Simultaneously deplete reactive oxygen species and inhibit pyroptosis by dopamine/thioketal-containing polymers delivering disulfiram in combination with Cu(II) for acute glaucoma

Abstract

Glaucoma is a worldwide prominent cause of irreversible vision damage, which is characterized by progressive loss of retinal ganglion cells (RGCs) and currently no effective treatment is available till far. Overexpression of reactive oxygen species (ROS) contribute to RGCs death. Moreover, pyroptosis mediate RGCs death also played a key role in neurodegeneration of glaucoma. However, there is no treatment available for glaucoma that can simultaneously prevent ROS generation and inhibit pyroptosis. Herein, bioinformatics analysis was firstly applied to identify the upregulation of a key protein N-terminal gasdermin D (N-GSDMD) can result in membrane pore formation in RGCs, leading to pyroptosis. Thereafter, disulfiram (DSF), a novel N-GSDMD inhibitor, was screened out which could be in combination with Cu(II) (DSF+Cu(II)) to significantly inhibit RGCs pyroptosis. To translate this effect in vivo, a ROS scavenging biodegradable polymer containing dopamine and thioketal bonds was designed to deliver DSF as nanoparticles (DSF-NPs). Once DSF-NPs were internalized by RGCs, the high intracellular ROS could break up the thioketal bonds to release dopamine for depleting ROS and simultaneously release DSF which could work in combination with Cu(II) for inhibiting RGCs pyroptosis. In vitro, DSF-NPs+Cu(II) was proved to protect R28 cells significantly better than DSF+Cu(II) under oxygen and glucose deprivation (OGD) conditions. In vivo, DSF-NPs could accumulate in the RGCs of an ischemia/reperfusion (I/R) mouse model after intravitreal injection, which further worked together with Cu(II) to significantly inhibit RGCs pyroptosis. Taken together, DSF-NPs+Cu(II) can selectively inhibit pyroptosis of RGCs, resulting in considerable protection from high intraocular pressure injury, providing a new therapeutic strategy for acute glaucoma.