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（由申请人提供）：青光眼是世界上视力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进行性视力丧失的唯一经过验证的解决方案。 该项目的目标是开发一种先进的局部给药系统，以提高眼部生物利用度并维持治疗效果，作为减少患者不依从性（青光眼治疗中的主要问题）的一种手段。 我们开发了一种新型混合树枝状聚合物水凝胶纳米颗粒平台（HDNP），可将其制成眼科水凝胶制剂，以提供亲水性和疏水性抗青光眼药物。 一次性局部滴注，降眼压效果持续4天。 该混合平台具有适应性强的结构和特性，可以微调药物释放动力学和剂量方案，以实现最佳和个性化的治疗。 这项拨款申请的中心假设是，可以使用无铜点击化学和我们的新型 HDNP 平台开发一种局部应用的纳米颗粒制剂，该制剂能够在单次给药后维持一周的眼压降低。 为了检验这一假设，我们提出以下三个目标。 目标 1：开发可点击的树枝状聚合物水凝胶和 HDNP (cHDNP)，以增强粘膜粘附、增强细胞进入并降低细胞毒性。 我们将通过避免光引发剂的使用和有害自由基的产生来开发一种新型、高效的可点击树枝状聚合物水凝胶。 我们将从结构和组成上优化混合纳米颗粒，以增强粘膜粘附、增强细胞进入并降低细胞毒性。 目标 2：确定 cHDNP 在单次局部给药后一周内是否会增强并维持眼组织中的药物暴露。 马来酸噻吗洛尔是一种广泛使用的抗青光眼药物，是一种有效的非心脏选择性β-肾上腺素受体阻断剂，将被用作模型药物。 我们将使用兔子模型确定 cHDNP 是否增强眼组织中纳米颗粒/药物的吸收和/或保留。 此外，我们将确定纳米颗粒进入结膜下空间是否有助于持续药物输送。 目标 3：确定 cHDNP 每周一次局部给药是否能在体内发挥持续的药效，而不会对眼睛产生任何不良影响。 我们将首先确定一种 cHDNP 制剂，在重复给药后能够在正常血压兔模型和慢性高眼压大鼠模型中持续、统计显着降低 IOP。 还将在大鼠和兔子模型中进行安全性研究。 开发长效抗青光眼药物剂型代表了改善长期患者依从性的未满足的临床需求。 所提出的局部纳米颗粒系统在比现有局部制剂更持久地维持药物输送和抗青光眼效果方面具有巨大前景。 这样的系统将极大地提高患者的依从性和依从性，并减少与青光眼治疗相关的医疗保健成本和社会负担。