Development and Characterization of a Novel Contrast Agent

新型造影剂的开发和表征

• 批准号: 7674661
• 负责人: MARGARET A. WHEATLEY
• 金额: $ 26.12万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7674661
• 关键词: Acute; Animals; Area; Arginine; Aspartic Acid; Benign; Binding; Caliber; Cell Culture Techniques; Cells; Centrifugation; Cessation of life; Communities; Contrast Media; 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; Modeling; Molecular; Nanotechnology; Neoplasm Metastasis; Pathology; Peptide Fragments; Performance; Physiologic pulse; Population; Preparation; Property; Publishing; 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; Toxic effect; Tween 80; Tweens; Ultrasonography; Work; attenuation; base; capillary bed; density; experience; falls; imaging modality; in vivo; interest; member; nano; nanoparticle; nanoscale; nanosized; novel; pressure; programs; receptor; response; sample fixation; 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对比剂（CA）以满足医学界的各种需求，并为医学和科学询问提供有用的工具。纳米尺寸的代理可以通过进入当前微米大小的药物被排除的病理领域来履行重要的诊断作用。我们发布了数据，显示我们可以生产具有具有出色成像属性的450 nm的纳米CA（CA-N）。我们最近的研究产生了250 nm的气泡。计划进一步调查。 AIM 1：通过适应由表面活性剂稳定的气泡组成的当前方法来生成直径10-500 nm Ca的方法。进行初步研究的ST68-N是一种纳米级剂，由Span60和Tweenso组成，稳定了不溶性的全氟碳气泡。跨度和补间表面活性剂家族的其他成员有不同的脂肪酸尾部组以及其他气体，例如硫六氟化物。要测试的假设是，壁成分将决定气体周围分子间力的填料密度和强度，因此气泡大小和稳定性。 AIM 2：表征/优化体外稳定性和回声性。确定有助于CA-N的回声性的关键参数。目标3：开发将疾病特异性靶向分子纳入气泡壁（TCA）的方法，并对组织培养进行测试。实体瘤的靶向将是主要重点。目标从目标中获得了三个优点：固定增加了局部浓度，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成分来增加TCA的体内寿命。和关键，它可以区分恶性和良性。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在体内识别CA-N和TCA的关键候选者。很大一部分癌症（约85％）涉及实体瘤，其中约50％导致转移和死亡。在转移之前，可以在早期阶段安全和非侵入性检测肿瘤的诊断工具将是医疗保健方面的巨大进步。

项目成果

Disposition of ultrasound sensitive polymeric drug carrier in a rat hepatocellular carcinoma model.

• DOI: 10.1016/j.acra.2011.06.013
• 发表时间: 2011-11
• 期刊: ACADEMIC RADIOLOGY
• 影响因子: 4.8
• 作者: Cochran, Michael C.;Eisenbrey, John R.;Soulen, Michael C.;Schultz, Susan M.;Ouma, Richard O.;White, Sarah B.;Furth, Emma E.;Wheatley, Margaret A.
• 通讯作者: Wheatley, Margaret A.

Development and optimization of a doxorubicin loaded poly(lactic acid) contrast agent for ultrasound directed drug delivery.

• DOI: 10.1016/j.jconrel.2009.12.021
• 发表时间: 2010-04-02
• 期刊: JOURNAL OF CONTROLLED RELEASE
• 影响因子: 10.8
• 作者: Eisenbrey, J. R.;Burstein, O. Mualem;Kambhampati, R.;Forsberg, F.;Liu, J. -B.;Wheatley, M. A.
• 通讯作者: Wheatley, M. A.

Ultrasound triggered cell death in vitro with doxorubicin loaded poly lactic-acid contrast agents.

• DOI: 10.1016/j.ultras.2009.03.003
• 发表时间: 2009-12
• 期刊: ULTRASONICS
• 影响因子: 4.2
• 作者: Eisenbrey, J. R.;Huang, P.;Hsu, J.;Wheatley, M. A.
• 通讯作者: Wheatley, M. A.

Development of an ultrasound sensitive oxygen carrier for oxygen delivery to hypoxic tissue.

• DOI: 10.1016/j.ijpharm.2014.11.023
• 发表时间: 2015-01-15
• 期刊: International journal of pharmaceutics
• 影响因子: 5.8
• 作者: Eisenbrey JR;Albala L;Kramer MR;Daroshefski N;Brown D;Liu JB;Stanczak M;O'Kane P;Forsberg F;Wheatley MA
• 通讯作者: Wheatley MA

Neural progenitor cells grown on hydrogel surfaces respond to the product of the transgene of encapsulated genetically engineered fibroblasts.

在水凝胶表面生长的神经祖细胞对封装的基因工程成纤维细胞的转基因产物做出反应。

• DOI: 10.1021/bm100699q
• 发表时间: 2010
• 期刊: Biomacromolecules
• 影响因子: 6.2
• 作者: Shanbhag,MihirS;Lathia,JustinD;Mughal,MohamedR;Francis,NicolaL;Pashos,Nicholas;Mattson,MarkP;Wheatley,MargaretA
• 通讯作者: Wheatley,MargaretA