conversion. Nature Photon 8, 455–461 (2014). https://doi.org/10.1038/nphoton.2014.90

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