Optical Systems for In Vivo Molecular Imaging of Cancer

描述(由申请人提供)： 癌症是一个主要的公共卫生问题。目前，癌症的分类是基于表型标志物的。独特的癌症分子标志物的识别导致了新的分子癌症治疗方法的发展。肿瘤分子特征的研究将具有重要的临床意义，包括：(1)更早发现癌症，(2)预测癌前病变进展的风险，(3)实时检测手术室切缘，(4)合理选择分子治疗方法，(5)在分子水平上监测治疗反应。成像癌症的分子特征需要可以在体内安全使用的分子特异性造影剂，以及成本效益高的成像系统，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。CT和MRI等放射成像方法虽然有助于描绘晚期癌症的深部范围，但对发现微小的上皮内病变不够敏感。光学成像是一种新的成像方式，可以对上皮组织进行实时、高分辨率的成像。光学成像系统价格低廉，坚固耐用，便于携带。光学成像系统非常适合于早期发现上皮内疾病，评估肿瘤边缘和对治疗的反应。 这项建议的目标是将光学成像系统和造影剂的开发与功能基因组学的进展结合起来。我们将开发可局部应用的分子特异性、光学活性造影剂。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对许多类型的癌症具有广泛的适用性；在这里，我们将开发和测试用于宫颈、口腔和肺的造影剂和成像系统，这些造影剂和成像系统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。这项建议的目的是：(1)开发光学活性对比剂，以靶向肿瘤的四个分子标记，包括EGFR、基质金属蛋白酶、端粒酶和αv整合素；(2)确定有前景的新生物标记物，将使用SAGE文库开发对比剂，并使用组合方法为新型对比剂确定有前景的分子探针；(3)开发廉价、便携式的光学系统，以非侵入性地实时成像肿瘤的形态和分子特征；以及(4)在日益复杂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以开发一种微型成像系统，当与这里开发的造影剂相结合时，该系统可以用于实时、分子检测肿瘤，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.