Targeted Design and Delivery of Cell Selective Imaging Agents for Computed Tomography (CT), Nuclear Medicine, PET, and Magnetic Resonance (MR)
CT and MRI Contrast Agents: CT projects include the development of polyiodinated lipophilic agents for hepatocytes-selective imaging as well as blood pool agents for CTA (angiography) and lymphography. MR interests utilize the same lipoprotein-like vehicle to deliver gadolinium chelates to hepatocytes for tumor imaging and a blood pool version may prove useful for detecting and characterizing atheroschlerotic plaques and other vascular anomalies. Utilizing a targeted delivery approach coupled with design and development of appropriate agents represents a significant enhancement over currently available imaging agents in all diagnostic modalities. We can now easily detect sub-300 micron liver tumors in live mice using the ImTek microCT scanner. Finally, combining the hepatocyte-selective ITG with a long acting radiopaque blood pool agent to temporarily enhance the vessels affords ultra-high-resolution liver tumor images. As a result of these studies, the surface of the chylomicron remnant-like carrier was modified in order to delay hepatocyte uptake thus resulting in prolonged blood pool activity (up to three hours). Combining these two versions of the ITG emulsion has eliminated the need to administer a subsequent small dose of urographic agent to get the highest contrast images of the tumor margins. An MRI blood pool agent is also under development. Such blood pool-selective agents may have widespread clinical use in CTA, MRA, cardiac, and atheroschlerotic conditions. Installation of a research MicroCT scanners has been vital toward further development of the hepatocyte-selective CT as well as CT and MR blood pool agents. Many of the initial CT imaging experiments in rodent models have been completed on these scanners at ultra high resolutions less than 20 micrometers. Moreover, ultra-high resolution blood pool imaging studies coupled with 3D reconstruction of the data may lead to very early detection and or characterization of atheroma or other vascular abnormalities. Such ultra high-resolution studies in rodents are not currently possible on large gantry clinical scanners. Results obtained on the MicroCT scanners may, however, provide a window to the future capabilities of our new agents as the resolution of commercial scanners continues to improve.
Tumor Selective Nuclear Medicine/PET Agents
Radioiodinated phospholipid analogs have proven useful in gamma camera imaging of a variety of human tumor xenografts and spontaneous tumor models in rodents. A promising second-generation analog, NM404, is currently undergoing clinical evaluation in lung cancer patients. The agent, which has shown remarkable tumor cells retention in 25/25 tumor models, can be defined as a diapeuticTM agent (Cellectar, LLC., Madison, WI) since it affords both tumor diagnostic and therapeutic potential. We are currently examining the tumor selectively of this agent in hyperplasia and neoplasia mouse models, and are initiating studies to evaluate its potential to predict tumor response to a variety of treatment modalities including external beam radiotherapy, chemotherapy, radio-frequency ablation, and surgical resection. We will soon be labeling this exciting compound with iodine-124, a new PET isotope with a 4 day half-life.