DEVELOPMENT OF A NEW CLASS OF ULTRASOUND CONTRAST AGENTS

该项目的长期目标是开发和评估新的 用于诊断超声的可注射造影剂。为实现这一 目的是研究将建立在第一次获得的专业知识， 授予期，其中表明，海藻酸盐的离子型凝胶化 可用于封装空气以产生稳定的微泡， 在体外和体内均产生回声。 问题仍然是减少 微泡的直径小于6微摩尔，以允许不受阻碍地通过 穿过肺床在藻酸盐研究期间， 开发了造影剂。它由表面稳定的 通过超声处理以下物质的含水混合物制备的微泡 特别是表面活性剂。体外和体内的初步研究 表明这种新药物具有很大临床应用潜力。一个关键 这种新制剂的特点是80%的气泡直径为 小于6微摩尔。 造影剂的开发将沿着两条战线进行。藻酸盐 系统仍然被认为是有价值的，主要是因为聚合物- 涂覆的气泡提供了长期稳定性的优点， 藻酸盐是水凝胶，是高度柔性和可变形的， 对压力具有良好的抵抗力，例如在 心最近有报道说，使用雾化器来生产 微米尺寸范围内的藻酸盐微胶囊， 体内疫苗递送。重点将放在适应这一新的 该技术包括在微米尺寸的胶囊中截留气体。在 此外，还将研究振动板液滴发生器的使用， 同样的目的。微米级微泡的成功生产将 随后进行广泛的体内和体外表征， 与回声有关的试剂（反向散射和衰减 系数）、稳定性（储存期间和体内注射后） 和生物相容性。 在进行这些研究的同时， 表面活性剂稳定的微泡。本发明的制剂已经被 以稳定性、衰减和反向散射为特征的 体外系数计划进行进一步的动物研究， 体内稳定性和作为造影剂的强度。此外，重要的是， 调查正在发生的稳定机制， 表面活性剂/空气界面在分子水平上。这将使我们能够 定义表面活性剂分子所需的结构性质， 稳定气泡，这反过来将使我们能够扩大范围 我们可以用在这种药剂中的分子。此外，它将 允许选择最佳的分子结构， 稳定涉及朗缪尔槽实验的物理/化学研究 将用于探测表面活性剂在空气中的分子相互作用- 水界面 开发一种有效的超声造影剂将是非常重要的 对医疗保健意义重大。超声波是一种相对便宜，安全， 诊断程序，不仅是非侵入性的，但也产生真实的 身体内部结构的时间图像。

The long term objective of this project is to develop and evaluate new injectable contrast agents for use in diagnostic ultrasound. Towards this aim the research will build upon expertise acquired during the first granting period, where it was shown that ionotropic gelation of alginate can be used to encapsulate air to produce stable microbubbles that are echogenic both in vitro and in vivo. The problem remains to reduce the microbubbles' diameter to below 6 micromoles, to allow unimpeded passage through the pulmonary bed. During the alginate studies an entirely new contrast agent was developed. It consists of surfactant-stabilized microbubbles which are prepared by sonication of aqueous mixtures of particular surfactants. Preliminary studies both in vitro and in vivo indicate that this new agent demonstrates great clinical potential. A key feature of this new agent is that 80% of the bubbles have a diameter of less than 6 micromoles. Contrast agent development will progress along two fronts. The alginate system is still considered to have merit, primarily because a polymer- coated bubble offers advantages of long-term stability and because calcium alginate, being a hydrogel, is highly flexible and deformable, resulting in good resistance to pressures such as those that are encountered in the heart. There have been recent reports of the use of atomizers to produce alginate microcapsules in the micron size range for use as vehicles for in vivo vaccine delivery. Emphasis will be placed on adapting this new technology to include entrapment of a gas in the micron-sized capsules. In addition, the use of a vibrating plate drop generator will be studied for the same purpose. Successful production of micron-sized microbubbles will be followed by extensive in vivo and in vitro characterization of the agent with respect to echogenicity (backscatter and attenuation coefficients), stability (both during storage and after in vivo injection) and biocompatibility. In parallel with these studies, there will be continued development of the surfactant-stabilized microbubbles. The present formulations have been characterized with respect to stability and to attenuation and backscatter coefficients in vitro. Further animal studies are planned to test both in vivo stability, and strength as a contrast agent. Also, it is important to investigate the mechanism of stabilization that is taking place at the surfactant/air interface at the molecular level. This will allow us to define the structural properties required of the surfactant molecule to stabilize air bubbles, which in turn will enable us to broaden the range of molecules available to us for use in this agent. In addition it will allow choice of the optimal molecular structures for maximum agent stability. Physical/chemical studies involving Langmuir trough experiments will be used to probe the molecular interactions of surfactants at air- water interfaces. Development of an effective ultrasound contrast agent would be highly significant to health care. Ultrasound is a relatively inexpensive, safe diagnostic procedure that is not only noninvasive, but also generates real time images of the internal structures of the body.