Ultra-Sensitive MR Probes for Molecular Diagnosis of Lung Cancer

描述(申请人提供)：这项研究的长期目标是开发超灵敏的磁共振成像(MRI)探针，可以通过MRI对肺癌进行特异性检测。磁共振成像是一种临床影像技术，在肿瘤的非侵入性诊断和治疗后评估中有着广泛的应用。虽然Gd-DTPA(Magnevist.)和其他小分子量试剂用于动态增强MRI应用效果良好，这些试剂不是很灵敏(检测下限为~10-4M)，因此不能用于体内特定的生物标志物的检测。在这一应用中，我们将研究超顺磁性聚合物胶束(SPPM)的使用，这种胶束负载了一簇磁性纳米颗粒，用于肺癌的分子成像。该平台展示了约20 PM的MRI检测灵敏度，这将是诊断肺癌的关键。从噬菌体筛选中鉴定出的一类新型肺癌靶向肽(LCPs)将被功能化到SPPM的表面以靶向肺癌细胞。分离的多肽表现出显著的结合亲和力(~lt；Nm)和细胞特异性(20-1000倍)来区分不同的细胞类型。我们的中心假设是，LCP编码的SPPM将允许在裸鼠原位肺癌模型中对不同类型的肺癌进行高度敏感和特异的诊断。为了验证这一假设，我们将实现以下具体目标：(1)建立ORS方法并优化SPPM成分以增强ORS对比度；(2)体外制备并鉴定LCP编码的SPPM；(3)验证LCP编码的SPPM用于体内肺癌诊断。该应用的成功实施将为胶束平台非侵入性诊断肺癌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，以提供肺部肿瘤的细胞特异性特征。这一认识有助于及时介入肺癌，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.