Ultrasound-Enhanced Delivery of Medications to the Eye

超声增强药物眼部给药 项目摘要 该项目的目标是开发一种安全有效的交付手段 穿过眼壁的大分子药物用于治疗疾病，特别是与年龄有关的疾病 黄斑变性(AMD)。AMD是一种进行性眼病，影响多达1500万人。 它是65岁以上成年人失明和失明的头号原因。 几种有希望的大分子药物现在正在接受评估 AMD的治疗。因为眼球的外壳(巩膜)相对不能渗透 高分子量药物，眼内注射是最广泛使用的手段来完成 输送到视网膜和脉络膜。因此，将大分子药物输送到 眼球必须每隔几周通过玻璃体内注射来完成，发生 并发症(感染、视网膜脱离、眼压升高)增加 累积起来。因此，大分子药物的非侵入性输送方法有 非常感兴趣。在过去，超声波已被证明能够使组织 对大分子具有渗透性。我们建议研究超声对不同疾病的影响。 荧光标记分子跨巩膜转运的频率、强度和持续时间 (右旋糖苷)进入兔眼。我们将使用分子量为10-kDa，70-kDa和 500 kDa，每个都有不同波长的荧光标签。(现在药物的相对分子质量 用于治疗AMD的蛋白质通常约为150 kDa。)我们将进行两个系列的 实验，第一个涉及使用非聚焦的20 kHz超声源，第二个 利用一种由两个900 kHz共焦环组成的新型超声设备。这个设备 提供了允许聚焦和避免潜在敏感结构的优点 如角膜、晶状体和黄斑。通过以略有不同的速度驱动这两个元素 频率，在与频差对应的较低频率上的‘节拍’是 已生成。我们将使用这个设备将兔眼暴露在20、60和900 kHz的超声波中。 然后，将荧光标记的右旋糖苷混合物注射到结膜外 环球网。治疗24小时后，将对眼睛进行固定、冰冻切片和检查 共聚焦显微镜。我们将可视化分子在巩膜、脉络膜内的分布 和视网膜来评估运输并描述可能发生的任何组织损伤 显微镜观察和细胞凋亡检测。

Ultrasound-Enhanced Delivery of Medications to the Eye Project Summary The objective of this project is the development of a safe and effective means to deliver macromolecular drugs across the wall of the eye for treatment of disease, especially age-related macular degeneration (AMD). AMD is a progressive eye disease affecting as many as 15 million Americans and is the number one cause of vision loss and legal blindness in adults over 65 years of age in the U.S. Several promising macromolecular drugs are now being evaluated for treatment of AMD. Because the outer shell of the eye (the sclera) is relatively impermeable to high molecular weight drugs, intraocular injection is the most widely used means to accomplish delivery to the retina and choroid. Consequently, delivery of macromolecular medications into the eye must be accomplished by intravitreal injections every few weeks, with the occurrence of complications (infection, retinal detachment, increased intraocular pressure) increasing cumulatively. For this reason, non-invasive methods for delivery of macromolecular drugs are of great interest. Ultrasound has in the past been shown to be capable of making tissues more permeable to macromolecules. We propose to investigate the effect of ultrasound of various frequencies, intensities and durations on transscleral transport of fluorescently labeled molecules (dextrans) into the rabbit eye. We will use dextrans of molecular weights of 10-kDa, 70-kDa and 500-kDa, each with a different wavelength fluorescent label. (Molecular weights of drugs now used for treatment of AMD are typically around 150-kDa.) We will conduct two series of experiments, the first involving use of an unfocused 20-kHz ultrasound source and the second utilizing a novel ultrasound device consisting of two 900-kHz confocal annuli. This device provides the advantage of allowing focusing and avoidance of potentially sensitive structures such as the cornea, lens and macula. By driving the two elements at slightly different frequencies, `beats' at a lower frequency corresponding to the frequency difference are generated. We will expose the rabbit eyes to 20-, 60- and 900-kHz ultrasound using this device. A mixture of the fluorescently labeled dextrans will then be injected subconjunctivally outside the globe. Twenty-four hours after treatment, the eyes will be fixed, cryosectioned and examined by confocal microscopy. We will visualize the distribution of the molecules within the sclera, choroid and retina to evaluate transport and characterize any tissue damage that might have occurred microscopically and by apoptosis assays.