Decyl-riboflavin: membrane-targeted lipophilic photosensitizer for lipid peroxidation and phototoxicity in HeLa cells under blue light irradiation.

Photodynamic therapy (PDT) exploits the controlled generation of reactive species to selectively destroy target cells, offering a minimally invasive alternative to conventional cancer and antimicrobial treatments. A key determinant of PDT efficacy is the ability of the photosensitizer (PS) to localize within lipid membranes, where proximity to polyunsaturated lipids maximizes oxidative damage. Riboflavin (Rf, Vitamin B2) is a biocompatible, naturally occurring PS with absorption in the blue light range; however, its inherent hydrophilicity limits membrane interaction. Here, we report the photochemical and biological characterization of 3-decyl-riboflavin (decyl-Rf), a lipophilic Rf derivative designed to direct oxidative damage specifically to the lipid bilayer under blue LED irradiation. Decyl-Rf generates singlet oxygen (Type II) while simultaneously operating through a Type I mechanism. This dual capacity translates into extensive lipid peroxidation and membrane disruption in biomimetic systems, effects essentially absent for hydrophilic Rf. Interaction studies with serum albumin reveal strong ground-state complex formation, which markedly reduces cellular uptake under serum-containing conditions. In HeLa cells, decyl-Rf is efficiently internalized and localizes preferentially in lipid-rich compartments, inducing significant phototoxicity upon blue light irradiation. These results position decyl-Rf as a potent membrane-targeted PS, with its lipid peroxidation capacity suggesting a possible contribution to regulated cell death pathways and provide a mechanistic foundation for lipophilic flavin derivatives as next-generation agents for blue light PDT in oncological and antimicrobial applications.