Development and Characterization of a Novel Contrast Agent

新型造影剂的开发和表征

• 批准号: 7268736
• 负责人: MARGARET A. WHEATLEY
• 金额: $ 25.7万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268736
• 关键词: Acute; Animals; Area; Arginine; Aspartic Acid; Benign; Binding; Caliber; Cells; Centrifugation; Cessation of life; Communities; Condition; Contrast Media; Cultured Cells; Data; Development; Diagnostic; Dimensions; Disease; Dose; Equilibrium; Evaluation; Family; Fatty Acids; Fluorocarbons; Gases; Glycine; Grant; Healthcare; Image; Immune system; Immunoglobulin Fragments; In Vitro; Individual; Integrins; Investigation; Lead; Lesion; Ligands; Lung; Malignant - descriptor; Malignant Neoplasms; Medical; Methodology; Methods; Micelles; Microbubbles; Modality; Modeling; Molecular; Nanotechnology; Neoplasm Metastasis; Pathology; Peptide Fragments; Performance; Physiologic pulse; Population; Preparation; Property; Publishing; Pulse taking; RGD (sequence); Research Personnel; Reticuloendothelial System; Role; ST68; Screening procedure; Series; Site; Solid Neoplasm; Span 40; Span 60; Specimen; Staging; Staining method; Stains; Structure; Sulfur Hexafluoride; System; Tail; Testing; Thinking; Toxic effect; Tween 60; Tweens; Ultrasonography; Work; attenuation; base; capillary bed; density; experience; falls; glycyl-arginyl-glycyl-aspartyl-serine; in vivo; interest; member; nano; nanoparticle; nanoscale; nanosized; novel; pressure; programs; receptor; response; sample fixation; size; surfactant; tissue culture; tool; tumor

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.

描述（由申请人提供）：长期目标是开发诊断超声造影剂（CA）以满足医学界的多样化需求，并为医学和科学探究提供有用的工具。纳米尺寸的试剂可以通过进入当前微米尺寸的试剂被排除在外的病理学区域来发挥重要的诊断作用。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)，具有出色的成像性能。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：通过采用当前由表面活性剂稳定的气泡组成的微米级试剂的方法，开发生产直径 10-500 nm CA 的方法。 ST68-N是一种由Span60和TweenSO组成的纳米级试剂，已进行了初步研究，可稳定不溶性全氟化碳气泡。 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，例如六氟化硫。要测试的假设是，壁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。目标 2：表征/优化体外稳定性和回声性。确定影响 CA-N 回声的关键参数。目标 3：开发将疾病状态特异性靶向分子整合到气泡壁 (tCA) 中的方法，并针对组织培养对其进行测试。实体瘤靶向将是主要焦点。瞄准具有三个优点：固定增加局部集中度并允许更大的对比度；通过隔离压力、剪切力和免疫系统的许多组成部分，tCA 的体内寿命得以延长；至关重要的是，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 的关键候选物以进行体内测试。很大一部分癌症（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，将是医疗保健领域的一大进步。