Targeting Lymphatic Vessels for Ligand Directed Imaging

摘要 。尤其是， 淋巴管内皮细胞的分子变化现象及其生物学作用(S) 淋巴血管在人类癌症转移级联中的作用尚不完全清楚 过境黑色素瘤综合征是一个引人入胜的临床例子，疾病的表现寻找一个 病理生理学基础。在我们最近的论文中，配体定向的淋巴管靶向揭示了 对黑色素瘤转移的机械论见解(Christian等人)。PNAS，2015)，我们进行了体外实验 用随机肽噬菌体文库筛选直接去除引流淋巴道的组合 来自黑色素瘤切除手术的患者。我们发现了一个功能性的配体-受体系统，通过 恶性黑色素瘤间一种新的同嗜性蛋白-蛋白相互作用的筛选、分离和验证 细胞和淋巴管内皮细胞。这一独特的、以前未被承认的发现提供了基础 用于开发和优化一种新的配体导向淋巴系统成像平台。 在这里，我们建议询问先前发现的与淋巴管表面结合的多肽配体。 疾病进展过程中的内皮细胞发展一种新的、配体导向的、非侵入性体内淋巴管 成像平台。具体地说，我们的目标是：(1)使用创新的化学和生物信息学数据挖掘 系统定义丰富的淋巴管归巢多肽的本体，(2)研究结合 选定的多肽配体及其相应受体的体外性质，以及(3)开发和 实施靶向成像系统以研究淋巴管内皮细胞。PPP2R1A，a的故乡多肽 新的强大的淋巴标志物，将被优先考虑。我们的长期目标是，在完成 这里提出的工作是发现与疾病进展和疾病进展相关的新淋巴生物标志物 产生一组基于配体的显像剂，这些显像剂专门针对淋巴管表面 血管内皮细胞用于预测和诊断的翻译应用。我们预计，新的特征是 淋巴分子地址和经过验证的相应配体和抗体将对 靶向药物的开发，首次建立了无创成像的平台 淋巴系统，并在未来有助于我们理解淋巴血管系统在 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.