de Cogan Felicity, Hill Lisa J, Lynch Aisling, Morgan-Warren Peter J, Lechner Judith, Berwick Matthew R, Peacock Anna F A, Chen Mei, Scott Robert A H, Xu Heping, Logan Ann
Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.
Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom.
Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2578-2590. doi: 10.1167/iovs.16-20072.
To evaluate the efficacy of anti-VEGF agents for treating choroidal neovascularization (CNV) when delivered topically using novel cell-penetrating peptides (CPPs) compared with delivery by intravitreal (ivit) injection.
CPP toxicity was investigated in cell cultures. Ivit concentrations of ranibizumab and bevacizumab after topical administration were measured using ELISA. The biological efficacy of topical anti-VEGF + CPP complexes was compared with ivit anti-VEGF injections using an established model of CNV.
CPPs were nontoxic in vitro. In vivo, after topical eye drop delivery, CPPs were present in the rat anterior chamber within 6 minutes. A single application of CPP + bevacizumab eye drop delivered clinically relevant concentrations of bevacizumab to the posterior chamber of the rat eye in vivo. Similarly, clinically relevant levels of CPP + ranibizumab and CPP + bevacizumab were detected in the porcine vitreous and retina ex vivo. In an established model of CNV, mice treated with either a single ivit injection of anti-VEGF, twice daily CPP + anti-VEGF eye drops or daily dexamethasone gavage for 10 days all had significantly reduced areas of CNV when compared with lasered eyes without treatment.
CPPs are nontoxic to ocular cells and can be used to deliver therapeutically relevant doses of ranibizumab and bevacizumab by eye drop to the posterior segment of mouse, rat, and pig eyes. The CPP + anti-VEGF drug complexes were cleared from the retina within 24 hours, suggesting a daily eye drop dosing regimen. Daily, topically delivered anti-VEGF with CPP was as efficacious as a single ivit injection of anti-VEGF in reducing areas of CNV in vivo.
评估与玻璃体内注射相比，使用新型细胞穿透肽（CPP）局部给药抗VEGF药物治疗脉络膜新生血管（CNV）的疗效。
在细胞培养中研究CPP的毒性。使用ELISA测量局部给药后玻璃体内雷珠单抗和贝伐单抗的浓度。使用已建立的CNV模型，将局部抗VEGF+CPP复合物的生物学疗效与玻璃体内抗VEGF注射进行比较。
CPP在体外无毒性。在体内，局部滴眼给药后，CPP在6分钟内出现在大鼠前房。单次应用CPP+贝伐单抗滴眼液可在体内将临床相关浓度的贝伐单抗递送至大鼠眼后房。同样，在猪玻璃体和视网膜离体样本中检测到临床相关水平的CPP+雷珠单抗和CPP+贝伐单抗。在已建立的CNV模型中，与未经治疗的激光照射眼相比，单次玻璃体内注射抗VEGF、每日两次CPP+抗VEGF滴眼液或每日地塞米松灌胃治疗10天的小鼠CNV面积均显著减小。
CPP对眼细胞无毒，可通过滴眼将治疗相关剂量的雷珠单抗和贝伐单抗递送至小鼠、大鼠和猪眼的后段。CPP+抗VEGF药物复合物在24小时内从视网膜清除，提示每日滴眼给药方案。每日局部给予CPP抗VEGF在体内减少CNV面积方面与单次玻璃体内注射抗VEGF同样有效。
