BASHY Dyes Are Highly Efficient Lipid Droplet-targeting Photosensitizers That Induce Ferroptosis Through Lipid Peroxidation

Ferroptosis is an iron-dependent lipid peroxidation-driven mechanism of cell death and a promising therapeutic target to eradicate cancer cells. In this study we discovered that boronic acid derived salicylidenehydrazone (BASHY) dyes are highly efficient singlet-oxygen photosensitizers (PSs; quantum yields up to 0.8) that induce ferroptosis triggered by photodynamic therapy. The best performing BASHY dye displayed a high phototoxicity against the human glioblastoma multiform U87 cell line, with an IC50 value in the low nanomolar range (4.40 nM) and a remarkable phototoxicity index (PI > 22700). Importantly, BASHY dyes were shown to accumulate in lipid droplets and this intracellular partition was found to be essential for the enhanced phototoxicity and the induction of ferroptosis through lipid peroxidation. The safety and phototoxcity of this platform were validated in in vivo studies on zebrafish embryos (Danio rerio).