Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
Brain Res Bull. 2010 Feb 15;81(2-3):320-6. doi: 10.1016/j.brainresbull.2009.08.001. Epub 2009 Aug 11.
Neovascular ocular diseases as exemplified by proliferative diabetic retinopathy (PDR), exudative age-related macular degeneration (AMD), and retinopathy of prematurity (ROP) are severe diseases affecting all age groups in the US. We asked whether a small molecule, carboxyamidotriazole (CAI) known for its anti-angiogenic and anti-tumor effects and its ability to be administered orally in humans, could have anti-angiogenic effects in ocular in vitro and in vivo angiogenesis models. The anti-proliferative effects of CAI were examined by BrdU incorporation using human retinal and dermal endothelial cells and human pigment epithelial cells. The effect of CAI was determined using the Matrigel tube formation assay. The mouse model of choroidal neovascularization (CNV) initiated by laser rupture of Bruch's membrane was used to quantify in vivo effects of aqueous beta-hydroxypropyl cyclodextrin (bHPCD) formulations of CAI on neovascularization. The pharmacokinetics (PK) of CAI after intravitreal administration of bHPCD-CAI was studied in rabbit. The intravitreal toxicology of bHPCD-CAI was also examined in rat ocular tissue. We observed that CAI treatment of human endothelial cells decreased cell proliferation in a dose-dependent manner. In the in vivo tests bHPCD-CAI treatment reduced choroidal neovascular lesion volume, also in a dose-dependent manner. The intravitreal PK of bHPCD-CAI demonstrated that highly efficacious concentrations of CAI are reached in the vitreous compartment. No ocular toxicology was observed with intravitreous injection of CAI. These studies support the potential of developing intravitreal CAI in an bHPCD ocular formulation for treatment of proliferative retinopathies in humans.
新生血管性眼病，如增生性糖尿病视网膜病变（PDR）、渗出性年龄相关性黄斑变性（AMD）和早产儿视网膜病变（ROP），是影响美国所有年龄段人群的严重疾病。我们想知道一种小分子化合物羧基三唑（CAI）是否具有抗血管生成和抗肿瘤作用，并且能够在人体中口服给药，它是否对眼部体外和体内血管生成模型具有抗血管生成作用。通过 BrdU 掺入法检测 CAI 对人视网膜和真皮内皮细胞以及人色素上皮细胞的增殖抑制作用。使用 Matrigel 管形成测定法确定 CAI 的作用。采用激光破坏布鲁赫膜引发脉络膜新生血管（CNV）的小鼠模型，定量评估水合β-羟丙基环糊精（bHPCD）制剂 CAI 对新生血管形成的体内作用。研究了 bHPCD-CAI 玻璃体内给药后 CAI 的药代动力学（PK）。还在大鼠眼部组织中检查了 bHPCD-CAI 的玻璃体内毒性。我们观察到 CAI 处理人内皮细胞以剂量依赖性方式降低细胞增殖。在体内试验中，bHPCD-CAI 处理也以剂量依赖性方式减少脉络膜新生血管病变体积。bHPCD-CAI 的玻璃体内 PK 表明，高效浓度的 CAI 达到玻璃体内腔室。玻璃体内注射 CAI 未观察到眼部毒性。这些研究支持开发 bHPCD 眼部制剂中的玻璃体内 CAI 用于治疗人类增生性视网膜病变的潜力。
