Hybrid Nanoparticles for Glaucoma

用于治疗青光眼的混合纳米颗粒

• 批准号: 8761610
• 负责人: UDAY B KOMPELLA
• 金额: $ 44.87万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761610
• 关键词: Adherence; Adrenergic Receptor; Adverse effects; Applications Grants; Biological Availability; Blindness; Cells; Chemistry; Chronic; Clinical; Copper; Dendrimers; Dose; Drug Delivery Systems; Drug Exposure; Drug Formulations; Eye; Free Radicals; Generations; Glaucoma; Glycolates; Health Care Costs; Hybrids; Hydrogels; Kinetics; Maintenance; Modeling; Ocular Hypertension; Oryctolagus cuniculus; Patient Noncompliance; Patients; Pharmaceutical Preparations; Physiologic Intraocular Pressure; Property; Rattus; Regimen; Solutions; Structure; System; Testing; Time; Timolol Maleate; Tissues; Topical application; Treatment Efficacy; Visual impairment; Work; antiglaucoma drug; compliance behavior; cytotoxicity; dosage; drug efficacy; improved; in vivo; nanoparticle; normotensive; novel; prevent; public health relevance; safety study; uptake

DESCRIPTION (provided by applicant): Glaucoma is a leading cause of visual impairment and blindness in the world. Long-term maintenance of low intraocular pressure (IOP) levels is the only proven solution among glaucoma patients for preventing or reducing progressive vision loss. The objective of this project is to develop an advanced topical delivery system to increase the ocular bioavailability and to sustain therapeutic efficacy as a means of reducing patient noncompliance, the leading problem in glaucoma therapy. We have developed a novel hybrid dendrimer hydrogel nanoparticle platform (HDNP), which can be fabricated into an ophthalmic hydrogel formulation to deliver both hydrophilic and hydrophobic antiglaucoma drugs. One-time topical instillation brings about sustained IOP-lowering effect for 4 days. This hybrid platform has adaptable structure and properties, making possible fine-tuning of drug release kinetics and dose regimen for optimal and personalized treatment. The central hypothesis of this grant application is that a topically applied nanoparticle formulation capable of sustaining IOP reduction for one week after single dosing can be developed using copper-free click chemistry and our novel HDNP platform. To test this hypothesis, we propose the following three aims. Aim 1: To develop clickable dendrimer hydrogel and HDNP (cHDNP) with enhanced mucoadhesion, enhanced cell entry, and reduced cytotoxicity. We will develop a novel, highly efficient clickable dendrimer hydrogel by avoiding photoinitiator use and generation of harmful free radicals. We will structurally and compositionally optimize hybrid nanoparticles for enhanced mucoadhesion, enhanced cell entry, and reduced cytotoxicity. Aim 2: To determine whether cHDNP enhances and sustains drug exposure in eye tissues for one week after single topical administration. Timolol maleate, a widely used antiglaucoma drug, a potent noncardioselective ¿-adrenoceptor blocking agent, will be used as a model drug. We will determine whether uptake and/or retention of the nanoparticles/drug is enhanced in eye tissues by cHDNP using a rabbit model. Furthermore, we will determine whether nanoparticle entry into the subconjunctival space contributes to sustained drug delivery. Aim 3: To determine whether cHDNP exerts sustained drug efficacy in vivo with once a week topical administration, without exerting any adverse effects on the eye. We will initially identify a cHDNP formulation capable of sustained, statistically significant reduction of IOP in a normotensive rabbit model and a chronic ocular hypertensive rat model following repeated administrations. Safety studies will also be conducted in rat and rabbit models. Developing long-acting antiglaucoma drug dosage formulations represents an unmet clinical need for improving long-term patient compliance. The proposed topical nanoparticle system has great promise in sustaining drug delivery and antiglaucoma effects longer than existing topical formulations. Such a system will profoundly improve patient compliance and adherence and reduce health care costs and societal burdens associated with glaucoma treatment.

描述（由适用提供）：青光眼是世界上视觉障碍和失明的主要原因。长期维持低眼压（IOP）水平是青光眼患者预防或减少渐进视力丧失的唯一可靠解决方案。该项目的目的是开发一个先进的局部递送系统，以增加眼部生物利用度，并维持治疗效率，以减少患者不合规，这是青光眼治疗中的主要问题。我们已经开发了一种新型的混合树状聚合物水凝胶纳米颗粒平台（HDNP），该平台可以被制造成眼科水凝胶配方，以递送亲水性和疏水性抗激瘤瘤药物。一次性局部插入带来了4天的持续降低降低效果。该混合平台具有适应性的结构和特性，使药物释放动力学和剂量方案的微调可能是最佳和个性化治疗的。该赠款应用的中心假设是，在可以使用无铜点击化学和我们的新颖HDNP平台开发单次剂量后，局部应用的纳米颗粒公式能够维持IOP减少一周。为了检验这一假设，我们提出以下三个目标。目标1：开发可单击的树枝状聚合物水凝胶和HDNP（CHDNP），具有增强的粘膜粘附，增强的细胞进入和细胞毒性降低。我们将通过避免使用光引发剂并产生有害的自由基，从而开发出一种新颖的，高效的单击树状聚合物水凝胶。我们将在结构和综合中优化杂化纳米颗粒，以增强粘膜粘附，增强细胞进入和细胞毒性的降低。 AIM 2：确定CHDNP是否在一次局部给药后是否增强并维持眼组织中的药物暴露一周。 Timoolol Maleate是一种广泛使用的抗肿瘤药物，一种潜在的非心脏选择性� -adrenoceptor阻断剂，将被用作模型药物。我们将使用兔模型来确定是否通过CHDNP在眼组织中增强了纳米颗粒/药物的摄取和/或保留。此外，我们将确定纳米颗粒是否进入膜下空间是否有助于持续的药物输送。目标3：确定CHDNP是否每周局部给药一次在体内持续的药物效率，而不会对眼睛产生任何不利影响。我们最初将确定能够在重复施用后，在正常的兔模型和慢性眼高血压大鼠模型中持续，统计学上显着降低IOP的CHDNP公式。安全研究还将在大鼠和兔模型中进行。开发长效抗肿瘤剂量剂量配方是改善长期患者依从性的临床需求。拟议的局部纳米颗粒系统在维持药物输送和抗肿瘤瘤作用方面具有巨大的希望，其影响比现有拓扑配方更长。这样的系统将极大地改善患者的依从性和依从性，并降低与青光眼治疗相关的医疗保健成本和社交伯伦斯。