Modulating aqueous humor outflow with engineered nanoparticles for glaucoma

项目摘要 青光眼仍然是全球第二大致盲原因。眼内压（IOP）升高是一种 眼内压是青光眼的特征性危险因素，目前所有的治疗都是为了降低或控制IOP，从而减缓眼内压的升高。 降低或减少随后的视力丧失。青光眼中的IOP升高主要是由于受损的房水 流出引流并因此增加流出阻力。当前的IOP降低策略包括 使用β受体阻滞剂、肾上腺素能激动剂或碳酸酐酶抑制剂减少房水， 使用白藜芦醇苷或两者的组合促进经由葡萄膜巩膜途径的房水流出 行动已经开发了包括纳米颗粒系统在内的各种制剂来递送抗青光眼药物 局部用药以促进通过葡萄膜巩膜途径的流出。小梁网（TM）通路是 控制眼内压的另一个主要的独立途径。然而，如何设计 基于纳米颗粒的输送系统，充分利用TM中的流出通道，以更有效地降低IOP 尚未进行系统研究，但将是本项目的重点。我们开创了一种非传统的 利用高度支化的可调树枝状聚合物形成纳米结构树枝状聚合物水凝胶颗粒的概念 （nDHPs）。我们发现，nDHP克服了大多数抗青光眼药物的脉冲输送，同步药物释放， 遵循零级动力学的释放（即，恒定的释放速率），具有良好的角膜渗透性，并能够长时间地 表演效果。基于nDHP，我们将测试通过减少房水来降低IOP的三管齐下策略 通过两个独立的途径--TM和葡萄膜巩膜--产生并同时促进流出。 我们的目标是通过我们新设计的基于nDHP的系统来最大化抗青光眼治疗益处。我们 假设基于nDHP的递送系统提供将药物掺入不同载体中的模块化平台， 增加其剂量有效性并协调其释放以延长抗青光眼的作用模式 方面的影响.为了验证这一假设，我们提出了以下目标。目的1）建立nDHP介导的短-和长- 在青光眼小鼠模型中通过调节房水产生和流出的长期IOP降低作用。 目的2）了解nDHP及其药物的眼部动态分布机制 通过流出通道。目的3）确定以nDHP为基础的固定组合物的抗青光眼作用 在控制IOP和减缓视力丧失方面的应用。我们的研究计划将调查这三个- 这一策略在降低IOP方面可能更有效。新配方基于 这种新的治疗干预将在临床上对改善青光眼治疗和患者 坚持。

PROJECT SUMMARY Glaucoma remains the second leading cause of blindness worldwide. Elevated intraocular pressure (IOP) is a characteristic risk factor for glaucoma, and all current treatments are to lower or control IOP and thereby slow down or reduce the subsequent vision loss. Elevated IOP in glaucoma is primarily due to impaired aqueous outflow drainage and consequently increased outflow resistance. Current IOP-reducing strategies include reduction of aqueous humor using beta-blockers, adrenergic agonists, or carbonic anhydrase inhibitors, promotion of aqueous humor outflow via the uveoscleral pathway using prostaglandins, or combination of both actions. Various formulations, including nanoparticulate systems, have been developed to deliver antiglaucoma drugs topically to promote outflow through the uveoscleral pathway. The trabecular meshwork (TM) pathway is another major independent route for controlling the intraocular pressure. Nevertheless, how to design nanoparticle-based delivery systems to fully utilize the outflow pathway in TM for more effective IOP reduction has not been systematically investigated but will be the focus of this project. We pioneered an unconventional concept of utilizing highly-branched tunable dendrimers to form nanostructured dendrimer hydrogel particles (nDHPs). We showed that nDHPs overcome the pulsatile delivery of most antiglaucoma drugs, synchronize drug release following zero-order kinetics (i.e., constant release rate), have good corneal permeation and enable long- acting effects. Based on nDHPs, we will test a three-pronged strategy to reduce IOP by reducing aqueous humor production and simultaneous outflow promotion through the two independent pathways—the TM and uveoscleral. Our objective is to maximize antiglaucoma therapeutic benefits by our newly designed nDHP-based system. We hypothesize that nDHP-based delivery systems provide a modular platform incorporating drugs in different modes of action to increase their dose effectiveness and coordinate their release for extended antiglaucoma effects. To test the hypothesis, we propose the following aims. Aim 1) Establish nDHP-mediated short- and long- term IOP lowering effects by modulation of aqueous humor production and outflow in a mouse model of glaucoma. Aim 2) Gain mechanistic understanding of dynamic ocular distributions of nDHPs and drugs delivered by nDHPs through the outflow pathways. Aim 3) Determine the antiglaucoma effects of nDHP-based fixed-combination formulations in controlling IOP and slowing down vision loss. Our proposed research will investigate the three- pronged strategy that it has potential to be more effective in achieving IOP reduction. The new formulation based on this novel therapeutic intervention will be clinically impactful for improving glaucoma treatment and patient adherence.