A LECTIN-CONTRAST AGENT FOR MULTIMODALITY MOLECULAR IMAGING OF TUMOR ANGIOGENESIS

描述(申请人提供)：这项提案的主要目标是开发一种新的凝集素靶向成像探针，利用分子磁共振成像(MRI)提高我们在血管生成过程中成像肿瘤血管结构和功能变化的能力。我们建议开发一种针对血管管腔的双重模式(MRI和光学)造影剂，使用来自Bandeiraea Simicifolia(GS-1)的凝集素(GS-1)，这是一种非免疫性来源的蛋白质，与内皮细胞结合，在体内最长可达18h，而不会从肿瘤血管渗出。目标1致力于开发基于T1脂质体的凝集素靶向造影剂，而目标2专注于开发基于T2超顺磁性凝集素靶向纳米颗粒的造影剂。有了这些新的造影剂，我们打算在人类转移性乳腺癌模型中表征伴随肿瘤进展的血管结构的重塑。我们将使用高分辨率3D MRI在体内进行这项工作，并首次在体外使用磁共振显微镜(MRI)，生成血管结构的第一个3D数字模型。这些新造影剂上的荧光标记将使激光扫描共聚焦显微镜直接验证MRI数据成为可能。这些数据将促进我们对血管生成和由此产生的图像对比度的基本机制的理解。它的低毒、血管特异性和广泛的体内半衰期，使我们的凝集素靶向造影剂成为监测患者抗血管生成治疗效果的宝贵新工具。这项名为《用于肿瘤血管生成的多模式分子成像的凝集素造影剂》的申请集中于开发一种新型的基于凝集素的分子磁共振造影剂，该造影剂通过单叶板栗凝集素与血管内皮细胞的亲和力来优先靶向血管。我们打算合成和表征这种造影剂的T1和T2版本，并利用它们来更好地了解肿瘤血管生成在人类转移性乳腺癌异种移植模型中的作用。

DESCRIPTION (provided by applicant): The primary goal of this proposal is to develop a de novo lectin-targeted imaging probe that improves our ability to image the structural and functional changes in tumor blood vessels during angiogenesis, using molecular magnetic resonance imaging (MRI). We propose to develop a dual-modality (MRI and optical) contrast agent targeted to the lumen of blood vessels using the lectin from Bandeiraea Simplicifolia (GS-1), a protein of non-immune origin that binds to endothelial cells, for up to 18h in vivo without extravasating from tumor vessels. Aim 1 is focused on developing a T1 liposome-based lectin-targeted contrast agent, while Aim 2 focuses on developing a T2 superparamagnetic lectin-targeted nanoparticle based contrast agent. With these new contrast agents, we intend to characterize the remodeling of the vascular architecture that accompanies tumor progression, in a human metastatic breast cancer model. We will do this in vivo using high-resolution 3D MRI, and for the first time ex vivo using MR microscopy (}MRI), producing the very first 3D }digital casts} of the vessel architecture. The fluorescent tag on these new contrast agents will enable direct validation of the MRI data with laser scanning confocal microscopy. These data will promote our understanding of the basic mechanisms underlying angiogenesis and resulting image contrast. Its low toxicity, blood vessel specificity and extensive half-life in vivo, could make our lectin-targeted contrast agents an invaluable new tool for monitoring the efficacy of anti-angiogenic therapies in patients. The application titled "A Lectin-Contrast Agent For Multimodality Molecular Imaging of Tumor Angiogenesis" is centered on developing a novel lectin-based contrast agent for molecular MRI, which preferentially targets blood vessels via the affinity of the lectin from Bandeiraea Simplicifolia for endothelial cells. We intend to synthesize and characterize, both T1 and T2 versions of this contrast agent, and employ them to better understand the role of tumor angiogenesis in a human metastatic breast cancer xenograft model.