Simultaneously deplete reactive oxygen species and inhibit pyroptosis by dopamine/thioketal-containing polymers delivering disulfiram in combination with Cu(II) for acute glaucoma
Simultaneously deplete reactive oxygen species and inhibit pyroptosis by dopamine/thioketal-containing polymers delivering disulfiram in combination with Cu(II) for acute glaucoma
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DOI：
10.1016/j.nantod.2022.101668
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发表时间：
2022-12
期刊：
影响因子：
17.4
通讯作者：
Xuezhi Zhou;Rong Rong-Rong;Ganghao Liang;Haibo Li;Mengling You;Z. Zeng;Haihua Xiao;D. Ji;
中科院分区：
文献类型：
--
作者：
Xuezhi Zhou;Rong Rong-Rong;Ganghao Liang;Haibo Li;Mengling You;Z. Zeng;Haihua Xiao;D. Ji;
青光眼是世界范围内不可逆视力损害的主要原因，其特征在于视网膜神经节细胞（RGC）的进行性丧失，目前尚无有效的治疗方法。活性氧（reactive oxygen species，ROS）的过度表达导致RGCs死亡。此外，视网膜节细胞的死亡也是青光眼神经退行性变的重要原因。然而，没有可用于青光眼的治疗方法可以同时防止ROS产生和抑制焦亡。本文首次应用生物信息学分析确定了关键蛋白N-末端gasdermin D（N-GSDMD）的上调可导致RGCs膜孔形成，导致细胞凋亡。筛选出一种新的N-GSDMD抑制剂双硫仑（DSF），它与Cu（II）（DSF+Cu（II））联用可显著抑制RGCs的焦亡。为了在体内转化这种效应，设计了一种含有多巴胺和硫代缩酮键的ROS清除生物可降解聚合物，以纳米颗粒（DSF-NP）的形式递送DSF。DSF-NPs被RGCs内化后，细胞内高浓度的活性氧（ROS）可破坏硫代酮键释放多巴胺，减少ROS，同时释放DSF，DSF可与Cu（II）结合抑制RGCs的焦亡。DSF-NPs玻璃体内注射后可在缺血/再灌注（I/R）小鼠模型的RGCs中积累，其进一步与Cu（II）共同作用以显著抑制RGCs焦亡。总而言之，DSF-NPs+Cu（II）可以选择性抑制RGCs的焦亡，从而对高眼压损伤产生相当大的保护作用，为急性青光眼提供了一种新的治疗策略。
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 effectin 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.