National Engineering Research Center of Ophthalmology and Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China.
State Key Laboratory of Ophthalmology, Optometry and Vision Science, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, 325027, People's Republic of China.
Int J Nanomedicine. 2023 May 9;18:2447-2463. doi: 10.2147/IJN.S403337. eCollection 2023.
Benzalkonium chloride (BAC) is widely employed as a preservative in eye drops, which will cause the death of corneal epithelial cells due to ROS production, DNA strand breakage, and mitochondrial dysfunction, resulting in dry eye disease (DED)-like changes in ocular surface tissues. In this study, Melatonin (MT) liposomes (TAT-MT-LIPs) designed by loading MT into TAT-modified liposomes have been developed, characterized, and used for inhibiting BAC-induced DED (BAC-DED).
The TAT was chemically grafted onto the Mal-PEG-DSPE by Michael's addition between the sulfhydryl group in TAT and the maleimide group in Mal-PEG-DSPE. TAT-MT-LIPs were prepared using film dispersion followed by the extrusion method and topically treated in rats once a day. BAC-DED was induced in rats by topical administration with 0.2% BAC twice daily. Defects, edema, and inflammation of the corneas, as well as IOP, were examined. Histologic analyses of corneas were performed to assess the change of mitochondrial DNA oxidation and NLRP3/Caspase-1/GSDMD signaling transduction.
After topical administration, TAT-MT-LIPs significantly alleviated DED-clinical symptoms of experimental animals by inhibiting tissue inflammation and preventing the loss of the corneal epithelium and conjunctival goblet cells. Our data suggested continuous ocular surface exposure of BAC-induced NLRP3/Caspase-1/GSDMD mediated corneal epithelium pyroptosis, which was not reported before. BAC caused substantial mt-DNA oxidation, which promoted the transduction of NLRP3/Caspase-1/GSDMD and consequent corneal epithelium pyroptosis. TAT-MT-LIPs could efficiently suppress the BAC-induced corneal epithelium pyroptosis and inflammation by inhibiting mt-DNA oxidation and the subsequent signal transmission.
NLRP3/Caspase-1/GSDMD mediated corneal epithelium pyroptosis is involved in the development of BAC-DED. The present study provided new insights into the adverse effects of BAC, which can serve as a new target for protecting corneal epithelium when applying BAC as a preservative in eye drops. The developed TAT-MT-LIPs can efficiently inhibit BAC-DED and give great potential to be developed as a new DED treatment.
苯扎氯铵（BAC）作为一种防腐剂广泛应用于滴眼液中，它会导致角膜上皮细胞因 ROS 产生、DNA 链断裂和线粒体功能障碍而死亡，从而导致干眼疾病（DED）样的眼表组织改变。在这项研究中，设计了通过将 MT 装载到 TAT 修饰的脂质体中制成的褪黑素（MT）脂质体（TAT-MT-LIPs），并对其进行了表征，用于抑制 BAC 诱导的 DED（BAC-DED）。
TAT 通过巯基与 Mal-PEG-DSPE 上的马来酰亚胺基团之间的迈克尔加成反应化学接枝到 Mal-PEG-DSPE 上。TAT-MT-LIPs 通过薄膜分散法随后进行挤压法制备，并每天一次局部用在大鼠上。通过每天两次局部给予 0.2% BAC 诱导大鼠 BAC-DED。检查角膜的缺陷、水肿和炎症以及 IOP。对角膜进行组织学分析，以评估线粒体 DNA 氧化和 NLRP3/Caspase-1/GSDMD 信号转导的变化。
局部给药后，TAT-MT-LIPs 通过抑制组织炎症和防止角膜上皮和结膜杯状细胞丢失，显著缓解了实验动物的 DED 临床症状。我们的数据表明，BAC 诱导的 NLRP3/Caspase-1/GSDMD 介导的角膜上皮细胞焦亡持续暴露于眼表面，这是以前没有报道过的。BAC 导致大量 mt-DNA 氧化，促进 NLRP3/Caspase-1/GSDMD 的转导，进而导致角膜上皮细胞焦亡。TAT-MT-LIPs 可以通过抑制 mt-DNA 氧化和随后的信号传递，有效地抑制 BAC 诱导的角膜上皮细胞焦亡和炎症。
NLRP3/Caspase-1/GSDMD 介导的角膜上皮细胞焦亡参与了 BAC-DED 的发生。本研究为 BAC 的不良作用提供了新的见解，为将 BAC 作为滴眼液中的防腐剂应用时保护角膜上皮提供了新的靶点。所开发的 TAT-MT-LIPs 可以有效地抑制 BAC-DED，并具有作为新的 DED 治疗方法的巨大潜力。
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