MR Signal Amplification for Receptor Imaging

描述（由申请人提供）：MRamp策略的设计目标是通过同时在两个水平上调节MR信号输出来提高MR成像的分子灵敏度：1)特异性：使用一对受体靶向酶，它们在特定组织室中共定位，并能够快速修饰低分子量顺磁性底物，从而使其在反应部位局部保留；2)敏感性：这种局部保留导致顺磁性底物的快速积累，从而产生由酶促反应的顺磁性产物的高密度和增加的弛缓性产生的放大MR信号。我们的开创性工作最终达到高潮：1)由几个研究小组在许多疾病状态下成像内源性过氧化物酶（例如髓过氧化物酶）；2)肿瘤模型中受体表达的成像。在这篇论文中，我们提出利用MRamp技术来应对表皮生长因子（EGF）受体和EpCAM细胞表面分子的磁共振分子成像作为转移靶向成像的潜在标记物的挑战。人表皮生长因子受体（EGFR）在15-20%的乳腺癌中过表达，其表达水平与乳腺癌转移能力相关。EGFR信号与骨退化有关，这通常发生在乳腺癌患者身上。本提案的目标是继续我们的研究，旨在开发和验证新型成像探针，该探针可用于使用MRI（高分辨率）和PET（高灵敏度）技术检测乳腺腺癌（MAC）骨转移中EGFR表达的体内变化。这项工作有望很容易转化为一种新的诊断能力（监测EGFR/EpCAM表达水平）的设计。MAC经常过表达EpCAM，而EGFR在转移中的表达是溶骨性肿瘤发展的一个可行标志。MRamp是为数不多的能够检测两种蛋白标记物（受体）共表达的技术之一。这项工作也将为转移性腺癌的病因和病理的临床和临床前研究提供新的实验工具。

DESCRIPTION (provided by applicant): The MRamp strategy was designed with the goal of improving the molecular sensitivity of MR imaging by modulating the MR signal output on two levels simultaneously: 1) specificity: the use of a pair of the receptor- targeted enzymes that co-localize in the specific tissue compartment and enable rapid modification of low molecular weight paramagnetic substrates resulting in their local retention at the reaction site; and 2) sensitivity: this local retention results in rapid accumulation of paramagnetic substrates that gives rise to an amplified MR signal generated by both the high density and increased relaxivity of the paramagnetic products of the enzymatic reaction. Our seminal work eventually culminated in: 1) imaging of endogenous peroxidases (e.g. myeloperoxidase) in many disease states by several research groups, and; 2) imaging of receptor expression in cancer models. In this renewal we propose to harness the MRamp technique to meet the challenges of MR molecular imaging of epidermal growth factor (EGF) receptor and EpCAM cell-surface molecule as potential markers for targeted imaging of metastasis. Human epidermal growth factor receptor (EGFR) is overexpressed in 15-20% of all breast carcinomas and its expression level correlates with the ability of breast cancer to metastasize. EGFR signaling is linked to bone degradation, which often occurs in patients with breast cancer. The goal of this proposal is to continue our research aimed at developing and validating novel imaging probes which can be applied to detection of in vivo changes in EGFR expression in bone metastases of mammary adenocarcinoma (MAC) using MRI (high resolution) and �PET (high sensitivity) techniques. This work is expected to be readily translatable to the design of a new diagnostic capability (monitoring levels of EGFR/EpCAM expression). MAC frequently overexpresses EpCAM while EGFR expression in metastasis is a viable marker for the development of osteolytic tumors. MRamp is one of the few available techniques that would make the detection of the coexpression of two protein markers (receptors) feasible. This work will also provide a new experimental tool for clinical and preclinical investigations regarding the etiology and pathology of metastatic adenocarcinoma.