Sentinel Node Detection via Targeted Fluorescence

Institution: University of California, San Diego
Investigator(s): David Vera, Ph.D. -
Award Cycle: 1998 (Cycle IV) Grant #: 4IB-0051 Award: $41,259
Award Type: IDEA
Research Priorities
Detection, Prognosis and Treatment>Imaging, Biomarkers, and Molecular Pathology: improving detection and diagnosis

Initial Award Abstract (1998)
If a fluorescent-tagged lymphnode imaging agent is administered at the periphery of a breast tumor, can a surgeon use an ultraviolet lamp to find and excise the lymphnode adjacent (the sentinel node) to the tumor? This project will answer this question.

Recent studies have shown that the success rate of sentinel node detection is increased when two agents (a radioactive tracer and a blue dye) are used in the same patient. Also, recent clinical trials have demonstrated that excision and histologic inspection of the sentinel lymphnode is highly predictive for the absence of metastatic disease, if the sentinel node is free of tumor cells. However, the same clinical trials also revealed that the sentinel node cannot always be detected for all patients. Therefore, while accurate sentinel node detection eliminates the need to dissect all of the axial lymphnodes, improvement in sentinel lymphnode detection has great potential benefit.

We propose a one-year project to combine the two detection methods into a single agent. First, we will synthesize a fluorescent-tagged imaging agent. This imaging agent, called a receptor-binding radiopharmaceutical, has been previously synthesized and tested in our laboratory; when injected under the skin, it travels to lymph nodes, where it recognizes and binds to a receptor molecule within the lymphnode tissue. Second, we will test the surgeon's ability to visualize the lymphnode (using an ultraviolet lamp to activate the fluorescent tag) by injecting it into the footpads of rabbits and imaging the fluorescence with a digital camera. Documentation of adequate fluorescence for lymphnode visualization will be necessary before a granting agency or pharmaceutical company will support the laboratory and safety studies required to bring the new agent to clinical use.

The radioactive tag will permit a radiologist to identify the location of the lymphnode prior to surgery; this will precisely locate the incision. After making the incision, the surgeon can then use a hand-held radiation detector for guidance to the lymphnode. The surgeon will then use an ultraviolet lamp to visualize the periphery of the lymphnode, and after excision, check to see if all of the tissue was removed.

This project combines detection technologies from the fields of nuclear medicine and microscopy. We will employ the biochemical methods which permit an imaging agent to recognize and bind to a specific tissue, which in this project will be lymphnode tissue. We will combine this biochemical technology will the methods employed by microscopy, which permit the visualization of fluorescent-labeled structures. Employing a dual detection method (nuclear imaging and visualization) will increase the accuracy of sentinel node detection. Our proposed agent has the potential to reduce the size of the surgical incision and the length of time during the surgery. This should translate into reduced morbidity.

The new sentinel lymphnode surgical procedure significantly reduces pain, complications, and cost. If successful, our new agent will increase the ability of the surgeon to find the sentinel node, so that more women (hopefully, 100%) can benefit from sentinel node detection.

Final Report (2000)
The specific aim of this one-year project is to synthesize and test a molecule that when injected around a breast tumor will deliver radioactivity and fluorescence to the first lymph node that receives lymph from the tumor site. Our hypothesis is that by rendering the lymph node fluorescent, our new agent will help the surgeon find the lymph node with the aid of an ultraviolet lamp. We proposed to accomplish this by attaching a fluorescent chemical to a radiolabeled molecule that binds to lymph nodes.

To date, we have synthesized the radiolabeled molecule. This radioactive molecule consists of a chain of sugars called glucose, to which we attached a molecule called DTPA. This molecule can be labeled with technetium-99m, which will make sugar chain radioactive. We have also attached another chemical to the chain, which is called mannose. The mannose permits the lymph node to avidly bind the radioactive chain. We have attached to the sugar chain the fluorescent agent, fluorescein and are now ready to test the agent's ability to visualize lymph nodes after injection into the foot pads of healthy anesthetized rabbits.