Research / Clinical Summary

David Vera, PhD Professor, Radiology Tumor Growth, Invasion & Metastasis Program Contact by Email

We have initiated a 4-year project in which we will synthesize and test a new class of blood pool agents for computed tomography (CT) and magnetic resonance (MR) imaging. Our objective is to develop a new class of imaging agent with the appropriate attributes for detection of tumors and other tissue pathology resulting from abnormal tissue vascularity. These attributes include adequate blood enhancement, favorable residence time within the blood, chemical stability in vitro and in vivo, and high plasma specificity. We expect this agent to provide increased sensitivity for cancer detection and staging, greater imaging flexibility, and increased patient comfort. Additionally, this structure will serve as a neutral carrier of for future class of nonparticulate receptor-binding CT and MRI contrast media.

The proposed agent is based on a molecular backbone of dextran to which multiple reporter units of Gd-DTPA are covalently attached. Using dextran as a molecular backbone offers many advantages. First, the fact that the agent is not a particle should increase biological safety. Second, as dextran is available in a variety of molecular weights, this will make it possible to optimize the agent’s blood residence time and tumor permeability. Third, dextran is composed of repeating glucose units, each of which has three potential attachment sites for each Gd-DOTA-reporter unit. This property will permit optimization of the agent. Fourth, the extensive human use experience with dextran increases the probability that the agent will be safe.

A Receptor-Binding Radiopharmaceutical for Sentinel Node Detection
Sentinel node imaging is a nuclear medicine examination, which identifies for the surgeon the first lymph node to receive lymphatic flow from the breast tumor site. Because this node will be invaded first by malignant breast cancer cells, its removal and microscopic examination is an extremely sensitive index of metastatic disease. Consequently, staging of the cancer by sentinel node imaging is improved over axillary node dissection. By identifying the sentinel node prior to surgery, a small incision can be used to remove the node. Moreover, the examination may rule out the axillary node as the sentinel node. This ability to avoid axillary node dissection decreases morbidity, expense, and permits the subject to return to normal activity much sooner after surgery.

An ideal sentinel node imaging agent would have a smaller size that would allow entry into lymphatic channels more readily, and would demonstrate ability to clear from the injection site more rapidly and completely. Also, it should have a high affinity for lymphoid tissue. The current agent, filtered Tc-99m sulfur colloid, exhibits slow injection site clearance and obscures detection sentinel node in cases when the node is in close proximity to the injection site. Furthermore, it lacks specificity in binding to the receptor within the lymphoid tissue. Within two to three hours post injection, sulfur colloid migrates farther from the sentinel node and accumulates in the distal nodes.

We are testing a new agent that localizes to sentinel nodes based on a specific receptor interaction. This agent, Technetium-99m-labeled MAG3-mannosyl-dextran, binds to a receptor which resides at the surface of reticuloendothelial cells within lymphnodes. It is composed of a 10-kilodalton molecule of dextran to which we attach multiple units of mannose and MAG3. This yields a molecule with a mean diameter of 5.5 nanometers, which is substantially smaller than filtered Tc-99m sulfur colloid. The mannose acts as a substrate for the receptor called mannose binding protein and the MAG3 serves as a chelating agent for labeling with technetium-99m. The result is a radiotracer that rapidly clears the injection site and binds to the sentinel lymph node.

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