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

基本信息

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
项目类别：
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

项目摘要

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.

青光眼是全世界不可逆转失明的主要原因之一。在美国，青光眼预计到 2050 年，青光眼患者将从 2010 年的 270 万增加到 630 万。视网膜神经节细胞变性，并伴有相应的不可逆的视觉功能缺陷，并且大多数患者的眼压（IOP）升高。虽然目前的药物治疗目标是降低眼压，迄今为止，这是一种临床上有效的治疗方法，可发挥降眼压和视网膜神经保护作用仍然难以捉摸，促使人们大力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，可降低血压正常的兔子的眼压，并在以下情况下发挥神经保护作用：视网膜神经元，表明在青光眼治疗中具有潜在的优越应用。然而，完整的如果没有有效的方法将 H2S 输送到眼组织中，就无法实现 H2S 的临床潜力。事实上，方便且传统的局部眼部给药方法（例如溶液、混悬液、乳剂、软膏等）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，它无法提供持续低水平的 H2S，而 H2S 是一种关键物质。治疗应用的必要条件。因此，该提案的主要目标是设计一种新颖的能够以持续的速率将 H2S 供应到前葡萄膜和视网膜的药物输送系统。我们假设结膜下注射一种新型 GYY4137（H2S 供体）负载的基于微粒的原位胶凝输送系统可以持续释放 H2S，并相应降低 IOP 前段的视网膜神经元的保护和后段视网膜神经元的保护。有证据表明一些结膜下给药的药物可以在体内进入眼后段。因此，由于其气态性质，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眼压，并进入后段以降低视网膜神经保护。因此，该项目的实验旨在解决以下问题： (a) GYY4137 负载的基于微粒的原位凝胶形成输送系统能否在前部和后部维持 H2S 后段在药理学范围内吗？ (b) H2S 的释放和分布概况如何来自眼组织的新颖配方，体外和体内？ (c) 新配方能否诱导和维持结膜下注射后降低眼压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在眼部治疗中的潜在应用并揭示了克服向眼组织输送各种 H2S 供体的障碍的策略。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Comparison of colorimetric, spectroscopic and electrochemical techniques for quantification of hydrogen sulfide.

硫化氢定量的比色法、光谱法和电化学技术的比较。

DOI：
发表时间：
2024-02
期刊：
影响因子：
2.7
作者：
Mhatre, Susmit;Rai, Anjali;Ali, Hatim;Patil, Akash;Singh, Neetu;Verma, Richa;Auden, John;Chandler, Cole;Dash, Alekha;Opere, Catherine;Singh, Somnath
通讯作者：
Singh, Somnath