Nanoparticles for the Treatment of Neovascularizations in the Eye

年龄相关性黄斑变性（AMD）和糖尿病性视网膜病变是导致失明的主要原因之一，在全世界共有1亿多人受到影响。湿型AMD和增殖性糖尿病视网膜病变（PDR）的致病机制都是内皮细胞增生和血管高通透性。由于血管内皮生长因子（VEGF）驱动这两个过程，因此眼内注射VEGF抗体已成为一种非常成功的治疗策略。然而，由于VEGF是视网膜组织维持的关键因素，其非特异性消除会引发严重的不良反应。这个项目的目标将是开发纳米颗粒，用于更有选择性的治疗策略。第一种方法是视网膜和脉络膜内皮特异性抗vegf策略，基于我们的发现，整合素受体靶向纳米颗粒在静脉注射后在视网膜血管中积聚。我们将设计脂质纳米颗粒，能够在全身给药后将环孢素A和伊曲康唑这两种有效的协同VEGF信号抑制剂转运到视网膜和脉络膜内皮细胞。第二种策略是vegf信号独立干预，基于我们的发现，配体修饰的纳米颗粒以一种优于自由配体的方式与细胞表面受体结合。利用这种多价结合纳米颗粒，我们将沉默在湿性AMD和PDR中表现出促炎作用的血管紧张素II受体1型（AT1R）。因此，我们将AT1R拮抗剂附着在量子点上，以识别此类颗粒的组织结合位点，或用于治疗目的的支链聚合物。这种结构既可以全身给药，也可以通过玻璃体内注射。这两种药物装载的治疗性脂质颗粒和多价结合AT1R拮抗剂将首先在体外测试和优化它们在细胞培养中的细胞结合行为。两者的生物分布将在健康小鼠中进行测试和进一步完善。载药的脂质纳米颗粒和多价AT1R拮抗剂在视网膜和脉络膜内皮中具有特别有利的分布，其疗效将最终在氧诱导新生血管的小鼠模型中进行测试。

Age-related macular degeneration (AMD) and diabetic retinopathy are among the leading causes of blindness and affect together worldwide more than 100 million people. The wet form of AMD and proliferative diabetic retinopathy (PDR) share pathogenic mechanisms of endothelial cell hyperproliferation and blood vessel hyperpermeability. Since vascular endothelial growth factor (VEGF) drives both processes, intraocular injections of VEGF antibodies evolved as a highly successful therapeutic strategy. However, since VEGF is a pivotal factor for retinal tissue maintenance its unspecific elimination triggers severe adverse effects. The goal of this project will be to develop nanoparticles for more selective therapeutic strategies. A first approach is a retinal and choroidal endothelium-specific anti-VEGF strategy and based on our discovery that integrin receptor-targeted nanoparticles accumulate in retinal blood vessels upon intravenous injection. We will design lipid nanoparticles that are able to transport cyclosporin A and itraconazole, two potent and synergistic VEGF signaling inhibitors, to retinal and choroidal endothelial cells following systemic administration. The second strategy is a VEGF-signaling independent intervention and rests on our finding that ligand-decorated nanoparticles bind to cell surface receptors in a way that is superior to that of a free ligand. With such multivalent binding nanoparticles we will silence the angiotensin II receptor type 1 (AT1R) which exhibits pro-inflammatory effects in wet AMD as well as PDR. We will, thereby, attach AT1R antagonists either to quantum dots to identify the tissue binding sites of such particles, or branched polymers for therapeutic purposes. Such constructs can either be administered systemically or via intravitreal injection. Both, drug loaded therapeutic lipid particles and multivalent binding AT1R antagonists, will first be tested and optimized in vitro for their cell binding behavior in cell culture. The biodistribution of both will be tested and further refined in healthy mice. The efficacy of drug loaded lipid nanoparticles and multivalent AT1R antagonists with a particularly favorable distribution into the retinal and choroidal endothelium will be finally tested in a mouse model of oxygen-induced neovascularization.