Collaborative Efforts Between the NYU Departments of Radiology and Chemistry in Contrast Agent Development
Figure 2. Fourth-generation polyamidoamine
(PAMAM) dendrimer. 64 separate amino side groups
are available for conjugation of multiple imaging agents
and therapeutic agents. The size of this molecule is
four nanometers, smaller than a molecule of hemoglobin
and the thickness of most cell membranes. Courtesy of
Dendritech, Inc.
We believe that in vivo monitoring of EGFR expression in HNSCC with a targeted contrast agent may provide advantages over standard imaging, potentially allowing further refinements in anti-EGFR therapy design, and an evaluation mechanism for future clinical trials. However, a means of in vivo noninvasive monitoring of EGFR expression is not currently available for use in these trials as a potential metric of treatment efficacy or a predictor of treatment response. Our eventual long-term goal is to create an array of in vivo molecular nanoprobes targeted against different markers of HNSCC including EGFR, and to test their efficacy in the prediction of disease outcome and treatment response. The development of a molecular imaging agent targeting EGFR would not only be significant in the imaging evaluation of drug therapy, but may also play a role in the detection of preclinical or precursor lesions. EGFR expression is also increased in dysplastic precursors to HNSCC, relative to normal tissues, and EGFR levels increase with increasing levels of dysplasia. Highly sensitive agents, therefore, could be promising in the early detection of HNSCC, particularly when coupled with optical imaging technologies for potential use during clinical examination of the aerodigestive tract.
Through work done in collaboration with James Canary, Ph.D., and Steven Isaacman of the Canary Lab in the NYU Department of Chemistry, we have synthesized a dual-function MRI and optical contrast agent directed against EGFR. This agent uses a highly branched nanoscale molecule known as a dendrimer (FIGURE 2), labeled with multiple gadolinium ions, for MR imaging contrast capability. The molecule is then attached to a fluorescent antibody to target EGFR. As stated previously, a wide array of different agents can be constructed from various chemical and biochemical components. Our goal was to develop an agent with multimodality imaging capability, with MR imaging to be used to evaluate the extraluminal extent of disease, with its attendant high spatial resolution and tissue contrast, and with optical imaging to be used for clinical or endoscopic detection of EGFR expression along the mucosal surfaces of the aerodigestive tract. Recent results demonstrate that this agent’s optical imaging capabilities, EGFR targeting, and relaxivity (a measure of the effectiveness of MRI contrast agents) are nearly one hundred times greater than those of current commercial agents. We are currently working with Leonard Liebes, Ph.D., of the NYU Cancer Institute and Daniel Turnbull, Ph.D., of the Department of Radiology to investigate properties of this and other agents in vivo.
Biological chemists are essential to help plan, synthesize, and characterize these agents. Other collaborators in the NYU Department of Chemistry include Kent Kirshenbaum, Ph.D., and Elizabeth Anderson, Ph.D., of the Kirshenbaum Lab, whose knowledge of peptide and peptoid chemistry, and synthetic click chemistry, has allowed for the creation of multiple chemical constructs with contrast agent potential. One of these is an MRI and optical contrast agent based on the protein cage of a viral capsid. The research focus of Young-Tae Chang, Ph.D., involves the use of fluorescent compounds to create a combinatorial molecular library for biomarker detection; using this strategy, his group has developed a class of unique fluorescent small molecules which specifically stain amyloid plaque for potential use in the imaging of Alzheimer’s disease. Exciting developments in this field are made possible through multidisciplinary effort; partnering with our Chemistry colleagues, we hope to continue to identify novel means of imaging disease on a molecular basis. Specifically, we anticipate exciting imaging developments to arise from the NYU Molecular Imaging and Contrast Agent (MICA) Working Group, led by Jens Jensen, Ph.D., (Radiology) and Dr. James Canary. This initiative was conceived as a multidisciplinary forum for discussing imaging and contrast agent research among various departments at NYU’s School of Medicine and Washington Square campuses, and as an opportunity to promote collaborative research between institutions. In intersecting partnerships with our clinical colleagues, we hope this teamwork will lead to a more expedient application and translation of new nanomolecular imaging technologies to pressing and challenging clinical problems.
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