MR Signal Amplification for Receptor Imaging

用于受体成像的 MR 信号放大

• 批准号: 9125816
• 负责人: Alexei A Bogdanov
• 金额: $ 37.69万
• 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 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9125816
• 关键词: Abnormal Cell; Adenocarcinoma; Adenocarcinoma Cell; Animals; Biochemical Reaction; Breast Adenocarcinoma; Breast Cancer Patient; Breast Carcinoma; Breast cancer metastasis; Cancer Model; Catheters; Cell Culture Techniques; Cell physiology; Cell surface; Cells; Clinical; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic; Disease; Drug Kinetics; E-Selectin; Electronics; Electrons; Endothelial Cells; Enzymes; Epidermal Growth Factor Receptor; Etiology; Funding; Generations; Goals; Gold; Health; Heart Diseases; Human; Hydrogen Peroxide; Image; Imaging Device; Immunoglobulin Fragments; In Vitro; Injection of therapeutic agent; Investigation; Laboratory Animals; Lead; Life; Link; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Medical; Medicine; Metastatic Adenocarcinoma; Metastatic Neoplasm to the Bone; Methods; Modeling; Modification; Molecular; Molecular Target; Molecular Weight; Monitor; Neoplasm Metastasis; One-Step dentin bonding system; Osteolytic; Output; Oxidation-Reduction; Oxidoreductase; PECAM1 gene; Pathology; Patients; Peroxidases; Pharmaceutical Preparations; Phenols; Physicians; Play; Positron-Emission Tomography; Prevention; Procedures; Progress Reports; Protocols documentation; Publications; Reaction; Receptor Signaling; Research; Resolution; Role; Safety; Schedule; Scientist; Seminal; Signal Transduction; Site; Specificity; Surface; TACSTD1 gene; Techniques; Testing; Time; Tissues; Translating; Work; base; bone; cofactor; density; design; enzyme activity; enzyme substrate; epidermal growth factor receptor VIII; glucose oxidase; imaging probe; improved; in vivo; in vivo imaging; interstitial; malignant breast neoplasm; meetings; mimetics; molecular imaging; nanoparticle; neoplastic cell; novel; novel diagnostics; novel therapeutics; overexpression; pre-clinical; protein biomarkers; receptor; receptor binding; receptor expression; response; targeted imaging; theranostics; tool; tumor

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.

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，定位在特定的组织区室中，并能够快速修饰低分子量顺磁性底物，站点; 2）灵敏度：这种局部保留导致顺磁性底物的快速积累，这引起由酶促反应的顺磁性产物的高密度和增加的弛豫率产生的放大的MR信号。我们的开创性工作最终达到了高潮：1）多个研究小组对许多疾病状态下的内源性过氧化物酶（例如髓过氧化物酶）进行成像，以及; 2）癌症模型中受体表达的成像。在这次更新中，我们建议利用MRamp技术来应对表皮生长因子（EGF）受体和EpCAM细胞表面分子作为转移靶向成像的潜在标记物的MR分子成像的挑战。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的能力相关。EGFR信号传导与骨降解有关，这通常发生在乳腺癌患者中。本提案的目的是继续我们的研究，旨在开发和验证新的成像探针，可用于使用MRI（高分辨率）和PET（高灵敏度）技术检测乳腺癌（MAC）骨转移中EGFR表达的体内变化。预计这项工作很容易转化为新的诊断能力（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可行标志物。MRamp是为数不多的可用技术之一，这将使检测两种蛋白质标记物（受体）的共表达成为可能。这项工作也将提供一个新的实验工具，为临床和临床前研究有关的病因和病理转移腺癌。