Hybrid Nanoparticles for Glaucoma

描述（由申请人提供）：青光眼是世界上视力损害和失明的主要原因。 长期维持低眼内压（IOP）水平是青光眼患者预防或减少进行性视力丧失的唯一行之有效的解决方案。 本项目的目的是开发一种先进的局部给药系统，以增加眼部生物利用度，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。 我们已经开发了一种新型的混合树枝状聚合物水凝胶纳米颗粒平台（HDNP），它可以被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。 一次性局部滴注可持续4天降低IOP。 这种混合平台具有适应性强的结构和性能，使得药物释放动力学和剂量方案的微调成为可能，以实现最佳和个性化治疗。 该授权申请的中心假设是，可以使用无铜点击化学和我们的新型HDNP平台开发能够在单次给药后维持IOP降低一周的局部应用的纳米颗粒制剂。 为了验证这一假设，我们提出了以下三个目标。 目的1：开发具有增强的粘膜粘附、增强的细胞进入和降低的细胞毒性的可点击树枝状聚合物水凝胶和HDNP（cHDNP）。 我们将通过避免使用光引发剂和产生有害的自由基来开发一种新型的、高效的可点击树枝状聚合物水凝胶。 我们将在结构和组成上优化混合纳米颗粒，以增强粘膜粘附，增强细胞进入和降低细胞毒性。 目的2：确定cHDNP在单次局部给药后是否增强和维持眼组织中的药物暴露一周。 马来酸噻吗洛尔是一种广泛使用的抗青光眼药物，一种有效的非心脏选择性β-肾上腺素受体阻滞剂，将被用作模型药物。 我们将使用兔模型确定cHDNP是否增强了纳米颗粒/药物在眼组织中的摄取和/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的药物递送。 目标3：为了确定cHDNP是否在每周一次局部给药的情况下在体内发挥持续的药物功效，而不会对眼睛产生任何不良影响。 我们将首先鉴定一种cHDNP制剂，其能够在重复给药后在正常血压兔模型和慢性高眼压大鼠模型中持续地、统计学上显著地降低IOP。 还将在大鼠和家兔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患者长期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维持药物递送和抗青光眼作用方面比现有的局部制剂具有更长的前景。 这种系统将极大地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保健成本和社会负担。

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.