Impact of Lipid Environment on Photodamage Activation of Methylene Blue

Abstract

Abstract Lipid membrane photodamage in photodynamic therapy involves the penetration of a photosensitizer into the membrane, followed by photoactivation through intersystem crossing. The efficiency of both processes, in which electrostatic interactions with the lipid environment play a crucial role, determines the cytotoxic effect of the photosensitizer. Herein, we model the penetration of the archetypal photosensitizer methylene blue into a lipid bilayer and theoretically analyse the impact of the lipid environment on the excited state electronic structure of the photosensitizer. We show that both penetration and intersystem crossing are energetically adverse. The rationalization of the factors behind these unfavourable processes allows us to suggest some rules for the functionalization of the photosensitizer in order to improve its phototoxicity inside the lipid bilayer.