Abstract
Hypoxia-inducible factor-1 (HIF-1) has been implicated in the pathogenesis of choroidal neovascularization (NV) and is an appealing target because it increases multiple pro-angiogenic proteins and their receptors. Acriflavine (ACF) binds HIF-1α and HIF-2α preventing binding to HIF-1β and inhibiting transcriptional activity of HIF-1 and HIF-2. Delivery of ACF to the eye by multiple routes strongly, but transiently, suppresses choroidal NV. We overcame design challenges and loaded highly water soluble ACF into poly(lactic-co-glycolic acid) (PLGA) microparticles (PLGA-ACF MPs) that release ACF in vitro for up to 60 days. Intravitreous injection of PLGA-ACF MPs in mice suppressed choroidal NV for at least 9 weeks and suprachoroidal injection of PLGA-ACF in rats suppressed choroidal NV for at least 18 weeks. Intravitreous, but not suprachoroidal injection, of PLGA-ACF MPs containing 38 μg of ACF in rabbits resulted in modest reduction of full-field electroretinogram (ERG) function. Over the span of 28 days after suprachoroidal injection of PLGA-ACF MP, rabbits had normal appearing retinas on fundus photographs, normal electroretinogram scotopic a- and b-wave amplitudes, no increase in intraocular pressure, and normal retinal histology. The active component of ACF, trypaflavine, had steady-state levels in the low nM range in RPE/choroid > retina for at least 16 weeks with a gradient from the side of the eye where the injection was done to the opposite side. These data suggest that suprachoroidal injection of PLGA-ACF MPs has the potential to provide a durable new treatment for retinal and choroidal vascular diseases.