GSH/pH-Sensitive Poly(glycerol sebacate dithiodiglycolate) Nanoparticle as a Ferroptotic Inducer through Cooperation with Fe³⁺

Ferroptosis is an iron-dependent, non-apoptotic cell death induced by an overload of iron initiated through Fenton and Haber-Weiss reactions. These two reactions lead to lethal levels of intracellular reactive oxygen species (ROS) and lipid peroxidation. In contrast, glutathione (GSH) and glutathione peroxidase 4 (GPX4) suppress ferroptosis by inhibiting lipid peroxidation. Herein, the ferric ion (Fe³⁺) carriers, poly(glycerol sebacate dithiodiglycolate) nanoparticles (PGSDTG NPs), were prepared via nanoprecipitation. The GSH/pH-dual sensitive Fe³⁺/PGSDTG NPs would disintegrate via the cleavage of disulfide and ester bonds in the presence of GSH and acidic conditions. The cleaved polymer segments along with released Fe³⁺ rendered cancer cells showing ferroptosis characteristics including ROS production, transferrin receptor 1 (TfR1) expression, and iron accumulation after treatment with Fe³⁺/PGSDTG NPs. The PGSDTG NPs played an important role in ferroptosis by triggering the oxidation of intracellular GSH and reducing the GPX4 expression. An in vivo experiment also showed that Caenorhabditis elegans (C. elegans) exhibited a shortened lifespan after treatment with NPs. These results indicated that the PGSDTG NPs were potential GSH/pH-sensitive metal ion carriers for anticancer treatment by inducing ferroptosis.