The reticuloendothelial (RES) or mononuclear phagocytic system (MPS) serves as one of the body’s key defense mechanisms for limiting the damages that pathogens, allergens and other toxic agents actually inflict on our bodies, locally and systemically. The cells of the MPS, monocytes and macrophages, are either freely circulating within the blood or fixed to various connective tissues. Macrophages are mononuclear phagocytes that arise from stem cells in the bone marrow, develop into monocytes, circulate in the blood for one to two days and then distribute into various tissues.
Macrophages serve an essential function in maintaining normal health as they are responsible for cleaning up cellular debris and recycling or eliminating cellular components. Macrophages are capable of phagocytosing particles as large as red blood cells and malarial parasites within a few hundredths of a second. Macrophages can themselves recruit other cells to assist them through secretion of cytokines. Macrophages are involved in the body’s mounting an effective response to numerous insults including: cancer, infection, inflammation and injury. In these settings macrophages actively sequester cells and cellular components that the body recognizes as damaged and/or foreign and has marked for destruction.
N1177‘s composition, size, and formulation have been optimized so that it will be taken up by macrophages. After N1177 is administered intravenously, it remains in the blood pool for 30 – 90 minutes and during that time can be used to image blood vessels and assess organ perfusion. After 2 to 3 hours, N1177 becomes sequestered within macrophages and then can highlight sites of insult and repair, such as atherosclerotic plaque, and thus improve the sensitivity and specificity of CT in heart disease, stroke or cancer.
Significance: Cardiovascular Diseases
According to the AHA, more than 70 million Americans have one or more types of cardiovascular disease (CVD). This year an estimated 700,000 will have a new coronary attack, and about 500,000 will have a recurrent attack. An additional 175,000 silent first heart attacks occur each year. In 2005, the estimated direct and indirect costs of CVD was $393 billion; of coronary heart disease $142 billion; and of stroke $56 billion. Better, earlier diagnosis could lead to better management of CVD and a marked reduction in the above human and monetary costs.
With recent technical innovations the clinical utility of multi-detector CT (MDCT) has been extended in the detection of atherosclerotic plaques in the coronary arteries. However, the potential for atherosclerotic plaques to rupture with catastrophic consequences is related more to the specific cellular (infiltration by inflammatory cells, chiefly macrophages) and biological composition (thin fibrous cap) rather than by their size or degree to which they occlude the vessel lumen. Therefore, a contrast agent that is aimed at detecting macrophages could improve the identification of vulnerable atherosclerotic plaques at high risk of acute coronary events.
Significance: Cancers
The clinical management of cancer patients is critically dependent on there being an accurate assessment of the extent of disease spread, or staging. The size of the primary tumor, involvement of regional lymph nodes draining the tumor, and the presence or absence of tumor deposits in distant organs all must be evaluated to guide the selection of appropriate therapy and monitor the response to therapy of cancer patients.
Imaging of the lymphatics can be performed using x-ray, ultrasound, CT, MRI, and various nuclear medicine techniques. The cross-sectional imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), excel at providing information on the size and location of a tumor as well as at documenting whether there are metastases at sites remote from the primary. However, these modalities by themselves display the architecture of lymph nodes rather poorly, if at all. Physicians now rely almost exclusively on arbitrary size criteria to assess whether there is extension of cancer into lymph nodes. Lymph nodes that are judged to be large (> 1 cm) in CTs and MRIs are considered highly suspicious for cancerous invasion, while those felt to be small (< 1 cm) are not. Furthermore, these techniques often fail to detect tumor deposits in lymph nodes that are not enlarged according to established size criteria, or they may raise suspicion of tumor involvement in lymph nodes that are enlarged due to other, nonmalignant processes. Finally, the images of adjacent lymph nodes or groups of nodes generated by these techniques can be misleading, appearing as one enlarged lymph node with metastasis.
Oncologists need to have improved methods that can accurately provide the following information:
1. Identification of metastatic deposits in the lymph nodes.
2. Guidance in lymph node biopsy and dissection.
3. Accurate staging (better assessment of disease spread).
4. Assessment of response to therapy.
5. Early detection of recurrence, remission or residual tumor.
NSI’s product, N1177, was developed to address these needs, and there is a significant body of preclinical and clinical evidence that supports its efficacy.
