MR SIGNAL AMPLIFICATION FOR RECEPTOR IMAGING

描述（由申请人提供）： 在体内成像特定分子生物标志物的能力将在癌症的最早检测、评估特定靶向治疗和监测疾病进展期间表达模式的动态变化中具有重要应用。然而，许多这样的分子生物标志物以低浓度存在，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MR信号放大策略（Mramp），用于与肿瘤中血管和血管外靶点相关的成像模型分子靶点。该策略依赖于酶介导的顺磁性底物的聚合，产生具有显着更高的原子弛豫率（r1和r2）的产品。该方法潜在地具有若干优点：1）它利用低分子量镧系元素络合物，其“就地”转化为大分子，2）这些低MW前体的开发在临床上是可行的，3）迄今观察到的弛豫率变化高于其它扩增策略，4）寡聚产物可以被设计为局部存在，和5）该方法可以以各种通用方式使用，潜在地允许读出许多不同的靶。到目前为止，我们已经表明，该方法在1）使用酶联免疫吸附测定格式的模型配体的MR检测和2）在内皮细胞表面上的促炎标记物E-选择素的成像中具有前景。两个主要目标将在拟议的研究：突变，组成型活性deltaEGFR和血管生成调节E-选择素。δ EGFR表达强烈上调VEGF表达，VEGF表达反过来上调内皮细胞中的E-选择素和管形成。选择这些靶点是因为它们在肿瘤增殖中的重要性、化疗的调节（例如EGFR酪氨酸激酶抑制剂[Chan，2002 #2547]）以及目前缺乏针对它们的成像标记物。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）的变化的新型顺磁性基底，后者可能对在更高分辨率和更高场强下成像特别感兴趣。

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.