Lymphatic Imaging

淋巴管是人体的第三循环，是肿瘤扩散的重要途径。淋巴管生成是一些肿瘤的特性，允许它们通过淋巴管繁殖。这个过程很难研究，因为淋巴管很小，难以接近。然而，通过注射各种大分子造影剂，包括放射性标记、光学标记和磁性标记，可以识别淋巴管及其引流模式。此外，在此过程中获得的知识对原发性和继发性淋巴水肿的诊断和管理具有重要意义，这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影响。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5-10nm之间的大分子药物是研究淋巴的理想药物，因为它们能快速吸收并转运到前哨淋巴结。前哨淋巴结成像很重要，因为目前的方法依赖于繁琐的蓝色染料和放射性硫胶体。我们已经开发了一种树突状分子，它可以用于核磁共振成像和光学成像的双重标记，可以在不使用核磁共振成像和光学成像电离辐射的情况下识别前哨淋巴结。通过比较不同大小的树状大分子，实现了淋巴剂的优化。我们发现非常小的药剂从淋巴中泄漏，效果不理想，而大的药剂则太慢。因此，第6代枝状大分子负载钆和光学荧光团是理想的。与Martin Brechbiel和Gary Griffiths合作，我们开发并测试了新的树状大分子合成方法，这将简化化学反应，可能用于临床翻译。我们还使用IgG作为淋巴成像的载体分子，并证明它具有生物相容性和适合淋巴成像的大小。此外，我们正在研究fda批准的用于淋巴成像的药物Ablavar，因为这种钆螯合物结合白蛋白并有效地成为大分子。我们目前正在研究一种含有钆的树状大分子，以供人类使用。该试剂使用具有高亲和力螯合物DOTA的医用级树状大分子。这可能有助于术前绘制淋巴阻塞和畸形。我们发现一种市售的、FDA批准的钆基制剂gadofosveset （Ablavar）可能足以识别淋巴通道，因为它与白蛋白结合，产生虚拟大分子。我们使用两个彩色量子点来研究乳房和手臂到腋窝淋巴结的引流，发现一些小鼠具有独立的引流系统，而另一些小鼠具有双引流淋巴结，即部分引流乳房和部分引流肢体的淋巴结。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人类儿童。阿魏木糖醇是一种含铁氧化物，在正常淋巴结中积累。我们正在GU恶性肿瘤患者中测试这种药物，看看它是否适合检测淋巴结转移。一项针对20名前列腺癌患者的初步研究已经结束，一项新的研究正在进行中。

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.