MRI AND NEAR-INFRARED IMAGING OF THE TUMOR VASCULATURE VIA A NEW MARKER

描述（由申请人提供）：需要更好的肿瘤成像方法来进行早期诊断和监测治疗干预的效果。在各种正在开发的成像策略中，一个非常有前途的类别是基于存在于构成肿瘤血管壁的内皮细胞（ECs）表面的标志物。近年来报道了许多肿瘤EC标记物，但迄今为止还没有一种被证明足以用于大规模临床应用。我们最近发现了一种新的肿瘤EC标记物，它存在于所有被分析的人类肿瘤类型中，无论是早期的还是晚期的，除了生殖腺的一些区域外，它不存在于所有正常组织中。根据我们目前掌握的信息，这个标记可能是一个比任何现有的更好的成像目标。本项目旨在证明该标记物可用于小鼠肿瘤模型的近红外和磁共振成像（MRI）。第一个目标包括纳米颗粒显像剂的合成和表征及其在细胞培养中的测试。纳米颗粒由氧化铁核心水包油乳液组成，既可用于靶向成像，也可用于抗癌药物的输送。这些颗粒将化学偶联到针对EC表面标记的抗体上，并将根据物理性质进行表征。纳米颗粒与培养细胞表达的标记物结合并产生荧光和MRI信号的能力也将得到验证。第二个目标是在裸鼠身上测试靶向对比剂，裸鼠携带的肿瘤是在注射人类肿瘤细胞后产生的。药物将通过静脉注射给药。提出的靶向成像程序旨在为后续临床试验奠定基础。所提出的成像策略有可能导致通过单个全身成像扫描来早期检测大多数实体癌的通用程序，而不依赖于其类型和位置。

DESCRIPTION (provided by applicant): Better tumor imaging methods are needed both for early diagnosis and for monitoring the effects of therapeutic interventions. Among various imaging strategies under development, a very promising category is based on markers present on the surface of the endothelial cells (ECs) that constitute the walls of the tumor blood vessels. A number of tumor EC markers have been reported in recent years but none proved so far good enough for large scale clinical use. We discovered recently a new tumor EC marker that is present in all tumor human tumor types analyzed, both early and advanced, and absent from all normal tissues except some areas of the gonads. Based on the information we have so far, this marker could be a better imaging target than any of the currently available. This project is aimed at demonstrating that the marker can be used for near infrared and magnetic resonance imaging (MRI) of tumors in mouse cancer models. The first aim consists in the synthesis and characterization of nanoparticulate imaging agents and their testing in cell cultures. The nanoparticles consist of an iron oxide core oil-in-water emulsion, which can be used for both targeted imaging and for delivery of anticancer drugs. The particles will be chemically coupled to antibodies against the EC surface marker and will be characterized in terms of physical properties. The ability of the nanoparticles to bind to the marker expressed by cells in culture and generate fluorescence and MRI signals will be also verified. The second Aim is to test the targeted contrast agents in nude mice that carry tumors that develop after injection of human tumor cells. The agents will be delivered by i.v. injection. The proposed targeted imaging procedures are intended to constitute the basis for subsequent clinical trials. The proposed imaging strategy has the potential to lead to a general procedure for early detection of the majority of solid cancers, independently of their type and location, by a single whole-body imaging scan. PUBLIC HEALTH RELEVANCE: We propose to develop a new magnetic resonance imaging (MRI) agent, targeted to tumors by a newly discovered tumor marker that is present on the surface of the blood vessels in most human tumor types and absent from normal tissues. The project has the potential to introduce a general screening procedure that would allow the detection, in a single session and using a single imaging agent, of most tumor types, independently of their location in the body, and at an early stage, when anticancer therapies have much higher chances of success.