Abstract
Purpose: :
Pathological intraocular neovascularization is the hallmark of late stage neovascular age-related macular degeneration (ARMD) and a leading cause of blindness in people over 50 in the western world. Current treatments focus on suppressing choroidal neovascularization (CNV) by targeting solely VEGF. Given the multifactorial nature of ARMD, and the requirement for chronic treatment, our purpose was to evaluate the efficacy of a new non-toxic broad spectrum antiangiogenic drug on ocular neovascularization.
Methods: :
Lodamin, an oral non-toxic formulation of TNP-470, was synthesized by conjugating TNP-470, a broad spectrum antiangiogenic drug, to polyethyleneglycol-poly lactic acid. Lodamin’s effects on angiogenesis, vascular leakage and inflammation were evaluated in a wide array of assays in C57BL/6 mice i.e. laser-induced CNV, corneal micropocket assay, delayed-type hypersensitivity (DTH) and Miles assay. ELISA, immunoblotting, histology and FACS techniques were used. Primary retinal pigment epithelial (RPE) cells were established from C57BL/6 mice. Electroretinography (ERG) was used to test retinal function and evaluate drug safety.
Results: :
CNV was suppressed after oral or intravitreal administrations of Lodamin: 7 and 14 d of oral treatment (15mg/kg) led to 27% and 70% inhibition respectively. A single intravitreal injection of 100µg or 300µg Lodamin led to 56% or 75% suppression, respectively, after 14 d. Reduction in infiltrating macrophages and in-situ pro-angiogenic and inflammatory signals were obtained. MCP-1/Ccl2 was 486±3 pg/mg in control CNV mice and 61% lower in Lodamin treated mice. Other factors including VEGF and TNF-α were also reduced. The effect on MCP-1 was found to be at the RPE level, where primary RPE cells treated with Lodamin showed a dose dependant reduction of MCP-1. Lodamin substantially reduced edema in CNV setting, and in non-ophthalmic models, DTH reaction and Miles assays. The drug had minimal toxicity as demonstrated by ERG and histology.
Conclusions: :
Lodamin was identified as highly potent broad-spectrum antiangiogenic drug that can be administered orally or intravitreously to treat ocular neovascularization. New therapies which target several key processes in ARMD could improve current disease treatment and prevention.
Keywords: drug toxicity/drug effects • age-related macular degeneration • choroid: neovascularization