Ultrasound-enhanced corneal drug delivery

超声增强角膜药物输送

• 批准号: 9247633
• 负责人: Jay Michael Stewart
• 金额: $ 39.16万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247633
• 关键词: Adverse effects; Aftercare; Anterior; Antibiotics; Antifungal Agents; Attention; BODIPY; Clinical; Clinical Trials; Clinical effectiveness; Collagen; Confocal Microscopy; Cornea; Corneal Diseases; Corneal Endothelium; Corneal Stroma; Corneal Ulcer; Custom; Debridement; Defect; Development; Diffusion; Drug Delivery Systems; Endothelial Cells; Endothelium; Epithelial; Epithelium; Excision; Eye; Eye Banks; Eyedrops; Fluorescence Microscopy; Formulation; Frequencies; Functional disorder; Fusarium; Geometry; Goals; Histologic; Histology; Human; In Vitro; Infection; Injection of therapeutic agent; Keratitis; Keratoconus; Keratoplasty; Label; Measures; Medical; Methods; Microbubbles; Modeling; Organism; Oryctolagus cuniculus; Outcome; Pain; Patient Care; Patients; Penetration; Permeability; Pharmaceutical Preparations; Photosensitization; Physicians; Physiologic pulse; Postoperative Pain; Procedures; Quality Control; Radiation; Residual state; Resort; Riboflavin; Risk; Safety; Site; Structure; Technology; Temperature; Testing; Therapeutic; Time; Tissues; Topical agent; Topical application; Transducers; Treatment Efficacy; Treatment Protocols; Ultrasonography; Ultraviolet Rays; Vancomycin; Viscosity; Voriconazole; absorption; acute toxicity; antimicrobial; cell injury; clinically relevant; corneal epithelium; crosslink; effective therapy; experimental study; improved; in vitro Model; in vivo; innovation; interest; novel therapeutics; time use; ultraviolet; uptake

Project Summary/Abstract Medical treatment of corneal disease depends upon effective penetration of topical agents into the cornea. In many instances the corneal epithelium serves as a barrier to diffusion, while in cases with epithelial defects drug penetration through the stroma can be unreliable or inadequate. This study proposes to evaluate ultrasound technology to enhance the permeability of the cornea and promote corneal uptake of selected topical medications – riboflavin, vancomycin, and voriconazole. Riboflavin is used in corneal cross-linking, a treatment for diseases of corneal weakening that stiffens the tissue through the interaction of riboflavin with ultraviolet energy. Since the epithelium is generally removed to achieve adequate riboflavin penetration in the cornea, subjecting patients to pain and the risk of infection, there is a need for an innovation that can increase stromal riboflavin uptake while avoiding epithelial removal. Since riboflavin is autofluorescent, it can be quantified in the cornea using confocal microscopy. Vancomycin-BODIPY is a labeled fluorescent version of the highly clinically relevant antibiotic and can also be detected in the cornea. It is a larger molecule and will therefore provide additional information in optimizing ultrasound parameters for generalizability to other drugs. A distinct but pressing clinical need relates to the treatment of fungal corneal ulcers, which frequently require excision of infected tissue, due in part to poor delivery of antifungal agents, such as voriconazole, into the deep stroma. We have shown a significant increase in penetration of riboflavin into the cornea following ultrasound exposure without epithelial debridement, and in preliminary experiments we observed an impressive penetration of vancomycin-BODIPY into the stroma without epithelium, as well as an improved riboflavin penetration at lower ultrasound settings by optimizing the viscosity of the solution formulation and generating microbubbles. The goal of this study therefore is to identify clinically useful ultrasound treatment regimes for riboflavin, vancomycin, and voriconazole delivery to improve patient care in a range of corneal conditions. In Aim 1, we will optimize ultrasound treatment parameters including frequency, intensity, duty cycle, and treatment time using an in vitro model of riboflavin and vancomycin-BODIPY application to the rabbit cornea, measuring drug permeation with confocal microscopy. In Aim 2, we will quantify the corneal delivery in vivo using the most effective settings identified in Aim 1. In Aim 3, we will test the ability of ultrasound to improve the delivery of voriconazole to the corneal stroma in a live rabbit model of Fusarium keratitis by quantifying the residual organisms in the cornea after treatment. In Aim 4 the safety of a clinically effective treatment regimen will be evaluated through clinical and histologic examination of the cornea at several time points with particular attention to endothelial cell damage or loss. The results can serve as the basis for clinical trials in patients undergoing cross-linking or with recalcitrant corneal infections and will provide proof of concept to investigate this technology for other applications, such as delivery of novel therapies for endothelial cell dysfunction.

项目摘要/摘要 角膜疾病的医学治疗取决于局部局部剂在角膜中的有效渗透。 许多实例角膜上皮是扩散的障碍，而在上皮缺陷的情况下 通过基质的药物穿透可能是不可靠的或不足的。这项研究提案要评估 超声技术以增强角膜的渗透性并促进角膜的吸收 局部药物 - 核黄素，万古霉素和伏立康唑。核黄素用于角膜交联， 核黄素与 紫外线。由于上皮通常被去除以实现足够的核黄素渗透 角膜，使患者遭受疼痛和感染的风险，需要创新可以增加 基质核黄素吸收，同时避免上皮去除。由于核黄素是自动荧光的，因此可以是 使用共聚焦显微镜在角膜中定量。万古霉素 - 博迪比是标记的荧光版本 高度相关的抗生素，也可以在角膜中检测到。它是一个较大的分子，将会 因此，提供了优化超声参数的其他信息，以使其对其他药物的普遍性。 一种明显但紧迫的临床需求与真菌角膜溃疡的治疗有关，这通常需要 检查受感染的组织，部分原因是抗真菌剂（例如伏立康唑）进入深处 基质。我们已经显示出超声后核黄素渗透到角膜的渗透显着增加 无上皮调试的暴露，在初步实验中，我们观察到了令人印象深刻的 万古霉素 - 博迪比渗透到没有上皮的基质中，以及改善的核黄素 通过优化溶液配方和生成的溶液的粘度，在较低的超声设置下穿透 微泡。因此，这项研究的目的是确定临床上有用的超声治疗方案 核黄素，万古霉素和伏立康唑的递送，以在一系列角膜状况下改善患者护理。 AIM 1，我们将优化超声处理参数，包括频率，强度，占空比和 使用核黄素的体外模型和万古霉素 - 博迪普在兔角膜上的治疗时间， 用共聚焦显微镜测量药物渗透。在AIM 2中，我们将在体内量化角膜递送 使用AIM 1中确定的最有效的设置。在AIM 3中，我们将测试超声改进的能力 通过量化的 治疗后角膜中的残留生物。在AIM 4中，临床有效治疗方案的安全性 将通过几个时间点对角膜的临床和组织学检查进行评估 注意内皮细胞损伤或损失。结果可以作为患者临床试验的基础 进行交联或与顽固的角膜感染，并将提供概念证明以调查 这项用于其他应用的技术，例如用于内皮细胞功能障碍的新型疗法。