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。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交树状聚合物水凝胶纳米颗粒平台（HDNP），它可以被制造成一种眼科水凝胶配方，以传递亲水性和疏水性抗青光眼药物。一次性局部滴注，可持续4天的降眼压效果。该混合平台具有适应性强的结构和性能，使药物释放动力学和剂量方案的微调成为可能，从而实现最佳和个性化的治疗。这项资助申请的中心假设是，局部应用的纳米颗粒配方能够在单次给药后维持一周的IOP降低，可以使用无铜点击化学和我们新颖的HDNP平台开发。为了验证这一假设，我们提出以下三个目标。目的1：开发可点击的树突水凝胶和HDNP (cHDNP)，增强黏附，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，开发一种新型、高效、可点击的树状聚合物水凝胶。我们将在结构和成分上优化混合纳米颗粒，以增强黏附，增强细胞进入，降低细胞毒性。目的2：确定单次局部给药后一周内cHDNP是否增强和维持眼组织的药物暴露。马酸替马洛尔是一种广泛使用的抗青光眼药物，是一种强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。我们将通过兔模型确定cHDNP是否能增强纳米颗粒/药物在眼组织中的吸收和/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的药物递送。目的3：确定每周一次外用cHDNP是否能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。我们将首先确定一种cHDNP配方，能够在正常血压的兔子模型和慢性眼压高的大鼠模型中持续地、统计学上显著地降低IOP。安全性研究也将在大鼠和家兔模型中进行。开发长效抗青光眼药物剂量配方是提高患者长期依从性的临床需求尚未得到满足。所提出的局部纳米颗粒系统在维持药物传递和抗青光眼效果方面比现有的局部配方有很大的希望。这样的系统将大大提高患者的依从性和依从性，并减少与青光眼治疗相关的医疗费用和社会负担。

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.