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 components 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.

缺氧诱导因子-1（HIF-1）与脉络膜新血管形成（NV）的发病机理有关，并且是一个有吸引力的靶标，因为它增加了多种促血管生成蛋白及其受体。Acriflavine（ACF）结合HIF-1α和HIF-2α，从而阻止与HIF-1β的结合并抑制HIF-1和HIF-2的转录活性。通过多种途径向眼睛输送ACF会强烈但短暂地抑制脉络膜NV。我们克服了设计难题，并将高度水溶性的ACF装入了在体外释放ACF的聚乳酸-乙醇酸共聚物（PLGA）微粒（PLGA-ACF MP）长达60天。玻璃体腔注射PLGA-ACF MPs抑制脉络膜NV至少9周，脉络膜上注射PLGA-ACF抑制大鼠脉络膜NV至少18周。玻璃体腔内但非脉络膜上注射家兔中含有38μgACF的PLGA-ACF MP导致全视野视网膜电图（ERG）功能适度降低。在脉络膜上注射PLGA-ACF MP后的28天内，兔子的眼底照片上的视网膜出现正常，视网膜电图暗视a波和b波幅值正常，眼压没有增加，并且视网膜组织学正常。ACF的活性成分Trypaflavine在RPE /脉络膜> nM范围内处于稳态水平，视网膜至少持续16周，从进行注射的眼侧到对侧逐渐倾斜。这些数据表明，PLGA-ACF MP的脉络膜上注射有潜力为视网膜和脉络膜血管疾病提供持久的新疗法。