Targeting retinal and choroid neovascularization using the small molecule inhibitor carboxyamidotriazole.
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.
Afzal
Aqeela
A
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
Caballero
Sergio
S
Palii
Stela S
SS
Jurczyk
Simona
S
Pardue
Machelle
M
Geroski
Dale
D
Edelhauser
Henry
H
Hochhaus
Guenther
G
Kim
Moon
M
Franklin
Alan
A
Shapiro
Gideon
G
Grant
Maria B
MB
D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D020256:Choroidal Neovascularization / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004596:Electroretinography / Q000379:methods; D004847:Epithelial Cells / Q000187:drug effects; D005260:Female; D006801:Humans; D056965:Injections, Intraocular / Q000379:methods; D007797:Laminin / Q000378:metabolism; D051379:Mice; D011509:Proteoglycans / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D012160:Retina / Q000033:anatomy & histology; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D012171:Retinal Vessels / Q000166:cytology; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*; D047392:beta-Cyclodextrins / Q000627:therapeutic use
D000970:Antineoplastic Agents; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D014230:Triazoles; D047392:beta-Cyclodextrins; C059485:matrigel; D000073738:2-Hydroxypropyl-beta-cyclodextrin; C062058:carboxyamido-triazole; D003094:Collagen; D001973:Bromodeoxyuridine
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