Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
Curr Neurovasc Res. 2017;14(1):46-52. doi: 10.2174/1567202614666161104115440.
This study aimed to evaluate the effect of liposomes loaded with diclofenac, a potent cyclooxygenase (COX)-1 and COX-2 inhibitor, on laser-induced choroidal neovascularization (CNV) in mice and non-human primates (common marmosets). CNV was induced by laser irradiation on the unilateral or bilateral eye of each mouse or common marmoset, respectively, under anesthesia. The CNV was visualized using fluorescence labeling with intravenous injection of fluoresceinconjugated dextran (molecular weight = 2,000 kDa), and quantified in the retinal pigment epithelia (RPE)-choroidal flatmounts. Diclofenac-loaded liposome or diclofenac ophthalmic solution was instillated to the eye surface daily for 14 days and 21 days in mice and common marmosets, respectively. In the mouse CNV model, 0.1% diclofenac-loaded liposome eye drops administered four times a day (q.i.d.) significantly reduced CNV formation in the RPE-choroidal flatmounts compared with those in empty liposome eye drops. Diclofenac-loaded liposome (0.1%) eye drops, administered once a day (s.i.d.), twice a day (b.i.d.), and three times a day (t.i.d.), also reduced CNV formation in a frequency-dependent manner. Furthermore, diclofenac-loaded liposome (0.03% and 0.1%) eye drops administered t.i.d. reduced CNV formation in a dose-dependent manner, significantly so at 0.1%. In the common marmoset CNV model, late hyperfluorescence and leakage by fluorescein angiograms was observed within or beyond the lesion borders at 17 days after laser irradiation, and diclofenac-loaded liposome eye drops (0.1% t.i.d.) tended to attenuate the late hyperfluorescence and leakage. Diclofenac-loaded liposomes had significantly reduced CNV formation in the RPE- choroidal flatmounts at 21 days after laser irradiation. In conclusion, diclofenac-loaded liposome eye drops enhance penetration to the RPE-choroid, and reduce the CNV formation. These results suggest that a drug-loaded liposome is a useful tool for drug delivery into the posterior segment of the eye.
本研究旨在评估载有双氯芬酸的脂质体对小鼠和非人灵长类动物（普通狨猴）激光诱导脉络膜新生血管（CNV）的作用。CNV 是通过在麻醉下分别对每只小鼠或普通狨猴的单侧或双侧眼睛进行激光照射而诱导产生的。通过静脉注射荧光素标记的葡聚糖（分子量=2000kDa）对 CNV 进行荧光标记，并在视网膜色素上皮（RPE）-脉络膜平面中进行定量。在小鼠和普通狨猴中，分别每日对眼部表面滴注载有双氯芬酸的脂质体或双氯芬酸眼用溶液 14 天和 21 天。在小鼠 CNV 模型中，与空脂质体眼滴相比，每日四次（q.i.d.）给予 0.1%载有双氯芬酸的脂质体滴眼剂可显著减少 RPE-脉络膜平面中的 CNV 形成。每日一次（s.i.d.）、每日两次（b.i.d.）和每日三次（t.i.d.）给予载有双氯芬酸的脂质体（0.1%）滴眼剂也以频率依赖性方式减少 CNV 形成。此外，每日三次（t.i.d.）给予 0.03%和 0.1%载有双氯芬酸的脂质体滴眼剂减少 CNV 形成呈剂量依赖性，在 0.1%时显著减少。在普通狨猴 CNV 模型中，在激光照射后 17 天，通过荧光素血管造影观察到晚期高荧光和渗漏，并且载有双氯芬酸的脂质体滴眼剂（0.1%，t.i.d.）倾向于减轻晚期高荧光和渗漏。在激光照射后 21 天，载有双氯芬酸的脂质体滴眼剂可显著减少 RPE-脉络膜平面中的 CNV 形成。总之，载有双氯芬酸的脂质体滴眼剂增强了向 RPE-脉络膜的渗透，并减少了 CNV 的形成。这些结果表明，载药脂质体是一种将药物递送至眼部后段的有用工具。
