Proton-dynamic therapy following photosensitiser activation by accelerated protons demonstrated through fluorescence and singlet oxygen production

M Grigalavicius,A Görgen,S Siem,T A Theodossiou,E Brondz,D Arous,M Mastrangelopoulou,N F J Edin,E Malinen,T Raabe-Henriksen,M Ménard,K Berg

doi:10.1038/s41467-019-12042-7

M Grigalavicius, A Görgen + Show 10 more

Open Access

https://doi.org/10.1038/s41467-019-12042-7

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Journal: Nature Communications	Publication Date: Sep 4, 2019
Citations: 25	License type: open-access

Affiliation: Oslo University Hospital, University of Oslo

Abstract

We demonstrate excitation of photosensitisers (PSs) by accelerated protons to produce fluorescence and singlet oxygen. Their fluorescence follows a pattern similar to the proton energy loss in matter, while proton-derived fluorescence spectra match the photon-induced spectra. PSs excited in dry gelatin exhibit enhanced phosphorescence, suggesting an efficient PSs triplet state population. Singlet oxygen measurements, both optically at ~1270 nm and through the photoproduct of protoporphyrin IX (PpIX), demonstrate cytotoxic singlet oxygen generation by proton excitation. The singlet oxygen-specific scavenger 1,4-diazabicyclo[2.2.2]octane (DABCO) abrogates the photoproduct formation under proton excitation, but cannot countermand the overall loss of PpIX fluorescence. Furthermore, in two cell lines, M059K and T98G, we observe differential cell death upon the addition of the PS cercosporin, while in U87 cells we see no effect at any proton irradiation dose. Our results pave the way for a novel treatment combining proton therapy and “proton-dynamic therapy” for more efficient tumour eradication.

Highlights

We demonstrate excitation of photosensitisers (PSs) by accelerated protons to produce fluorescence and singlet oxygen
The photodynamic action is effected through the generation of reactive oxygen species (ROS) either by: (i) charge transfer between PS and molecules, which could involve oxygen superoxide anion and hydrogen peroxide leading to the formation of hydroxyl radicals[5] or (ii) energy transfer, resulting in the generation of deleterious singlet oxygen [O2 (1Δg) or 1O2]
The main advantage of protons over high energy therapeutic X-rays is the lack of exit dose, as all their energy is delivered before, and especially at, the Bragg peak, while the main benefit of protons over visible therapeutic light is that protons can excite atoms over a broad energy range because of the continuous electromagnetic interactions with atomic electrons

Summary

Introduction

We demonstrate excitation of photosensitisers (PSs) by accelerated protons to produce fluorescence and singlet oxygen. PSs excited in dry gelatin exhibit enhanced phosphorescence, suggesting an efficient PSs triplet state population Singlet oxygen measurements, both optically at ~1270 nm and through the photoproduct of protoporphyrin IX (PpIX), demonstrate cytotoxic singlet oxygen generation by proton excitation. Proton therapy[6], the treatment of cancer with accelerated protons, can be tumour-specific, as protons with appropriate initial kinetic energy can deposit a high amount of radiant energy at any selected depth. When the protons reach low energies, they rapidly deposit their remaining energy over a small region called the Bragg peak This peak is the therapeutic/cytotoxic window that needs to be spatially-matched to the targeted cancerous lesion. We present proof of principle of our hypothesis on two glioblastoma multiforme (GBM) cell lines These findings are the first step towards a novel hybrid cancer treatment combining proton therapy with singlet-oxygen and other ROS-mediated cytotoxicity

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