Abstract
Eye drops account for more than 90% of commercialized ophthalmic drugs. However, eye drops have certain shortcomings, such as short precorneal retention time and weak corneal penetration. The requirement of frequent instillation of eye drops also causes poor patient compliance, which may lead to further aggravation of the disease. We aimed to develop a cationic liposome formulation to increase the bioavailability of the therapeutic agent and solve the aforementioned problems. In the present study, we prepared cationic liposomal tacrolimus (FK506) with a surface potential of approximately +30 mV, which could bind to the negatively charged mucin layer of the ocular surface. Our results showed that the content of FK506 in the cornea was increased by 93.77, 120.30, 14.24, and 20.36 times at 5, 30, 60, and 90 min, respectively, in the FK506 liposome group (0.2 mg/ml) compared with the free drug group (0.2 mg/ml). Moreover, FITC-labeled FK506 liposomes significantly prolonged the ocular surface retention time to 50 min after a single dose. In addition, the results of the Cell Counting Kit-8 assay, live and dead cell assay, sodium fluorescein staining, and hematoxylin and eosin staining all indicated that FK506 liposomes had good biological compatibility in both human corneal epithelial cells and mouse eyeballs. Compared with the free drug at the same concentration, FK506 liposomes effectively inhibited vascular endothelial growth factor-induced green fluorescent protein-transduced human umbilical vein endothelial cell migration and tube formation in vitro. In a mouse corneal neovascularization model induced by alkali burns, FK506 liposomes (0.2 mg/ml) enhanced corneal epithelial recovery, inhibited corneal neovascularization, and reduced corneal inflammation, and its therapeutic effect was better than those of the commercial FK506 eye drops (1 mg/ml) and the free drug (0.2 mg/ml). Collectively, these results indicate that cationic FK506 liposomes could increase the efficacy of FK506 in the corneal neovascularization model. Therefore, cationic FK506 liposomes can be considered as a promising ocular drug delivery system.
Highlights
Corneal neovascularization (CoNV), one of the most common causes for reduced corneal transparency and vision loss, can be induced by inflammation and a variety of angiogenic stimuli (Chuang et al, 2019; Chen et al, 2021)
IL-6 can promote the expression of vascular endothelial growth factor (VEGF) (Tian et al, 2021), and these two factors lead to the increase in vascular permeability and the formation of new blood vessels. These results indicate that FK506 liposomes may inhibit CoNV and inflammation by blocking the pathways related to VEGF, matrix metalloproteinase (MMP), and IL-6
We demonstrated the potential of cationic FK506 liposomes in improving the ocular bioavailability and therapeutic effects of hydrophobic FK506
Summary
Corneal neovascularization (CoNV), one of the most common causes for reduced corneal transparency and vision loss, can be induced by inflammation and a variety of angiogenic stimuli (Chuang et al, 2019; Chen et al, 2021). CoNV therapy; previous studies have reported the antiangiogenesis and anti-inflammation effects of FK506 in treating corneal alkali burns in mice (Park et al, 2015; Chen et al, 2018; Wu et al, 2019). Previous studies have reported that some FK506 formulations, such as liposomes (Pleyer et al, 1993; Whitcup et al, 1998; Zhang et al., 2010; Dai et al, 2013), micelles (Lin et al, 2019), and niosomes (Li et al, 2014; Zeng et al, 2016), have effectively enhanced the corneal permeability and have been evaluated in animal models of uveitis, dry eye, and corneal transplantation. To the best of our knowledge, no previous research has evaluated the potential of cationic FK506 liposomes in the treatment of corneal alkali burns
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