Development and Characterization of a Novel Contrast Agent

描述（由申请人提供）：长期目标是开发诊断超声造影剂（CA），以满足医学界的各种需求，并为医学和科学研究提供有用的工具。纳米尺寸的试剂可以通过进入目前微米尺寸的试剂被排除在外的病理学区域来实现重要的诊断作用。我们公布的数据显示，我们可以生产平均尺寸为450 nm的纳米CA（CA-N），具有优异的成像性能。我们最近的研究产生了250 nm的气泡。计划进行进一步调查。目标1：通过调整目前用于由表面活性剂稳定的气泡组成的微米级试剂的方法，开发生产10-500 nm直径CA的方法。ST 68-N是一种由Span 60和TweenSO组成的纳米级稳定剂，已对其进行了初步研究。Span和Tween系列表面活性剂的其他成员具有不同的脂肪酸尾基和其他气体如六氟化硫。要测试的假设是，壁成分将决定气体周围的分子间力的堆积密度和强度，因此气泡的大小和稳定性。目的2：表征/优化体外稳定性和回声反射性。确定影响CA-N回声的关键参数。目的3：开发将疾病状态特异性靶向分子掺入泡壁（tCA）的方法，并针对组织培养测试它们。实体瘤靶向将是主要焦点。从靶向获得三个优点：固定增加局部浓度并允许更大的对比度;通过隔离远离压力、剪切力和免疫系统的许多组分来增加tCA的体内寿命;并且关键的是，它能够区分恶性和良性。目标4：体内表征包括剂量反应、衰减、反向散射和多普勒增强，研究tCA的被动和主动靶向，并进行非临床急性毒性评估。我们假设，我们的体外细胞工作将使我们能够确定CA-N和tCA的关键候选人进行体内测试。大部分癌症（约85%）涉及实体瘤，其中约50%导致转移和死亡。一种能够在转移之前的早期阶段安全地、非侵入性地检测肿瘤的诊断工具将是医疗保健的一大进步。

DESCRIPTION (provided by applicant): The long-term objective is to develop diagnostic ultrasound contrast agents (CA) to fulfill the diverse needs of the medical community, and provide useful tools for medical and scientific inquiry. An agent of nano dimensions could fulfill an important diagnostic role by gaining access to areas of pathology from which current micron sized agents are excluded. We published data showing we can produce nano CA (CA-N) with a mean size of 450 nm that have excellent imaging properties. Our most recent studies have produced bubbles of 250 nm. Further investigation is planned. Aim 1: Develop methods to produce 10-500 nm diameter CA by adaptation of the current method for micron- sized agent composed of surfactant-stabilized gas bubbles. ST68-N, upon which preliminary studies have been conducted, is one nano-scale agent composed of Span60 and TweenSO stabilizing an insoluble perfluorocarbon gas bubble. Other members of the Span and Tween family of surfactants are available with differing fatty acid tail groups, and other gases such as sulfur hexafluoride. The hypothesis to be tested is that the wall constituents will dictate the packing density and strength of inter-molecular forces around the gas, hence bubble size and stability. Aim 2: Characterize/optimize in vitro stability and echogenicity. Identify key parameters contributing to the echogenicity of CA-N. Aim 3: Develop methods to incorporate disease- state specific targeting molecules into the bubble wall (tCA), and test them against tissue culture. Solid tumor targeting will be the main focus. Three advantages are gained from targeting: fixation increases the local concentration and allows for greater contrast; in vivo lifetime of tCA is increased by sequestration away from pressure, shear forces, and many of the components of the immune system; and pivotal, it enables distinction between malignant and benign. Aim 4: In vivo characterization including dose response, attenuation, backscatter and Doppler enhancement, study both passive and active targeting of tCA and conduct a nonclinical acute toxicity assessment. We hypothesize that our in vitro cell work will allow us to identify key candidates for CA-N and tCA to be tested in vivo. A large percentage of cancers (approximately 85%) involve solid tumors, and roughly 50% of these lead to metastasis and death. A diagnostic tool that could safely and non-invasively detect tumors at an early stage, before metastasis, would be a great advance in health care.