Sensitive and Specific Molecular Imaging of Pulmonary Nodules

描述（由申请人提供）：存在确定在癌症患者的高分辨率CT扫描上检测到的肺部病变是否是转移性疾病的基本需求。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断层成像方法，以分子特异性和高分辨率非侵入性标记和检测肺部癌细胞。我们的方法使用超极化（HP）气体MR成像来可视化肿瘤特异性功能化氧化铁纳米颗粒（SPION）靶向的癌细胞。本申请的目的是在转移性癌症的小鼠模型中优化该证明的方法，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础事实。中心假设是，这种新的成像方法将超过CT的灵敏度，同时增加了区分转移性病变和良性病变所需的分子特异性。这项研究的基本原理是，开发一种能够以高灵敏度和特异性非侵入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，拟议中的研究与NIH使命的一部分有关，即通过发展和加速生物医学技术的应用来改善健康。在强有力的初步数据的指导下，将通过追求三个特定目标来检验中心假设：1）建立理论和实际检测限，2）优化图像采集、SPION传输和肿瘤可视化方法，以及3）直接比较该方法与CT的灵敏度和特异性。这些目标的实现将使该技术能够用于临床转化。第一个目标是建立SPION图像对比度的理论模型，并通过对流过体模的HP气体进行成像来验证该模型，所述体模包含良好表征的且逐渐变小的SPION分布。第二个目标将开发和测试图像采集策略，以提高灵敏度，优化SPION的静脉内输送，以实现SPION靶向前后的成像，并实施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微CT进行比较，以成像转移性癌症与非癌性病变混合的小鼠模型。所提出的方法是创新的，因为它结合了两种尖端技术，在肺部癌细胞的分子成像方面取得了潜在的飞跃，肺部是一个在历史上构成巨大成像挑战的器官。这项研究意义重大，因为正在开发的成像方法为肺转移瘤的灵敏检测和分子表征开辟了全新的能力，并且更广泛地使肺部的高分辨率分子成像变得可行。 公共卫生相关性：拟议的研究将开发一种微创成像技术，使医生能够确定在癌症患者的X射线CT扫描中检测到的肺部病变是否是转移瘤。这样的信息允许医生在患者治疗的尽可能早的阶段给予正确的治疗。这项拟议中的研究与公共卫生有关，因为肺癌成像的新工具不仅会改善患者的治疗，还将加速研究，以开发更好的治疗方法。

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.