Utilization of Nitrogen-Doped Graphene Quantum Dots to Neutralize ROS and Modulate Intracellular Antioxidant Pathways to Improve Dry Eye Disease Therapy

• Published in: International journal of nanomedicine 2024-01, Vol.19, p.2691-2708
• Main Authors: Wu, Zixia, Xia, Weibo, Ou, Liling, Zheng, Ling, Hou, Bingying, Pan, Tonghe, Sun, Wenjie, Koole, Leo H, Shao, Yongqing, Qi, Lei
• Format: Article
• Language: English
• Subjects: Animals; antioxidant; Antioxidants - pharmacology; Citric acid; dry eye disease; Dry Eye Syndromes - drug therapy; Eye diseases; Free radicals (Chemistry); Genetic aspects; Genetic transcription; Graphene; Graphite; Graphite - chemistry; Humans; Hydrogen Peroxide; Inflammation; Mice; NF-E2-Related Factor 2; Nitrogen - chemistry; nitrogen doped graphene quantum dots; nrf2 antioxidant pathway; Ophthalmic Solutions; Organic compounds; Original Research; Patient compliance; Peptides; Poloxamer; Polyethylenes; Polypropylenes; Quantum Dots - chemistry; Reactive Oxygen Species; Urea
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S445398

Patients afflicted with dry eye disease (DED) experience significant discomfort. The underlying cause of DED is the excessive accumulation of ROS on the ocular surface. Here, we investigated the nitrogen doped-graphene quantum dots (NGQDs), known for their ROS-scavenging capabilities, as a treatment for DED. NGQDs were prepared by using citric acid and urea as precursors through hydrothermal method. The antioxidant abilities of NGQDs were evaluated through: scavenging the ROS both extracellular and intracellular, regulating the nuclear factor-erythroid 2-related factor (Nrf2) antioxidant pathway of human corneal epithelial cells (HCECs) and their transcription of inflammation related genes. Furthermore, NGQDs were modified by Arg-Gly-Asp-Ser (RGDS) peptides to obtain RGDS@NGQDs. , both the NGQDs and RGDS@NGQDs were suspended in 0.1% Pluronic F127 (w/v) and delivered as eye drops in the scopolamine hydrobromide-induced DED mouse model. Preclinical efficacy was compared to the healthy and DPBS treated DED mice. These NGQDs demonstrated pronounced antioxidant properties, efficiently neutralizing free radicals and activating the intracellular Nrf2 pathway. In vitro studies revealed that treatment of H O -exposed HCECs with NGQDs induced a preservation in cell viability. Additionally, there was a reduction in the transcription of inflammation-associated genes. To prolong the corneal residence time of NGQDs, they were further modified with RGDS peptides and suspended in 0.1% Pluronic F127 (w/v) to create RGDS@NGQDs F127 eye drops. RGDS@NGQDs exhibited superior intracellular antioxidant activity even at low concentrations (10 μg/mL). Subsequent in vivo studies revealed that RGDS@NGQDs F127 eye drops notably mitigated the symptoms of DED mouse model, primarily by reducing ocular ROS levels. Our findings underscore the enhanced antioxidant benefits achieved by modifying GQDs through nitrogen doping and RGDS peptide tethering. Importantly, in a mouse model, our novel eye drops formulation effectively ameliorated DED symptoms, thereby representing a novel therapeutic pathway for DED management.