Novel ocular hypotensive and neuroprotective microparticle-based hydrogen sulfide delivery system

新型降眼压和神经保护微粒硫化氢输送系统

• 批准号: 10359973
• 负责人: CATHERINE A OPERE
• 金额: $ 43.65万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10359973
• 关键词: Address; Anterior; Aqueous Humor; Attenuated; Binding Proteins; Blindness; Cardiovascular system; Characteristics; Ciliary Body; Clinical; Cornea; Cystathionine; Cystathionine beta-Synthase; Cysteine; Diffusion; Disease; Drainage procedure; Drug Delivery Systems; Emulsions; Environment; Enzymes; Eye; Family suidae; Formulation; Funding; Gases; Gel; Glaucoma; Glutamates; Health Occupations; Human; Hydrogen Sulfide; Hydrolysis; In Situ; In Vitro; Injectable; Injections; Iris; Lead; Light; Link; Location; Lyase; Metabolism; Methods; Modeling; Modification; Nature; Nerve Degeneration; Neural Retina; Neurons; Neuropathy; New Zealand; Ocular Hypotension; Ointments; Oryctolagus cuniculus; Osmolar Concentration; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Actions; Pharmacology; Pharmacy Schools; Physiologic Intraocular Pressure; Play; Posterior eyeball segment structure; Primates; Process; Research; Retina; Retinal Degeneration; Role; Signal Transduction; Signaling Molecule; Smooth Muscle; Structure of retinal pigment epithelium; Sulfur; Surface; Suspensions; Syringes; System; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Topical application; Training; Translations; Uvea; Vision; absorption; antiglaucoma drug; aqueous; base; biomaterial compatibility; career; controlled release; corneal epithelium; design; effective therapy; experimental study; in vivo; neuroprotection; neurotransmission; normotensive; novel; novel therapeutics; ocular hypotensive; ocular surface; protective effect; retinal ganglion cell degeneration; retinal neuron; success; targeted treatment; treatment strategy; undergraduate student

Glaucoma is one of the leading causes of irreversible blindness worldwide. In the USA, glaucoma is projected to increase from 2.7 million in 2010 to 6.3 million by 2050. Glaucoma is characterized by progressive degeneration of retinal ganglion cells with corresponding irreversible deficits in visual function, and in a majority of patients, elevation in intraocular pressure (IOP). While current medication therapies target reduction in IOP, so far, a clinically effective treatment that exerts both ocular hypotensive and retinal neuroprotective actions remain elusive, prompting intense search for potential therapeutic options. There is evidence that hydrogen sulfide (H2S), a colorless odoriferous gas, attenuates IOP in normotensive rabbits and exerts neuroprotection in retinal neurons, suggesting a potential superior application in management of glaucoma. However, the full clinical potential of H2S cannot be realized without an efficient method for its delivery into ocular tissues. Indeed, the convenient and conventional topical ocular delivery approaches (e.g. solutions, suspensions, emulsions, ointments, etc) are not appropriate because ocular surface is predominantly aqueous, and most H2S- donors release the gas in aqueous medium. Additionally, it cannot provide a low sustained level of H2S, a critical requisite for therapeutic application. The main objective of this proposal, therefore, is to design a novel drug delivery system capable of supplying H2S into the anterior uvea and retina at a sustained rate. We hypothesize that subconjunctival injection of a novel GYY4137 (H2S donor)-loaded microparticle-based in situ gelling delivery system can release H2S at a sustained rate with corresponding reduction in IOP in the anterior segment and protection of retinal neurons in the posterior segment. There is evidence that some subconjunctivally administered drugs can gain access to the posterior segment of the eye, in vivo. Thus, due to its gaseous nature, it is conceivable that H2S released on subconjunctival administration can simultaneously gain access into the anterior segment for reduction of IOP and the posterior segment for retinal neuroprotection. Experiments in this project have therefore been designed to address the following questions: (a) Can GYY4137 loaded microparticle-based, in situ gel forming delivery system sustain H2S in the anterior and posterior segments within a pharmacological range? (b) What are the release and distribution profiles of H2S from the novel formulation in ocular tissues, in vitro and in vivo? (c) Can the novel formulation induce and sustain a reduction in IOP and mitigate retinal neurodegeneration following subconjunctival injection? We anticipate that satisfactory completion of these aims will not only demonstrate the potential application of H2S in ocular therapy and reveal strategies to overcome barriers to delivery of a wide range of H2S-donors to ocular tissues.

青光眼是世界范围内不可逆失明的主要原因之一。在美国，预计会出现青光眼 从2010年的270万增加到2050年的630万。青光眼的特征是进行性 视网膜神经节细胞变性，伴有相应的不可逆的视觉功能缺陷， 的患者，眼内压（IOP）升高。虽然目前的药物治疗以降低IOP为目标， 迄今为止，一种临床上有效的治疗，发挥眼睛肿胀和视网膜神经保护作用， 仍然难以捉摸，促使人们积极寻找潜在的治疗方案。有证据表明氢 硫化物（H2S）是一种无色有气味的气体，可降低正常血压兔的IOP，并对 视网膜神经元，提示在青光眼管理中的潜在上级应用。但全面 如果没有将H2S递送到眼组织中的有效方法，就不能实现H2S的临床潜力。 事实上，方便和常规的局部眼部递送方法（例如溶液，悬浮液， 乳剂、软膏剂等）是不合适的，因为眼表面主要是水性的，并且大多数H2S- 供体在水介质中释放气体。此外，它不能提供低的持续水平的H2S，这是一个关键的问题。 治疗应用的必要条件。因此，本提案的主要目标是设计一部小说， 能够以持续的速率将H2S供应到前葡萄膜和视网膜中的药物递送系统。我们 假设结膜下注射新GYY 4137（H2S供体）-负载的基于微粒 原位胶凝递送系统可以以持续速率释放H2S，并相应降低IOP 保护后段视网膜神经元。有证据表明 一些结膜下给药的药物可以在体内进入眼睛的后段。因此，在本发明中， 由于其气体性质，可以想象，结膜下给药时释放的H2S可以 同时进入前段以降低IOP，进入后段以降低视网膜压。 神经保护因此，本项目的实验旨在解决以下问题： (a)GYY 4137装载的微粒基原位凝胶形成递送系统能否在前部和后部维持H2S， 后节在药理学范围内？(b)H2S的释放和分布概况是什么 从新的配方在眼组织，在体外和体内？(c)新的配方能诱导和维持 结膜下注射后IOP降低并减轻视网膜神经变性？我们预计 这些目标的圆满完成不仅将证明H2S在眼科治疗中的潜在应用 并揭示了克服将多种H2S供体递送至眼组织的障碍的策略。