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），以满足医学界的不同需求，并为医学和科学探究提供有用的工具。纳米尺寸的药物可以通过进入目前微米尺寸的药物无法进入的病理区域来实现重要的诊断作用。我们发表的数据表明，我们可以生产出平均尺寸为450纳米的纳米CA (CA- n)，具有优异的成像性能。我们最近的研究已经产生了250纳米的气泡。计划进一步调查。目的1：在现有的由表面活性剂稳定气泡组成的微米级剂的制备方法的基础上，开发制备10-500 nm直径的CA的方法。ST68-N是一种纳米级剂，由Span60和TweenSO组成，稳定不溶性全氟碳气泡，已进行了初步研究。Span和Tween家族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，壁面成分将决定气体周围的堆积密度和分子间力的强度，从而决定气泡的大小和稳定性。目的2：表征/优化体外稳定性和回声性。确定影响CA-N回声性的关键参数。目标3：发展将疾病状态特异性靶向分子纳入泡壁（tCA）的方法，并对其进行组织培养试验。实体肿瘤靶向将是主要的焦点。定位有三个优点：固定增加了局部浓度并允许更大的对比；tCA的体内寿命通过远离压力、剪切力和许多免疫系统成分的隔离而增加；最关键的是，它能区分恶性和良性。目标4：体内特性包括剂量反应、衰减、后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的关键候选者，以便在体内进行测试。大部分癌症（约85%）涉及实体瘤，其中约50%导致转移和死亡。如果有一种诊断工具能够安全、无创地在肿瘤转移前的早期阶段检测出肿瘤，将是医疗保健领域的一大进步。

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.