兔玻璃体内注射聚N-异丙基丙烯酰胺-聚氧化乙烯纳米粒的眼内毒理学效应
王丽曌1,王雨生1,陈晓农2,崔志利1,杜红俊1,马吉献1,傅亦恬1
基金项目：全军医药卫生科研项目(No.06M261)；中国陕西省自然科学基金(No.2004C246)；德国洪堡基金会(Alexander von Humboldt Foundation)仪器设备捐赠基金(V-8151/02085,To YS Wang)
作者单位：1 (710032)中国陕西省西安市，第四军医大学西京医院眼科全军眼科研究所；2 (100029)中国北京市，北京化工大学材料科学与工程学院
作者简介：王丽曌，女，硕士研究生（导师：王雨生教授）。
通讯作者：王雨生，眼科主任，教授，博士生导师，
研究方向：眼部新生血管基础和临床眼外
伤[email protected]
收稿日期：2008-04-21修回日期：2008-05-04
Ocular toxicity of intravitreous injection of PNIPAAm-PEO nanoparticles in rabbits
Li-Zhao Wang1,Yu-Sheng Wang1,Xiao-Nong Chen2,Zhi-Li Cui1,Hong-Jun Du1,Ji-Xian Ma1,Yi-Tian Fu1
Foundation items: Supported by the Military Medical and Health Research Foundation (No. 06M261) ; Nature Science Foundation of Shaanxi Province, China (No. 2004C246);the equipment donation from the Alexander von Humboldt Foundation in Germany to YS Wang, V-8151/02085
1Department of Ophthalmology, Xijing Hospital, Eye Institute of General Army, the Fourth Military Medical University, Xian 710032, Shaanxi Province, China；2College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029,China
Correspondence to: Yu-Sheng Wang．Department of Ophthalmo-logy, Xijing Hospital, Eye Institute of General Army, the Fourth Military Medical University, Xi’an 710032, Shaanxi Province, [email protected]
Received:2008-04-21Accepted:2008-05-04
Abstract
AIM: To assess the potential of PNIPAAm-PEO nanoparticles as ocular sustained drug delivery carrier by investigating the retinal toxicity of intravitreal injection and also their interaction with the ocular tissue in vivo.
METHODS: New Zealand rabbits were randomly divided into 5 groups. Rabbits in group 1, 2, 3 and 4 received intravitreal injection of the PNIPAAm-PEO nanoparticles at different dosage respectively, which are 1mg/0.1mL, 2mg/0.1mL, 3mg/0.1mL, and 4mg/0.1mL. Rabbits in group 5 as controls received intravitreal injection of sterilized water 0.1mL. After intravitreal injections, the eyes were examined by slit-lamp microscope, ophthal-moscopy, light microscope and some also by trans-mission electronic microscope. To all eyes, ERG was recorded. While these diluent at different concentration were also used as eye dropping locally in order to observe the stimulation of ocular tissue in rabbits.
RESULTS: The rabbit ocular surface showed no signs of inflammation or alteration after different dosage PNIPAAm-PEO exposure compared with the controls. No evidence of toxicity was found in rabbits eyes after intravitreal injections of the PNIPAAm-PEO nanoparticles at 1mg/0.1mL and 2mg/0.1mL, but intravitreal injections at 3mg/0.1mL and 4mg/0.1mL induced toxic effects on the retinas, which could make the b-wave of ERG diminished, and mainly showed extensive vacuolar degeneration in histopathology. In group 3, changes in retina were observed by light microscope from 3 to 14 days, but electron microscope changes were more observable. However, obvious changes of all of exami-nations were found in group 4 in the whole 14 days, when the decline rates of b-wave of ERG were above 30%.
CONCLUSION: The PNIPAAm-PEO nanoparticles are well tolerated by the ocular surface tissues. They can reduce retina toxicity at the dosage of more than 3mg/0.1mL in vitreous. So these facts add further support for the potential use of the PNIPAAm-PEO nanoparticles for ocular drug delivery, and ocular safety problems should be paid more attention to while the large dose intravitreal injections.
KEYWORDS: PNIPAAm-PEO; nanoparticles; toxicity; intravitreal injection
Wang LZ, Wang YS, Chen XN, et al. Ocular toxicity of intravitreous injection of PNIPAAm-PEO nanoparticles in rabbits. Int J Ophthalmol
(Guoji Yanke Zazhi)2008;8(6):1122-1125
摘要
目的：评估玻璃体腔内注射新型缓释给药载体聚N-异丙基丙烯酰胺-聚氧化乙烯(PNIPAAm-PEO)纳米粒的眼内毒理学效应。
方法：玻璃体腔注射不同浓度(1mg/0.1mL，2mg/0.1mL，3mg/0.1mL，4mg/0.1mL)的PNIPAAm-PEO纳米稀释液后于不同时间点行裂隙灯、检眼镜、视网膜电图以及组织病理学检测。对照组注射0.1mL无菌生理盐水。将所用不同浓度稀释液局部点眼，观察局部组织的刺激反应。
结果：兔眼角结膜对检测浓度范围内的PNIPAAm-PEO有良好耐受性，眼部无刺激症状。玻璃体腔内注射1mg和2mg组未见明显视网膜毒性反应。3mg组眼底检查无异常，ERG-b波1~3d下降幅度>30%，第7~14d略有恢复；第14d光镜下视网膜部分感光细胞外节间隙增宽，外丛状层以内结构空泡变性，细胞排列正常；电镜下各层均有较明显的结构改变，广泛的细胞水肿和空泡变性，细胞间隙增宽，感光细胞膜盘结构基本正常。4mg组ERG-b波波幅下降>30%；第1~14d组织病理学观察均有明显视网膜结构破坏，广泛空泡变性，部分感光细胞的盘膜崩解，层状结构紊乱、模糊不清。
结论：PNIPAAm-PEO纳米粒的眼部耐受性良好，具有用作眼部给药载体的潜力，但大剂量使用时应注意眼部安全性问题。
关键词：聚N-异丙基丙烯酰胺-聚氧化乙烯；纳米微粒；毒理效应；玻璃体腔注射
王丽曌,王雨生,陈晓农,等.兔玻璃体内注射聚N-异丙基丙烯酰胺-聚氧化乙烯纳米粒的眼内毒理学效应.国际眼科杂志2008；8（6）：1122-1125 |
