MR SIGNAL AMPLIFICATION FOR RECEPTOR IMAGING

用于受体成像的 MR 信号放大

• 批准号: 7107640
• 负责人: Alexei A Bogdanov
• 金额: $ 30.84万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7107640
• 关键词: bioimaging /biomedical imaging; biomagnetism measurement; biomarker; enzyme linked immunosorbent assay; epidermal growth factor; genetic strain; growth factor receptors; hollow fiber separation technique; image enhancement; laboratory rat; magnetic resonance imaging; oxidoreductase; phantom model; polymerization; selectins; tissue /cell culture; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): The ability to image specific molecular biomarkers in vivo would have important applications in the earliest detection of cancer, in assessing specific targeted therapies and for monitoring dynamic changes in expression patterns during disease progression. Many of such molecular biomarkers however, exist at low concentrations, necessitating novel amplification strategies. The overall goal of the proposal is to investigate a new enzyme-mediated MR signal amplification strategy (Mramp) for imaging model molecular targets associated with vascular and extravascular targets in tumors. The strategy relies on enzyme-mediated polymerization of paramagnetic substrates yielding products with significantly higher atomic relaxivity (r1 and r2). This method potentially has several advantages: 1) it utilizes low molecular weight lanthanide complexes which are converted into large molecules "on site", 2) the development of these low MW precursors is clinically viable, 3) the so far observed relaxivity changes are higher than with other amplification strategies, 4) the oligomerized products can be designed to reside locally and 5) the method can be used in a variety of generic ways potentially allowing the read-out of many different targets. So far, we have shown that the method holds promise in the 1) MR detection of a model ligand using an enzyme-linked immunoadsorbent assay format and 2) in imaging of a pro-inflammatory marker, E-selectin on the surface of endothelial cells. Two primary targets will be investigated in proposed research: a mutant, constitutively active deltaEGFR and angiogenesis-modulated E-selectin. deltaEGFR expression strongly upregulates VEGF expression which, in turn, upregulates E-selectin and tube formation in endothelial cells. These targets were chosen because of their importance in tumor proliferation, modulation by chemotherapy (e.g. EGFR tyrosine kinase inhibitors [Chan, 2002 #2547]) and the current absence of imaging markers directed against them. To further increase the sensitivity of MRamp we will investigate novel paramagnetic substrates exploiting changes in T1 (Gd) and T2/T2* effect (Dy), The latter may be of particular interest for imaging at higher resolution and higher field strengths.

描述(由申请人提供)： 在体内成像特定分子生物标记物的能力将在癌症的早期检测、评估特定的靶向治疗以及监测疾病进展过程中表达模式的动态变化方面具有重要应用。然而，许多这样的分子生物标记物存在于低浓度，需要新的扩增策略。该提案的总体目标是研究一种新的酶介导的磁共振信号放大策略(MRAMP)，用于成像与肿瘤中血管和血管外目标相关的模型分子靶点。该策略依赖于酶介导的顺磁性底物聚合，产生具有显著更高的原子弛豫度的产品(R1和R2)。这种方法有几个潜在的优点：1)它利用低分子稀土络合物，这些低分子稀土络合物可以“现场”转化为大分子；2)这些低分子前驱体的开发在临床上是可行的；3)到目前为止观察到的弛豫度变化比其他扩增策略更高；4)寡聚产物可以设计为驻留在本地；5)该方法可以以各种通用的方式使用，潜在地允许读出许多不同的靶标。到目前为止，我们已经证明，该方法在1)使用酶联免疫吸附分析技术检测模型配体和2)对内皮细胞表面的促炎标志物E-选择素进行成像方面是有希望的。在拟议的研究中，将研究两个主要靶点：突变的、结构性活性的deltaEGFR和血管生成调节的E-选择素。DeltaEGFR的表达强烈上调了血管内皮生长因子的表达，进而上调了E-选择素和血管内皮细胞的管状形成。之所以选择这些靶点，是因为它们在肿瘤增殖中的重要性，化疗(例如，EGFR酪氨酸激酶抑制剂[Chan，2002#2547])的调节作用，以及目前缺乏针对它们的成像标志物。为了进一步提高MRAmp的灵敏度，我们将研究利用T1(Gd)和T2/T2*效应(Dy)变化的新型顺磁衬底，后者可能对更高分辨率和更高场强的成像特别感兴趣。