Lymphatic Imaging

淋巴管代表着体内的第三循环，是肿瘤扩散的重要途径。淋巴管生成是一些肿瘤的一种特性，它允许它们通过淋巴管传播。这个过程一直很难研究，因为淋巴管很小，很难接触到。然而，通过注射各种大分子造影剂，包括放射性标记的、光学标记的和磁性标记的，可以识别淋巴管及其引流模式。此外，在这一过程中获得的知识对原发性和继发性淋巴水肿的诊断和治疗具有重要意义，淋巴水肿可能是癌症治疗的严重并发症。最后，大分子造影剂的发展对其他疾病也有意义。MIP正在使用成像方法研究淋巴管在癌症中的作用。我们发现，直径在5-10 nm之间的大分子试剂是研究淋巴管的理想选择，因为它们可以快速摄取和转运到前哨淋巴结。前哨结节成像很重要，因为目前的方法依赖于笨重的蓝色染料和放射性硫胶。我们已经开发了一种树枝状大分子，它是MRI成像和光学成像的双重标记，可以使用MRI和光学成像在没有电离辐射的情况下识别前哨结节。通过比较不同大小的树枝状大分子，实现了淋巴制剂的优化。我们发现，极小的药剂从淋巴管中渗出，效果不佳，而大药剂则太慢。因此，负载Gd和光学荧光团的第六代树枝状大分子是理想的。与其他人合作，我们开发并测试了具有新合成的树枝状大分子，简化了可能的临床翻译的化学。然而，我们最终放弃了树枝状大分子，因为它们从体内清除的时间非常长。我们还使用了免疫球蛋白作为淋巴成像的载体分子，并证明了它是一种生物相容性好、大小合适的淋巴成像材料。我们使用了两种颜色的量子点来研究乳房和手臂到腋窝淋巴结的引流，发现一些小鼠有独立的引流系统，而另一些小鼠则表现出双引流结节，即部分引流乳房和部分引流肢体的结节。此外，我们还探索了同时使用多达5个不同波长的量子点，以建立头部和颈部复杂的淋巴引流模式。然而，量子点的生物相容性是一个令人担忧的问题。我们与波士顿儿童医院合作开发了一种磁共振造影剂，用于患有原发性淋巴水肿的儿童。我们发现，注射到猪脚中的Gd很快就会使胸腔导管浑浊。然而，出现了更好的技术，将Gd注射到腹股沟淋巴结中。阿魏酸甘油是一种含铁的氧化物，在正常的结节中积聚。我们正在GU恶性肿瘤患者身上测试这种药物，以确定静脉注射是否适合检测淋巴转移。一项对20名前列腺癌患者的初步研究已经结束，今年发表了一项新的研究。我们与HIV/AIDS小组合作，了解结肠的淋巴引流。我们正在开发一种方法，通过识别与炎症区域相关的“哨兵”结节来识别相关的淋巴结。通过了解影像上的引流模式，有可能更好地了解HIV引起结肠炎的机制。此外，我们正在研究慢性感染SIV动物的结构成像变化，这些动物表现为纤维化。

The lymphatics represent the third circulation in the body and are an important route of spread for tumors. Lymphangiogenesis is a property of some tumors that allows them to propagate via the lymphatics. This process has been difficult to study because the lymphatics are small and inaccessible. However, by injecting various kinds of macromolecular contrast agents, including radiolabeled, optically labeled and magnetically labeled it is possible to identify the lymphatics and their drainage patterns. Moreover, the knowledge gained in this process has implications for the diagnosis and management of primary and secondary lymphedema, which can be a serious complication of cancer therapy. Finally, the development of macromolecular contrast agents has implications for other diseases. The MIP is investigating the role of the lymphatics in cancer using imaging methods. We have found that macromolecular agents of between 5-10nm in diameter are ideal for studying the lymphatics based on their rapid uptake and transit to the sentinel nodes. Sentinel node imaging is of importance because current methods rely on cumbersome blue dyes and radioactive sulfur colloid. We have developed a dendrimer that is dual labeled for MRI imaging and optical imaging that would allow the identification of the sentinel node without ionizing radiation using MRI and optical imaging. By comparing different sized dendrimers optimization of the lymphatic agent was achieved. We found that very small agents leaked from the lymphatics and were unsatisfactory whereas large agents were too slow. Therefore, the Generation 6 dendrimer loaded with Gadolinium and an optical fluorophore was ideal ideal. Working others, we have developed and tested dendrimers with new syntheses that simplified the chemistry for possible clinical translation. However, we ultimately abandoned dendrimers because of their very long clearance times from the body. We have also used IgG as a carrier molecule for lymphatic imaging and shown it to be a biocompatible and suitably sized for lymphatic imaging. We have employed two color QDs to investigate the drainage of the breast and arm to the axillary lymph nodes and found that some mice had independent drainage systems whereas other mice demonstrated dual draining nodes , i.e. nodes that partly drained the breast and partly drained the limb. Additionally we have explored the use of up to 5 QDs of differing wavelength simultaneously in order to establish the complex lymphatic drainage patterns in the head and neck. However, the biocompatibility of QDs is a concern. We collaborated with Boston Childrens Hospital to develop a MR contrast agent for use in children with primary lymphedema. We found that gadolinium injected into the foot of pigs quickly opacified the thoracic duct. However, better techniques have emerged in which gadolinium is injected into inguinal lymph nodes. Ferumoxytol is an iron containing oxide that accumulates in normal nodes. We are testing this agent in patients with GU malignancies to see if intravenous administration is suitable for detecting lymph node metastases. A preliminary study of 20 patients with prostate cancer has concluded and a new study was published this year. We collaborated with the HIV/AIDS group to understand the lymphatic drainage of the colon. We are developing a method of identifying the relevant lymph nodes by identifying the "sentinel" nodes related to areas of inflammation. In understanding the drainage patterns on imaging it may be possible to better understand the mechanisms of HIV induced colitis. Additionally we are studying structural imaging changes in chronically infected animals with SIV demonstrating fibrosis.