Ultrasound-Enhanced Ocular Drug Delivery

描述（由申请人提供）：该提案重点关注治疗性超声在改善眼部药物递送中的应用。拟议的研究将解决一个重要的临床问题，因为在眼睛内的治疗部位通常很难达到治疗水平的药物。角膜是递送眼科药物的主要途径，其充当生物屏障，并且通常少于10%的所施用的药物可以渗透到眼睛的前部，而几乎没有渗透到眼睛的后部。我们之前已经证明，将兔角膜暴露于治疗性超声可以导致高达10倍的药物模拟化合物进入眼睛，而角膜组织的变化很小。我们现在建议研究可以通过超声增强药物递送来解决的临床相关问题，例如促进抗生素和抗炎药物的递送以治疗眼部感染和炎症。我们的主要目标是找到超声参数，可以提供临床相关的药物输送到眼睛的增强，同时只产生轻微的和可逆的变化，在眼睛组织。首先，我们建议开发一种理论模拟模型，该模型可以预测在各种参数（频率，强度，持续时间和占空比）下应用超声之前和之后，角膜对眼部药物（不同亲水性和分子大小）的渗透性。然后，我们将开发用于药物输送的治疗性超声设备，该设备将允许完全控制不同的超声参数。这些器械将在体外和体内实验中进行测试。实验将利用白化病兔的眼睛，这是眼部药物递送的常用动物模型。将通过使用标准方法测量穿过暴露于超声或假处理（无超声应用）的角膜的药物量来确定超声应用于眼部药物递送的可行性。治疗安全性将通过在治疗后即刻和治疗后14天内对超声诱导的角膜结构和屏障特性变化进行眼科和组织学观察来确定。我们的长期目标是开发一种廉价，快速和微创的药物输送超声方法，可应用于门诊或医院，使药物渗透到感染/炎症的眼组织中，并以足够的浓度输送药物，以对抗细菌，真菌或病毒，然后才产生永久性视力丧失。 公共卫生相关性：严重的眼部感染/炎症通常会导致角膜瘢痕导致视力丧失。我们相信，治疗性超声波可以提供一种廉价且相对简单的方法来改善药物进入眼睛的输送。与目前使用的方法相比，该方法可以允许更快地治疗角膜感染/炎症，从而潜在地防止眼睛组织的永久性损伤。

DESCRIPTION (provided by applicant): This proposal focuses on the application of therapeutic ultrasound in improving ocular drug delivery. The proposed research will address an important clinical problem since it is often difficult to achieve therapeutic levels of drugs at the treatment sites inside the eye. Cornea, which is a dominant route for delivery of ophthalmic drugs, acts as a biological barrier and usually less than 10% of the applied drug can penetrate into the front of the eye with virtually no penetration into the back of the eye. We have previously shown that exposing rabbit cornea to therapeutic ultrasound can lead to up to 10 times more delivery of a drug-mimicking compound into the eye, with only minimal changes in the corneal tissues. We are now proposing to work on clinically relevant problems that can be addressed with ultrasound-enhanced drug delivery, such as promoting delivery of antibiotics and anti-inflammatory drugs for treatment of eye infections and inflammations. Our main objective is to find ultrasound parameters that can provide clinically relevant enhancement of the delivery of medications into the eye, while producing only minor and reversible changes in the eye tissues. First, we are proposing to work on the development of a theoretical simulation model which can predict the permeability of the cornea for ocular medications (of different hydrophilicity and molecular size), before and after application of ultrasound at various parameters (frequency, intensity, duration, and duty cycle). We will then develop therapeutic ultrasound devices for drug delivery that will allow complete control of different ultrasound parameters. These devices will be tested in in-vitro and in-vivo experiments. The experiments will utilize eyes of albino rabbits, which are a usual animal model for ocular drug delivery. Feasibility of ultrasound application in ocular drug delivery will be determined by using standard methods for measurement of the amounts of drug that crosses the cornea which is exposed to ultrasound or sham-treated (no ultrasound application). Safety of the treatment will be determined by using ophthalmic and histological observations of ultrasound-induced changes in the corneal structure and barrier properties, immediately after the treatment and up to 14 days after the treatment. Our long-term goal is to develop an inexpensive, fast and minimally-invasive ultrasound method for drug delivery that can be applied in an outpatient clinic or in the hospital to allow medications to penetrate into eye tissues with infection/inflammation and deliver the drugs at a sufficient concentration to fight bacteria, fungi or viruses before they produce a permanent loss in vision. Public Health Relevance: Major eye infections/inflammations often result in the loss of vision due to corneal scarring. We believe that therapeutic ultrasound can offer an inexpensive and relatively simple method for improved delivery of medications into the eye. This method may allow faster treatment of corneal infections/inflammations as compared to currently used methods, thus potentially preventing permanent damage of the eye tissues.