Enhanced Photodynamic Therapy using Angiostatin with Verteporfin PDT in a Laser-injury Rat Model

Abstract

Abstract: : Purpose: Previous studies had shown increased cytotoxicity of verteporfin photodynamic therapy (PDT) combined with the anti-angiogenic drug angiostatin for bovine retinal microcapillary endothelium (bRME) but not for human retinal pigment epithelium (hRPE) in vitro. Here, we investigated the selectivity and the efficacy of PDT combined with angiostatin in vivo. Methods: Choroidal neovascular membranes (CNV) were induced in Brown-Norway rats using Argon/Dye laser. After the initial laser CNV induction, rats were treated with either angiostatin bolus injections intraperitoneally (12 and 24 hours before PDT) at 50 mg/kg or continuous administration of angiostatin through subcutaneously implanted osmotic pumps at 15mg/kg/day. Verteporfin PDT was performed at verteporfin dose of 3 or 6 mg/m2 using an irradiance of 600mW/cm2 and fluence of 10 and 25 J/cm2. Fluorescein angiograms performed 20 days after laser injury but before PDT, as well as 1 and 7 days after PDT were graded in a masked fashion using grading standards of CNV leakage. Non-parametric and parametric techniques were used to evaluate treatment effects. Results: Angiostatin alone did not prevent CNV growth using either model of administration. Bolus intraperitoneal administration of angiostatin prior to verteporfin PDT did not increase the efficacy of verteporfin PDT on CNV closure (P>.40 for differences in leakage between eyes treated with PDT vs. PDT with angiostatin at both timepoints and fluences).Continuous subcutaneous administration of angiostatin was significantly associated with CNV closure (ß=2.63, P=.002) in regression analysis adjusting for the effects of fluence. Conclusions: Continuous administration of angiostatin potentiated the efficacy of verteporfin PDT for CNV closure in a laser-injury rat model. Combined therapy of anti-angiogenic drugs and PDT may limit the damage to normal structure and improve PDT results. Lesions without angiographic leakage after PDT, number (%)  

Keywords: age-related macular degeneration • choroid: neovascularization • photodynamic therapy