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。临床前研究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，负载了Gd和光学荧光团的第六代树枝状大分子似乎是理想的。与Martin Brechbiel和Gary Griffiths合作，我们开发并测试了具有新合成的树枝状大分子，这些合成应该会简化可能的临床翻译的化学。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。此外，我们正在研究FDA批准的淋巴成像药物Ablavar，因为这种Gd螯合物与白蛋白结合，并有效地成为大分子。我们目前正在研究一种负载Gd的树状大分子，用于潜在的人类用途。该试剂使用具有高亲和力螯合物DOTA的医用级树枝状大分子。这对术前淋巴阻塞和畸形的标测是有用的。我们已经发现了一种商业化的，FDA批准的基于Gd的试剂，Gadofosveset(Ablavar)可能足以识别淋巴通道，因为它与白蛋白结合，产生了一个虚拟的大分子。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。临床翻译：我们一直在与波士顿儿童医院合作开发一种磁共振造影剂，用于患有原发性淋巴水肿的儿童。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试剂，看看它是否适合检测淋巴转移。对20名前列腺癌患者的初步研究已经结束，一项新的研究将正在进行中。

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. Pre-clinical research 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 appears ideal. Working with Martin Brechbiel and Gary Griffiths we have developed and tested dendrimers with new syntheses that should simplify the chemistry for possible clinical translation. 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. Furthermore, we are investigating the FDA-approved drug Ablavar for lymphatic imaging as this gadolinium chelate binds albumin and effectively becomes macromolecular. We are currently working on a dendrimer loaded with Gadolinium for potential human use. This agent uses medical grade dendrimers with a high affinity chelate, DOTA. This could be useful in the pre operative mapping of lymphatic obstruction and malformations. We have found that a commercially available, FDA approved Gadolinium based agent, gadofosveset (Ablavar) may be sufficient to identify the lymphatic channels because it binds to albumin creating a virtual macromolecule. 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. Clinical Translation: We have been collaborating with Boston Childrens Hospital to develop a MR contrast agent for use in human children with primary lymphedema. Ferumoxytol is an iron containing oxide that accumulates in normal nodes. We are testing this agent in patients with GU malignancies to see if it is suitable for detecting lymph node metastases. A preliminary study of 20 patients with prostate cancer has concluded and a new study will be underway.