Targeting Lymphatic Vessels for Ligand Directed Imaging

摘要 .特别是 淋巴管内皮细胞的分子变化现象及其生物学作用 人类癌症转移级联中的淋巴管系统还不完全清楚 综合征的过境黑色素瘤是一个迷人的临床例子，疾病介绍，在寻找一个 病理生理基础在我们最近的论文中，配体定向靶向淋巴管揭示了 黑色素瘤转移的机制见解（Christianson et al. PNAS，2015），我们进行了离体 使用直接去除的引流淋巴管的随机肽噬菌体文库的组合筛选 黑色素瘤切除手术中的患者。我们发现了一个功能性的配体-受体系统， 选择、分离和验证恶性黑色素瘤之间的新的嗜同性蛋白质-蛋白质相互作用 细胞和淋巴管内皮细胞。这一独特的和以前未被认识的发现提供了基础 用于开发和优化淋巴系统配体导向成像的新平台。 在这里，我们建议询问以前确定的肽配体，结合到淋巴细胞表面， 在疾病进展过程中的内皮细胞，以开发新的，配体导向的，非侵入性的体内淋巴 成像平台。具体而言，我们的目标是：（1）使用创新的化学和生物信息学数据挖掘 系统来定义富集的淋巴管归巢肽的本体，（2）研究结合 所选肽配体及其相应受体的体外性质，以及（3）开发和 实施有针对性的成像系统来研究淋巴管内皮。归巢PPP 2 R1 A的肽，a 新的强大的淋巴标记物，将被优先考虑。我们的长远目标是，在完成 这里提出的工作是发现与疾病进展相关的新的淋巴生物标志物， 产生一组特异性靶向淋巴表面的基于配体的成像剂， 用于预后和诊断翻译应用。我们预计， 淋巴分子地址和验证，相应的配体和抗体将具有很大的价值， 靶向药物的开发，首次建立了非侵入性成像平台 淋巴系统，并在未来，有助于我们了解淋巴管系统在 人类疾病

ABSTRACT . In particular, the The phenomenon of molecular changes to the lymphatic endothelial cells and the biological role(s) of the lymphatic vasculature in the metastatic cascade of human cancer are not entirely understood syndrome of in-transit melanoma is a fascinating clinical example of disease presentation in search of a pathophysiological basis. In our recent paper, Ligand-directed targeting of lymphatic vessels uncovers mechanistic insights in melanoma metastasis (Christianson et al. PNAS, 2015), we performed ex vivo combinatorial screens using random peptide phage libraries of draining lymphatic channels removed directly from patients during melanoma excision surgeries. We discovered a functional ligand-receptor system by selecting, isolating, and validating a new homophilic protein-protein interaction between malignant melanoma cells and lymphatic endothelial cells. This unique and previously unrecognized finding provides the foundation for the development and optimization of a new platform for ligand-directed imaging of the lymphatic system. Here, we propose to interrogate previously identified peptide ligands that bind to the surface of the lymphatic endothelium during disease progression to develop a novel, ligand-directed, non-invasive in vivo lymphatic imaging platform. Specifically, our goals are to: (1) Use innovative chem- and bio-informatics data mining systems to define the ontology of enriched lymphatic vessel homing peptides, (2) Investigate the binding properties of selected peptide ligands and their corresponding receptors in vitro, and (3) Develop and implement targeted imaging systems to study the lymphatic endothelium. Peptides that home to PPP2R1A, a new powerful lymphatic marker, will be prioritized. Our long-term goal, subsequent to the completion of the work proposed here, is to discover new lymphatic biomarkers associated with disease progression and generate a panel of ligand-based imaging agents that specifically target the surface of the lymphatic endothelium for prognostic and diagnostic translational applications. We anticipate that the newly characterized lymphatic molecular addresses and validated, corresponding ligands and antibodies will be of great value for the development of targeted agents, establishing for the first time, a platform for non-invasive imaging of the lymphatic system, and, in the future, contribute to our understanding of the role by the lymphatic vasculature in human disease.