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

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。

Ocular toxicity of intravitreous injection of PNIPAAm-PEO nanoparticles in rabbits

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.·