Collaborative Efforts Between the NYU Departments of Radiology and Chemistry in Contrast Agent Development
Figure 1: Molecular imaging applications
Currently, an area of intense interest in radiology research, and medical research as a whole, is that of molecular imaging. While there is some debate regarding exactly what constitutes molecular imaging, one definition from a recent multidisciplinary summit held by the Radiologic Society of North America and the Society of Nuclear Medicine is that “Molecular imaging techniques directly or indirectly monitor and record the spatio-temporal distribution of molecular or cellular processes for biochemical, biological, diagnostic or therapeutic applications.” Despite the fact that some existing imaging technologies, including much of nuclear medicine and magnetic resonance spectroscopy (and some may argue even MRI as a whole), fall within this rubric of “molecular imaging,” it is the convergent research advances in multiple fields which have contributed to the present drive in molecular imaging research.
Overall, advances in biomedical research have allowed for a better understanding of the molecular basis of disease; bioinformatic analyses of genomic and proteomic studies hold promise for the continued identification of specific biomarkers relevant in disease processes, and developments in structural biology have improved our understanding of the design of key biological molecules. Tandem progress in chemical biology has enhanced our ability to use synthetic chemistry to study biological systems. Increased sophistication of bioconjugation strategies and the manipulation of particles on a nanometer (10-9m) scale allow the creation of molecules suited for therapeutic use and detection purposes. These hold the potential, if harnessed in concert with rapid developments in imaging technologies, to push the limits of disease detection. While progress in these fields will independently impact molecular imaging research, it is clear that a multidisciplinary approach is essential to best propel the field.
A series of research collaborations have evolved with the NYU Department of Chemistry in the development of contrast agents. From a diagnostic standpoint, a wide variety of molecular agents can be rationally designed to serve as contrast agents in MR, optical, or radionuclide imaging (FIGURE 1). There are a series of different nanoplatforms or scaffolds which can be employed to fabricate a contrast agent, and there are different targeting agents and activation schemes that can be used to further refine the mechanisms of action of these agents.
Many difficulties exist in the successful implementation of contrast agents, particularly for cancer imaging. A goal of the Cancer Nanotechnology Plan of the National Cancer Institute is identification of tumors by the time they have reached a size of 100,000 cells, a decrease from current detection limits of approximately 1,000,000,000 cells. Even if each individual cell was relatively large, this would represent a tumor of just over one millimeter in size, a significant challenge to our current capabilities of signal detection. This aside, there are additional chemical characteristics, including stability at biological pH, solubility, molecular size, and ease of synthesis, which need to be considered. Furthermore, biological properties such as biocompatibility and immunogenicity are critical if the agent is to be used in living beings. Given the number of possible agents, with a nearly infinite number of chemical permutations, high throughput analyses will be important to sift through the body of potential agents to find those of greatest promise. The complex demands of this research increase the need for collaborative efforts such as those between the NYU Departments of Radiology and Chemistry. While still embryonic, this teamwork has already given rise to encouraging results in molecular imaging research.
One of our efforts in contrast agent research is the development of agents designed to evaluate head and neck squamous cell carcinoma (HNSCC). HNSCC remains a significant source of morbidity and mortality, with approximately 40,000 new diagnoses in the United States annually. Many patients present with advanced, unresectable disease, which carries a particularly poor prognosis. Treatment often entails concurrent chemotherapy and radiation; only those with less advanced disease undergo extensive and disfiguring surgical procedures. The epidermal growth factor receptor (EGFR) has emerged recently as a target for anti-cancer drug therapies, given the high level of epidermal growth factor expression in HNSCC cells, and its correlation with poor prognosis. The role of EGFR expression in HNSCC has not been fully explored; however, it is known that EGFR signaling plays an important role in processes key to the development of cancer, such as growth, invasion, angiogenesis, and the development of metastases. Multiple clinical trials have shown the ability of anti-EGFR agents to improve survival in advanced stage HNSCC, both in combination therapy and as monotherapy.
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