Modulating aqueous humor outflow with engineered nanoparticles for glaucoma

用工程纳米颗粒调节房水流出以治疗青光眼

• 批准号: 10649763
• 负责人: Xiaorong Liu
• 金额: $ 51.33万
• 依托单位: MISSOURI UNIVERSITY OF SCIENCE & TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10649763
• 关键词: ANGPT1 gene; Adrenergic Agonists; Adrenergic beta-Antagonists; Adult; Aqueous Humor; Artificial nanoparticles; Behavioral; Betaxolol; Biological Assay; Biological Availability; Blindness; Brimodine; Carbonic Anhydrase Inhibitors; Characteristics; Clinical; Combined Modality Therapy; Cornea; Dendrimers; Dose; Drainage procedure; Drug Delivery Systems; Drug Formulations; Effectiveness; Electroretinography; Excision; Eye; Formulation; Foundations; Frequencies; Glaucoma; Hydrogels; Impairment; Kinetics; Label; Long-Term Effects; Mediating; Mus; Nanostructures; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Physiologic Intraocular Pressure; Production; Prostaglandins; Research; Resistance; Retina; Rho-associated kinase; Risk Factors; Route; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; System; Testing; Therapeutic; Time; Tissues; Trabecular meshwork structure; Visual Acuity; Wild Type Mouse; Work; anterior chamber; antiglaucoma drug; aqueous; compliance behavior; design; improved; in vivo; kinase inhibitor; liquid chromatography mass spectrometry; mass spectrometric imaging; mouse model; nanoparticle; nanoparticulate; near infrared dye; novel therapeutic intervention; particle; treatment adherence; treatment duration

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.

项目概要 青光眼仍然是世界范围内导致失明的第二大原因。 青光眼的特征性危险因素，目前所有的治疗方法都是为了降低或控制眼压，从而减缓 降低或减少青光眼随后的眼压升高主要是由于房水受损。 目前的降低眼压的策略包括流出引流并因此增加流出阻力。 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， 使用前列腺素或两者的组合促进房水通过葡萄膜巩膜途径流出 已开发出多种制剂，包括纳米颗粒系统，以提供抗青光眼作用。 局部促进药物通过葡萄膜巩膜途径流出。 然而控制眼压的另一个主要独立途径是如何设计。 基于纳米颗粒的输送系统，充分利用 TM 中的流出途径，更有效地降低眼压 还没有被系统地研究过，但将是我们这个项目的重点。 利用高度支化可调谐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) 我们证明 nDHPs 克服了大多数抗青光眼药物的脉冲输送，同步药物。 遵循零级动力学（即恒定释放速率）释放，具有良好的角膜渗透性并能够长期 基于nDHP，我们将测试通过减少房水来降低眼压的三管齐下的策略。 通过两个独立的途径（TM 和葡萄膜巩膜）产生和同时促进流出。 我们的目标是通过我们新设计的基于 nDHP 的系统最大限度地提高抗青光眼治疗效果。 保持基于 nDHP 的输送系统提供了一个模块化平台，将不同药物组合在一起 提高其剂量有效性并协调其释放以延长抗青光眼的作用方式 为了检验这一假设，我们提出以下目标 1) 建立 nDHP 介导的短期和长期目标。 通过调节青光眼小鼠模型中房水的产生和流出来降低眼压。 目标 2) 了解 nDHP 和 nDHP 传递的药物的动态眼部分布的机制 目标 3) 确定基于 nDHP 的固定组合的抗青光眼效果。 我们提出的研究将调查三个方面的配方：控制眼压和减缓视力丧失。 基于新配方的多管齐下的策略有可能更有效地实现眼压降低。 这种新型治疗干预措施将对改善青光眼治疗和患者产生临床影响 坚持。