Abstract
Photodynamic therapy uses photosensitizers (PS) to kill cancer cells by generating reactive oxygen species – like singlet oxygen (SO) - upon illumination with visible light. PS membrane anchoring augments local SO concentration, which in turn increases photodynamic efficiency. The latter may suffer from SO’s escape into the aqueous solution or premature quenching. Here we determined the time constants of SO escape and quenching by target molecules to be in the nanosecond range, the former being threefold longer. We confined PS and dipolar target molecules either to different membrane monolayers or to the same leaflet and assessed their abundance by fluorescence correlation spectroscopy or membrane surface potential measurements. The rate at which the contribution of the dipolar target molecules to membrane dipole potential vanished, served as a measure of the photo-oxidation rate. The solution of the reaction–diffusion equations did not indicate diffusional rate limitations. Nevertheless, reducing the PS-target distance increased photodynamic efficiency by preventing other SO susceptible moieties from protecting the target. Importantly, our analytical model revealed a fourfold difference between SO generation rates per molecule of the two used PSs. Such analysis of PS quantum yield in a membrane environment may help in designing better PSs.
Highlights
Photosensitizers (PS) play a key role in cancer photodynamic therapy[1,2,3]
Δφb is a superposition of changes in membrane surface potential Δφs and membrane dipole potential Δφd[15,16]: Δφb = Δφs + Δφd φs is accessible via measurements of the electrophoretic mobility of lipid vesicles
Using the Gouy Chapman theory, φs can be calculated from ζ
Summary
Photosensitizers (PS) play a key role in cancer photodynamic therapy[1,2,3]. They adhere to cancer cells and kill them when excited by light due to the generation of reactive oxygen species (ROS)[4]. PS that respond to visible light may be tuned to mainly produce singlet oxygen (SO), which, in turn, preferentially targets membrane proteins. The efficacy of this approach crucially depends on (i) PS’ membrane affinity[5], (ii) the quantum yield of SO generation, (iii) SO lifetime, τl, and (iv) SO dwell time τdw in the membrane. If we take membrane thickness d = 4 nm as the characteristic diffusion span between the hits, we find τdw = d2/D = 3 ns. An increase in diffusion span due to PS burial into the hydrophobic membrane interior should augment τdw (and τr), which in turn, could increase photodynamic efficiency. We observed τl to be in the nanosecond range indicating that SO rarely escapes from the membrane and that augmenting photodynamic efficiency requires shortening of the DT to PS distances
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