Optical Systems for In Vivo Molecular Imaging of Cancer

描述（由申请人提供）： 癌症是一个重大的公共卫生问题。目前，癌症的分类是基于表型标记。癌症独特分子标志物的鉴定导致了新的分子癌症疗法的发展。肿瘤的分子特征化具有重要的临床意义，包括（1）早期发现肿瘤，（2）预测癌前病变进展的风险，（3）真实的实时检测手术室切缘，（4）合理选择分子治疗，（5）在分子水平上实时监测对治疗的反应。成像癌症的分子特征需要分子特异性造影剂，其可以安全地在体内使用，以及具有成本效益的成像系统，以快速和非侵入性地成像这些试剂在体内的摄取、分布和结合。放射影像学成像方式，如CT和MRI，虽然用于描绘进展期癌的深度范围，但对检测小的上皮内病变不够敏感。光学成像是一种新的模态，其使得能够对上皮组织进行真实的实时、高分辨率成像。光学成像系统便宜、坚固且便携。光学成像系统非常适合于上皮内疾病的早期检测，并评估肿瘤边缘和对治疗的反应。 该提案的目标是将光学成像系统和造影剂的发展与功能基因组学的进展相结合。我们将开发分子特异性，光学活性造影剂，可以局部应用。我们还将开发廉价、坚固和便携的成像系统，以监测目标生物标志物的三维轮廓。这些造影剂和成像系统将广泛适用于许多类型的癌症;在这里，我们将开发和测试用于宫颈，口腔和肺部的造影剂和成像系统，这些疾病占全球肿瘤发病率和死亡率的20%以上。我们将在动物模型中测试这些造影剂和成像系统的安全性和有效性，为支持I期和II期临床试验提供数据。本研究的目的是：（1）开发具有光学活性的造影剂，以靶向肿瘤形成的四种分子特征，包括EGFR、MMP、端粒酶和α v整合素;（2）利用SAGE文库鉴定有希望的新生物标志物，并利用组合方法鉴定有希望的新型造影剂的分子探针;（3）开发廉价的便携式光学系统，以真实的时间非侵入性地对瘤形成的形态学和分子特征进行成像;和（4）在逐渐增加复杂性的活生物系统中测试这些试剂、递送制剂和成像系统。(5)我们的最终目标是整合这些研究，开发一种微型成像系统，当与这里开发的造影剂结合时，可以用于肿瘤的真实的分子检测，并在分子水平上监测病变是否对治疗有反应。

DESCRIPTION (provided by applicant): Cancer is a major public health problem. Currently, classification of cancer is based on phenotypic markers. The identification of unique molecular markers of cancer has led to development of new molecular cancer therapies. Movement toward a molecular characterization of cancer would have important clinical benefits, including (1) detecting cancer earlier, (2) predicting risk of precancerous lesion progression, (3) detecting margins in the operating room in real time, (4) selecting molecular therapy rationally and (5) monitoring response to therapy in rear time at a molecular level. Imaging the molecular features of cancer requires molecular-specific contrast agents which can safely be used in vivo as well as cost-effective imaging systems to rapidly and non-invasively image the uptake, distribution and binding of these agents in vivo. Radiographic imaging modalities such as CT and MRI, although useful for delineating the deep extent of advanced carcinomas, are not sufficiently sensitive to detect small, intraepithelial lesions. Optical imaging is a new modality which enables real time, high resolution imaging of epithelial tissue. Optical imaging systems are inexpensive, robust and portable. Optical imaging systems are ideally suited for early detection of intraepithelial disease and to assess tumor margins and response to therapy. The goal of this proposal is to integrate development of optical imaging systems and contrast agents with advances in functional genomics. We will develop molecular-specific, optically active contrast agents that can be applied topically. We will also develop inexpensive, rugged and portable imaging systems to monitor the three-dimensional profile of targeted biomarkers. These contrast agents and imaging systems will have broad applicability to many types of cancer; here, we will develop and test agents and imaging systems for the cervix, oral cavity and the lung, which represent more than 20% of both tumor incidence and mortality worldwide. We will test the safety and efficacy of these contrast agents and imaging systems in animal models, providing data to support phase I and II clinical trials. The aims of this proposal are to: (1) Develop optically active contrast agents to target four molecular signatures of neoplasia, including EGFR, MMP, telomerase and alpha v integrin; (2) to identify promising new biomarkers for which contrast agents will be developed using SAGE libraries, and to identify promising molecular probes for novel contrast agents using combinatorial methods; (3) to develop inexpensive, portable optical systems to image the morphologic and molecular signatures of neoplasia noninvasively in real time; and (4) to test these agents, delivery formulations and imaging systems in living biological systems of progressively increasing complexity. (5) Our final aim is to integrate these studies to develop a miniature imaging system, which when coupled with the contrast agents developed here, can be used for real time, molecular detection of neoplasia and to monitor, at the molecular level, whether a lesion is responding to therapy.