Development and Characterization of a Novel Contrast Agent

描述(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，并为医学和科学研究提供有用的工具。纳米尺度的试剂可以通过进入目前微米尺度的试剂被排除在外的病理区域来发挥重要的诊断作用。我们发表的数据表明，我们可以制备平均尺寸为450 nm的纳米CA(CA-N)，具有优异的成像性能。我们最新的研究产生了250纳米的气泡。进一步的调查正在计划中。目的1：采用微米级表面活性剂稳定气泡法制备直径为10~500 nm的CA。已经进行了初步研究的ST68-N是一种由SPAN60和TweenSO组成的纳米级试剂，可以稳定不溶的全氟化碳气泡。斯潘和吐温系列表面活性剂的其他成员有不同的脂肪酸尾基，以及其他气体，如六氟化硫。要检验的假设是，壁面成分将决定气体周围分子间作用力的堆积密度和强度，从而决定气泡的大小和稳定性。目的2：体外稳定性和回声性能的表征和优化。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整合到泡壁(TCA)中的方法，并测试它们与组织培养的关系。实体瘤靶向将是研究的主要焦点。靶向有三个优点：固定增加局部浓度并允许更大的对比度；体内TCA的寿命通过隔离压力、剪切力和免疫系统的许多组件而延长；最关键的是，它能够区分恶性和良性。目的：从剂量反应、衰减、背向散射和多普勒增强等方面研究TCA的被动和主动靶向性，并进行非临床急性毒性评价。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的关键候选对象，以便在体内进行测试。很大比例的癌症(约85%)涉及实体瘤，其中约50%会导致转移和死亡。一种能够在肿瘤转移前的早期阶段安全、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.