Dejneka Nadine S, Wan Shanhong, Bond Ottrina S, Kornbrust Douglas J, Reich Samuel J
OPKO Ophthalmics, Miami, FL 33137, USA.
Mol Vis. 2008 May 28;14:997-1005.
The primary objective of these investigations was to determine the ocular biodistribution of bevasiranib, a small interfering RNA (siRNA) targeting vascular endothelial growth factor A (VEGF-A), following a single intravitreal injection to rabbit eyes.
A tissue distribution and pharmacokinetic study was conducted with (3)H-bevasiranib prepared in balanced-salt solution (BSS). Single doses of either 0.5 mg/eye or 2.0 mg/eye of (3)H-bevasiranib were given by intravitreal injection to Dutch-Belted rabbits (both eyes were treated). Subgroups of rabbits were serially-sacrificed at various times up to 7 days following dosing for collection of tissue samples. The right eye of each rabbit was collected whole, and the left eye was dissected to isolate five ocular tissues. All samples were analyzed by liquid scintillation counting to determine the concentrations of bevasiranib equivalents. An ocular disposition study was also performed with non-radiolabeled bevasiranib, which was administered to Dutch-Belted rabbit eyes via intravitreal injection at a dose of 2.0 mg/eye. Twenty-four hours post-dose, the eyes were enucleated and dissected into eight individual ocular structures that were analyzed for intact bevasiranib using a locked nuleic acid (LNA) noncompetitive hybridization-ligation enzyme-linked immunosorbent assay.
Following intravitreal injection of 0.5 mg or 2.0 mg radiolabeled bevasiranib to Dutch-Belted rabbits, bevasiranib was detected in the vitreous, iris, retina, retinal pigment epithelium (RPE), and sclera (+choroid). As expected, the highest concentrations were found in the vitreous, and vitreous levels steadily decreased over time, while concentrations of radioactivity in the other ocular tissues increased to maximum values between 24 h and 72 h after dosing. Of these tissues, the highest concentration of radioactivity was detected in the retina. The LNA assay further confirmed the presence of intact bevasiranib in these tissues 24 h following intravitreal injection of non-radiolabeled bevasiranib (2 mg/eye).
These studies demonstrate distribution of bevasiranib throughout the eye following intravitreal injection, including extensive uptake into the retina.
这些研究的主要目的是确定单次玻璃体内注射靶向血管内皮生长因子A（VEGF-A）的小干扰RNA（siRNA）贝伐西单抗后，其在兔眼内的眼部生物分布。
用平衡盐溶液（BSS）配制的³H-贝伐西单抗进行组织分布和药代动力学研究。将单剂量0.5mg/眼或2.0mg/眼的³H-贝伐西单抗通过玻璃体内注射给予荷兰带兔（双眼均接受治疗）。在给药后长达7天的不同时间点，对兔亚组进行连续处死以收集组织样本。每只兔的右眼整体收集，左眼解剖以分离出五种眼组织。所有样本通过液体闪烁计数法进行分析，以确定贝伐西单抗等效物的浓度。还用非放射性标记的贝伐西单抗进行了眼部处置研究，该药物以2.0mg/眼的剂量通过玻璃体内注射给予荷兰带兔眼。给药后24小时，将眼球摘除并解剖成八个单独的眼部结构，使用锁定核酸（LNA）非竞争性杂交-连接酶联免疫吸附测定法分析其中完整的贝伐西单抗。
向荷兰带兔玻璃体内注射0.5mg或2.0mg放射性标记的贝伐西单抗后，在玻璃体、虹膜、视网膜、视网膜色素上皮（RPE）和巩膜（+脉络膜）中检测到贝伐西单抗。正如预期的那样，玻璃体中的浓度最高，且玻璃体水平随时间稳步下降，而其他眼组织中的放射性浓度在给药后24小时至72小时之间增加至最大值。在这些组织中，视网膜中检测到的放射性浓度最高。LNA测定进一步证实，在玻璃体内注射非放射性标记的贝伐西单抗（2mg/眼）24小时后，这些组织中存在完整的贝伐西单抗。
这些研究表明，玻璃体内注射后贝伐西单抗在眼内广泛分布，包括大量摄取到视网膜中。
