PMID- 38510793 OWN - NLM STAT- MEDLINE DCOM- 20240322 LR - 20240322 IS - 1178-2013 (Electronic) IS - 1176-9114 (Print) IS - 1176-9114 (Linking) VI - 19 DP - 2024 TI - Utilization of Nitrogen-Doped Graphene Quantum Dots to Neutralize ROS and Modulate Intracellular Antioxidant Pathways to Improve Dry Eye Disease Therapy. PG - 2691-2708 LID - 10.2147/IJN.S445398 [doi] AB - PURPOSE: 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. METHODS: 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. In vivo, 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. RESULTS: These NGQDs demonstrated pronounced antioxidant properties, efficiently neutralizing free radicals and activating the intracellular Nrf2 pathway. In vitro studies revealed that treatment of H(2)O(2)-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 mug/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. CONCLUSION: 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. CI - (c) 2024 Wu et al. FAU - Wu, Zixia AU - Wu Z AD - National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, the People's Republic of China. FAU - Xia, Weibo AU - Xia W AD - National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, the People's Republic of China. FAU - Ou, Liling AU - Ou L AD - National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, the People's Republic of China. FAU - Zheng, Ling AU - Zheng L AD - National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, the People's Republic of China. FAU - Hou, Bingying AU - Hou B AD - National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, the People's Republic of China. FAU - Pan, Tonghe AU - Pan T AD - Ningbo Eye Hospital, Affiliated to Wenzhou Medical University, Ningbo, Zhejiang, 310000, the People's Republic of China. FAU - Sun, Wenjie AU - Sun W AD - National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, the People's Republic of China. FAU - Koole, Leo H AU - Koole LH AD - National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, the People's Republic of China. FAU - Shao, Yongqing AU - Shao Y AD - Ningbo Eye Hospital, Affiliated to Wenzhou Medical University, Ningbo, Zhejiang, 310000, the People's Republic of China. FAU - Qi, Lei AU - Qi L AUID- ORCID: 0000-0002-3473-5246 AD - National Engineering Research Center of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, the People's Republic of China. LA - eng PT - Journal Article DEP - 20240315 PL - New Zealand TA - Int J Nanomedicine JT - International journal of nanomedicine JID - 101263847 RN - 0 (Antioxidants) RN - 0 (Reactive Oxygen Species) RN - 7782-42-5 (Graphite) RN - N762921K75 (Nitrogen) RN - BBX060AN9V (Hydrogen Peroxide) RN - 9038-95-3 (UCON 50-HB-5100) RN - 0 (NF-E2-Related Factor 2) RN - 106392-12-5 (Poloxamer) RN - 0 (Ophthalmic Solutions) RN - 0 (Peptides) RN - 0 (Polyethylenes) RN - 0 (Polypropylenes) SB - IM MH - Mice MH - Humans MH - Animals MH - Antioxidants/pharmacology MH - Reactive Oxygen Species MH - *Graphite/chemistry MH - *Quantum Dots/chemistry MH - Nitrogen/chemistry MH - Hydrogen Peroxide MH - NF-E2-Related Factor 2 MH - Poloxamer MH - *Dry Eye Syndromes/drug therapy MH - Inflammation MH - Ophthalmic Solutions MH - Peptides MH - *Polyethylenes MH - *Polypropylenes PMC - PMC10950682 OTO - NOTNLM OT - Nrf2 antioxidant pathway OT - antioxidant OT - dry eye disease OT - nitrogen doped graphene quantum dots COIS- The authors report no conflicts of interest in this work. EDAT- 2024/03/21 06:43 MHDA- 2024/03/22 06:45 PMCR- 2024/03/15 CRDT- 2024/03/21 04:15 PHST- 2023/12/11 00:00 [received] PHST- 2024/02/26 00:00 [accepted] PHST- 2024/03/22 06:45 [medline] PHST- 2024/03/21 06:43 [pubmed] PHST- 2024/03/21 04:15 [entrez] PHST- 2024/03/15 00:00 [pmc-release] AID - 445398 [pii] AID - 10.2147/IJN.S445398 [doi] PST - epublish SO - Int J Nanomedicine. 2024 Mar 15;19:2691-2708. doi: 10.2147/IJN.S445398. eCollection 2024.