Ultra-Sensitive MR Probes for Molecular Diagnosis of Lung Cancer

描述（由申请人提供）：本研究的长期目标是开发超灵敏的磁共振成像（MRI）探头，通过MRI提供肺部肿瘤的癌症特异性检测。MRI是一种临床成像技术，在癌症的非侵入性诊断和治疗后评估中具有广泛的应用。虽然Gd-DTPA（Magnevist.）和其它小分子量试剂对于动态对比增强MRI应用效果良好，但这些试剂不是非常敏感（检测下限为~10-4 M），因此不能用于检测体内的特定生物标记物。在这个应用中，我们将研究使用超顺磁性聚合物胶束（SPPM），这是装载了一个集群的磁铁矿纳米粒子的肺癌分子成像。该平台通过MRI证明了约20 pM的检测灵敏度，这对于诊断肺癌至关重要。从噬菌体筛选中鉴定出的一类新型肺癌靶向肽（LCP）将在SPPM表面功能化以靶向肺癌细胞。分离的肽显示出显著的结合亲和力（<nM）和细胞特异性（20-1000倍）以区分不同的细胞类型。我们的中心假设是，LCP编码的SPPM将允许在无胸腺裸鼠原位肺肿瘤模型中对不同类型的肺癌进行高度敏感和特异性的诊断。为了验证这一假设，我们将进行以下具体目标：（1）建立ORS方法并优化SPPM组合物以增强ORS对比度;（2）体外制备和表征LCP编码的SPPM;以及（3）验证LCP编码的SPPM用于体内肺癌诊断。该申请的成功执行将为胶束平台用于肺癌无创诊断奠定技术基础和临床前疗效。公共卫生相关性：将开发一种新的MRI成像方法和超灵敏分子探针的组合，以提供肺肿瘤的细胞特异性表征。这些知识有助于及时干预肺癌，实现个性化用药。

DESCRIPTION (provided by applicant): The long-term goal of this research is to develop ultra-sensitive magnetic resonance imaging (MRI) probes that can provide cancer-specific detection of lung tumors by MRI. MRI is a clinical imaging technique that has broad applications in non-invasive diagnosis and post-therapy assessment for cancer. Although Gd-DTPA (Magnevist.) and other small molecular weight agents work well for dynamic contrast enhancement MRI applications, these agents are not very sensitive (lower limit of detection is ~10-4 M) and therefore cannot be used for detecting specific biological markers in vivo. In this application, we will investigate the use of superparamagnetic polymeric micelles (SPPM) that are loaded with a cluster of magnetite nanoparticles for molecular imaging of lung cancer. This platform demonstrated ~20 pM sensitivity of detection by MRI that will be essential for diagnosing lung cancers. A novel class of lung cancer-targeting peptides (LCPs) identified from phage screening will be functionalized on the surface of SPPM to target lung cancer cells. The isolated peptides demonstrated remarkable binding affinities (<nM) and cell specificities (20-1000 fold) to discriminate between different cell types. Our central hypothesis is that LCP-encoded SPPM will allow for highly sensitive and specific diagnosis of different types of lung cancer in an orthotopic lung tumor model in athymic nude mice. To test this hypothesis, we will carry out the following specific aims: (1) Establish ORS method and optimize SPPM compositions to enhance ORS contrast; (2) produce and characterize LCP-encoded SPPM in vitro; and (3) validate LCP-encoded SPPM for diagnosis of lung cancer in vivo. Successful execution of this application will establish the technology foundation and preclinical efficacy of the micelle platform for non-invasive diagnosis of lung cancer. PUBLIC HEALTH RELEVANCE: A combination of novel MRI imaging method and ultra-sensitive molecular probes will be developed to provide cell-specific characterization of lung tumors. This knowledge can facilitate timely intervention of lung cancer to achieve personalized medicine.