Sensitive and Specific Molecular Imaging of Pulmonary Nodules

描述（由申请人提供）：一个基本的需求是确定在癌症患者的高分辨率CT扫描上发现的肺部病变是否为转移性疾病。虽然CT具有非凡的敏感性，但它缺乏特异性来进行这种关键的区分。因此，我们研究的长期目标是开发一种新的层析成像方法，以分子特异性和高分辨率无创标记和检测肺部癌细胞。我们的方法使用超极化（HP）气体磁共振成像来观察被肿瘤特异性功能化氧化铁纳米颗粒（SPIONs）靶向的癌细胞。本申请的目的是在转移性癌症小鼠模型中优化该演示方法，建立其理论和实际检测限，并直接将该方法与micro-CT进行比较，同时使用组织学建立基本真理。中心假设是，这种新的成像方法将超越CT的敏感性，同时增加区分转移性病变和良性病变所需的分子特异性。提出这项研究的基本原理是，开发一种可以无创地、高灵敏度和特异性地表征肺结节的技术，不仅可以改善患者的预后，还可以推动肺癌研究的进展。因此，拟议的研究与NIH的使命有关，即通过开发和加速生物医学技术的应用来改善健康。在强大的初步数据指导下，中心假设将通过三个具体目标进行验证：1)建立理论和实践的检测限，2)优化图像采集，SPION传递和肿瘤可视化方法，3)直接比较该方法与CT的敏感性和特异性。这些目标的完成将使该技术定位于临床翻译。第一个目标是建立SPION图像对比度的理论模型，并通过成像HP气体流过具有良好表征的、SPION分布逐渐减小的幻影来验证该模型。第二个目标是开发和测试一种图像采集策略，以提高灵敏度，优化spion静脉注射，使spion前后的成像靶向，并实施一种增强的图像分析方法，以进一步提高该方法的检测灵敏度。最终目的是将完全优化的方法与micro-CT对转移性癌混合非癌病变小鼠模型的成像进行比较。这种方法的创新之处在于，它结合了两种尖端技术，在肺癌细胞的分子成像方面实现了潜在的巨大飞跃，而肺癌细胞历来对成像构成巨大挑战。这项研究具有重要意义，因为正在开发的成像方法为肺转移的敏感检测和分子表征开辟了全新的能力，并且更广泛地使肺中的高分辨率分子成像变得可行。

DESCRIPTION (provided by applicant): A fundamental need exists to determine whether pulmonary lesions detected on a cancer patient's high- resolution CT scan are metastatic disease. While CT has extraordinary sensitivity, it lacks the specificity to make this critical distinction. The long-term goal of our research, therefore, is to develop a new tomographic imaging method to non-invasively tag and detect cancer cells in the lungs with molecular specificity and high resolution. Our approach uses hyperpolarized (HP) gas MR imaging to visualize cancer cells that have been targeted by tumor-specific functionalized Iron Oxide Nanoparticles (SPIONs). The objective of this application is to optimize this demonstrated method in mouse models of metastatic cancer, establish its theoretical and practical detection limits, and directly compare this method to micro-CT, while using histology to establish ground truth. The central hypothesis is that this new imaging method will surpass the sensitivity of CT, while adding the molecular specificity needed to distinguish metastatic from benign lesion. The rationale for the proposed research is that development of a technique that can non-invasively characterize pulmonary nodules with high sensitivity and specificity will not only improve patient outcomes, but also drive progress in lung cancer research. Thus, the proposed research is relevant to that part of the NIH Mission that pertains to improving health by developing and accelerating the application of biomedical technologies. Guided by strong preliminary data, the central hypothesis will be tested by pursuing three Specific Aims: 1) Establish the theoretical and practical detection limits, 2) Optimize the image acquisition, SPION delivery, and tumor visualization methods, and 3) Directly compare the method's sensitivity and specificity against CT. Completion of these aims will position this technology for clinical translation. The first aim establishes a theoretical model of SPION image contrast and validates the model by imaging HP gas flowing through a phantom containing well- characterized, and progressively smaller distributions of SPIONs. The second aim will develop and test an image acquisition strategy to increase sensitivity, optimize intravenous delivery of SPIONs to enable imaging pre- and post-SPION targeting, and implement an enhanced image analysis approach to further increase the detection sensitivity of the method. The final aim compares the fully optimized method against micro-CT to image mouse models of metastatic cancer mixed with non-cancerous lesions. The proposed approach is innovative because it combines two cutting-edge technologies to take a potential quantum leap in molecular imaging of cancer cells in the lung-an organ that has historically posed enormous imaging challenges. The proposed research is significant because the imaging method being developed opens up an entirely new capacity for sensitive detection and molecular characterization of pulmonary metastases, and more broadly enables high-resolution molecular imaging in the lung to become feasible. PUBLIC HEALTH RELEVANCE: The proposed studies will develop a minimally invasive imaging technique to enable physicians to determine whether pulmonary lesions detected on a cancer patient's x-ray CT scan are metastases. Such information permits the physician to administer the right therapy at the earliest possible stage in the patient's treatment. The proposed research has relevance to public health because new tools in imaging pulmonary cancers will not only improve patient treatment, but will also accelerate research to develop better therapies.