This research seeks to validate and investigate the utility of long circulating dextran based iron oxide (LCDIO) contrast agents for the assessment of active tumor growth in local and regional lymph nodes during cancer spread. During the current funding we have made considerable progress in developing, characterizing and understanding the mechanism of action of lymphotropic drug carriers both for therapeutic and diagnostic purposes. Using this understanding our data supports the hypothesis that LCDIO imaging is not only feasible in humans, but superior to non-contrast MR imaging for the detection of lymph node metastases. While results from current phase 3 clinical trials are entirely consistent with prior observations in animal models, simple image interpretation (e.g. overall changes in nodal signal intensity) leaves many of the most interesting questions regarding the non-invasive assessment of lymph nodes unanswered. For example, recent clinical questions regarding the non-invasive assessment of lymph nodes unanswered. For example, recent clinical trials demonstrate that minimal nodal tumor burden in non-enlarged nodes is indeed detectable by LCDIO enhanced MR imaging. We hypothesize that microscopic tumor cell clusters in nodes cause functional lymphatic abnormalities detectable my MR imaging, before changes in morphology or size become apparent. Examples of such functional abnormalities include altered intranodal lymphatic fluid flow due to micrometastases in the sinuses, or increased neovascular permeability and blood flow. Using genetically engineered tumor cells, radiotracer studies and compartmental analysis we will now directly correlate nodal tumor burden with LCDIO accumulation. Combined with cell biology studies on cellular uptake into different nodal populations a more complete picture of LCDIO transport to lymph nodes and its magnetic effects will be obtained. The approach will be validated in human lymph nodes using MR imaging, immunohistochemistry against the dextran coat of LCDIO and correlative analysis. The latter studies are especially are especially relevant since little data exists on nodal LCDIO distribution and correlative histology in human lymph nodes. By providing a quantitative assessment of LCDIO transport to lymph nodes. By providing a quantitative assessment of LCDIO transport to lymph nodes this research should enhance the non-invasive characterization of nodal status in patients with known primary cancers and may ultimately aid in the design of novel therapeutic lymphotropic drug carriers.
Showing the most recent 10 out of 27 publications
