Targeting retinal and choroid neovascularization using the small molecule inhibitor carboxyamidotriazole

• Type of Material: Article
• Authors: Ageela Afzal, University of Florida; Sergio Caballero, University of Florida; Stela S. Palii, National Institute of Health; Simona Jurczyk, Pharmor, Inc.; Machelle Pardue, Emory University; Dale Geroski, Emory University; Henry Edelhauser, Emory University; Guenther Hochhaus, University of Florida; Moon Kim, Atlanta VA Medical Center; Alan Franklin, Pharmor, Inc.; Gideon Shapiro, Pharmor, Inc.; Maria B. Grant, University of Florida
• Language: English
• Date: 2010-02-15
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Elsevier Inc. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.brainresbull.2009.08.001
• Title of Journal or Parent Work: Brain Res Bull.
• Volume: 81
• Issue: 2-3
• Start Page: 320
• End Page: 326
• Keywords: MEDIATED SIGNAL-TRANSDUCTION; Carboxyamidotriazole; Therapy; Life Sciences & Biomedicine; MACULAR DEGENERATION; Endothelial cell; CALCIUM; Neurosciences & Neurology; ANGIOGENESIS; Science & Technology; Choroidal Neovascularization; EFFICACY; CELLS; PROLIFERATION; RECEPTOR; Angiogenesis; Animal model; Neurosciences; GROWTH; CAI
• Research Categories: Health Sciences, Pharmacology

Abstract

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.