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

上睑下垂 活性氧 化学 体内 药理学 细胞生物学 细胞凋亡 程序性细胞死亡 生物化学 生物 生物技术
作者
Xuezhi Zhou,Rong Rong,Ganghao Liang,Haibo Li,Mengling You,Zhou Zeng,Haihua Xiao,Dan Ji,Xiaobo Xia
出处
期刊:Nano Today [Elsevier]
卷期号:47: 101668-101668 被引量:9
标识
DOI:10.1016/j.nantod.2022.101668
摘要

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.
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