Hybrid Nanoparticles for Glaucoma

用于治疗青光眼的混合纳米颗粒

• 批准号: 8927646
• 负责人: UDAY B KOMPELLA
• 金额: $ 41.4万
• 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/8927646
• 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; 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; personalized medicine; prevent; 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(申请人提供)：青光眼是世界上导致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被证实的解决方案。本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的一种手段，这是青光眼治疗中的主要问题。我们开发了一种新型的杂化树枝状大分子水凝胶纳米颗粒平台(HDNP)，它可以制成眼用水凝胶配方，同时提供亲水性和疏水性抗青光眼药物。一次性局部滴注，持续4天的降眼压效果。这种混合平台具有适应性的结构和性能，使得微调药物释放动力学和剂量方案成为可能，以实现最佳和个性化的治疗。这项资助申请的中心假设是，使用无铜点击化学和我们的新型HDNP平台，可以开发出一种局部应用的纳米颗粒配方，能够在单次给药后持续一周的眼压降低。为了验证这一假设，我们提出了以下三个目标。目的1：研制可点击的树枝状大分子水凝胶和HDNP(CHDNP)，增强粘附性，增强细胞进入，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的、高效的可点击树枝状大分子水凝胶。我们将在结构和成分上优化杂化纳米颗粒，以增强粘附性、增强细胞进入和降低细胞毒性。目的2：确定单次局部给药一周后，cHDNP是否增加和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�肾上腺素能受体阻滞剂，将被用作模型药物。我们将使用兔模型来确定cHDNP是否增强了纳米粒/药物在眼组织中的摄取和/或滞留。此外，我们将确定纳米颗粒进入结膜下间隙是否有助于持续的药物输送。目的：在不对眼睛产生不良影响的情况下，每周给药一次，以确定cHDNP是否在体内发挥持续的药效。我们将首先在正常血压兔模型和慢性高眼压大鼠模型中确定一种能够在重复给药后持续、统计显著降低眼压的cHDNP配方。安全性研究也将在大鼠和兔子模型中进行。开发长效抗青光眼药物剂量配方代表着提高患者长期依从性的临床需求尚未得到满足。建议的局部纳米颗粒系统在维持药物输送和抗青光眼效果方面比现有的局部制剂有很大的希望。这样的系统将大大提高患者的依从性和依从性，并降低与青光眼治疗相关的医疗成本和社会负担。