Tomographic Molecular Imaging for Breast Cancer

描述（由申请人提供）：用于分子成像的近红外光学探针的最新发展为乳腺癌成像带来了巨大的希望。靶向和可激活的探针与特定靶标相互作用，因此可以在细胞或分子水平上对生物过程进行成像。靶向探针结合到特定的靶标，如受体，并可用于成像受体表达和分布，而可活化探针可用于成像基质降解酶如MMP或组织蛋白酶的活性。这种探针沿着光学成像可以产生用于肿瘤形成和转移的体内成像的独特的、高灵敏度的技术。在不久的将来，这些探头中的一些将不可避免地用于临床环境。尽管在分子成像技术的进步，然而，最近的努力已经集中在开发体内荧光增强光学断层扫描（FDOT），可用于乳腺癌成像的临床设置。在这个应用中，我们建议采用多模态方法，一个组合的MR/FDOT动物成像系统，以提高FDOT的准确性，从而提高MRI在区分良性和恶性乳腺癌的性能。几项研究已经证明，MRI可以检测出在乳房X光检查和超声检查中隐藏的恶性癌症，因此它已迅速成为筛查年轻女性的最流行的成像方式。然而，尽管MRI具有高灵敏度，但其特异性低，因此它也可以检测到许多良性病变。作为该组合系统的对应物，FDOT将使用靶向/活化探针显著增加MRI的特异性。类似地，MRI将通过提供先验信息来提高FDOT的定量准确性，这使得所提出的系统成为真正的多模态成像方法。一旦开发出组合系统并通过体模研究进行优化，将通过使用MMP敏感的可激活荧光成像探针和表达不同水平MMP活性的两种不同细胞系，通过动物研究评价系统的性能。本申请中提出的原理证明混合MR/FDOT成像模态是一种创新方法，也是迈向这种临床多模态成像系统的第一步。通过适当的设计修改，所提出的技术在未来的人体临床试验中具有很大的转化潜力。 虽然乳房X线摄影在检测早期乳腺癌方面非常敏感，但对于那些有致密乳房组织、乳房植入体或因既往治疗而形成疤痕组织的女性，效果并不好。乳腺MRI被认为是这些患者人群的最佳模式。然而，目前可用的临床MR造影剂Gd-DTPA是一种低分子量的细胞外试剂，在乳腺癌表征中不能提供高特异性。同时，近年来分子影像学探针的发展表明，在不久的将来，这些令人兴奋的探针中的一些很有可能用于临床。因此，我们的重点是使用荧光断层扫描系统作为MRI的辅助手段，沿着使用靶向/可激活探针来提高特异性。这些探头现在仅可用于动物成像，并且有必要通过动物研究来评估这种系统的性能。因此，本申请旨在开发用于大鼠成像的混合MR/FDOT系统。如果成功的话，在这个项目中开发的仪器可以很容易地修改为临床乳腺成像和我们的努力的结果将提供一个复杂的工具，可以提供高灵敏度和高特异性的检测和肿瘤的表征。

DESCRIPTION (provided by applicant): Recent development of NIR optical probes for molecular imaging holds great promise for breast cancer imaging. Targeted and activable probes interact with specific targets and therefore make it possible to image biological processes at the cellular or molecular level. Targeted probes bind to specific targets, such as receptors, and can be used to image receptor expression and distribution, while activable probes can be employed to image the activity of matrix-degrading enzymes such as MMPs or cathepsins. Such probes along with optical imaging may yield a unique, highly sensitive technology for in vivo imaging of tumor formation and metastasis. It is inevitable that in the near future some of these probes will be available for use in clinical settings. Despite the advances in molecular imaging technology, however, only recently efforts have been focused on developing in vivo fluorescent enhanced optical tomography (FDOT) that can be used in clinical settings for breast cancer imaging. In this application, we propose to employ a multi-modality approach, a combined MR/FDOT animal imaging system, to improve the accuracy of FDOT and in turn to improve the performance of MRI in distinguishing benign and malignant breast cancers. Several studies have proven that MRI detects malignant cancers which are occult on mammogram and ultrasound, and as such it has fast becoming the most popular imaging modality for screening young women. However, despite its high sensitivity, MRI has low specificity, such that it also detects many benign lesions. As a counterpart of this combined system, FDOT will increase the specificity of the MRI substantially using the targeted/activated probes. Similarly, MRI will improve the quantitative accuracy of FDOT by providing a-priori information, which makes the proposed system a true multi-modality imaging approach. Once the combined system is developed and optimized with phantom studies, the performance of the system will be evaluated with animal studies by using MMP sensitive activable fluorescence imaging probes and two different cell lines that express different levels of MMP activity. The proof-of-principle hybrid MR/FDOT imaging modality proposed in this application is an innovative approach and a first step towards such a clinical multi-modality imaging system. With appropriate modifications in design, the proposed technology has a great translational potential for future human clinical trials. PUBLIC HEALTH RELEVANCE Although mammography is very sensitive in detecting early breast cancer, it does not work well in women who have dense breast tissues, breast implants, or scar tissues due to previous treatment. Breast MRI is considered as the optimal modality in these patient populations. However, the currently available clinical MR contrast agent Gd-DTPA is a low molecular weight extracellular agent that does not provide high specificity in breast cancer characterization. In the mean time, the recent developments in the molecular imaging probes showed that it is very possible to have some of these exciting probes for clinical use in the near future. Therefore, we focused our efforts on to improve the specificity using a fluorescence tomography system as adjunct to MRI along with targeted/activable probes to increase the specificity. These probes are now only available for animal imaging and it is necessary to evaluate the performance of such a system with animal studies. Hence, this application is aimed at developing a hybrid MR/FDOT system for imaging of rats. If successful, the instrumentation developed during this project can be easily modified for clinical breast imaging and the outcome of our effort will offer a sophisticated tool that could provide high sensitivity and high specificity in the detection and characterization of tumors.