Tracking pancreatic adenocarcinoma response to treatment using targeted, multi-modal nanoparticles
Mentor: Anna Moore, PhD (MGH)
Early diagnosis and efficient treatment of tumors are essential to the survival of cancer patients. New molecular based therapies are beginning to allow treatment regimens that take advantage of a tumor's unique molecular characteristics. However, there is a need for more sophisticated imaging techniques to enable the effective application of these therapies. Imaging probes that are able to target tumors would help to facilitate earlier diagnoses, monitor tumor response to existing therapies, and facilitate the development of novel therapeutics. One class of probe currently being studied and refined are cross-linked, iron oxide nanoparticles carrying EPPT peptides. This molecule is a targeted, multi-modal imaging probe referred to as MN-EPPT. The EPPT peptide attached to the nanoparticle’s dextran coat is able to bind to the underglycosylated mucin-1 antigen, (uMUC-1) which is specifically expressed on the surface of human adenocarcinomas. As a result, the probe is able to accumulate selectively in tumor cells. uMUC-1 is present on almost 50% of all human cancers, including breast, prostate, lung, and pancreatic cancers, among others. The nanoparticles are designed for use with two different, yet complementary imaging modalities. The iron oxide is superparamagnetic, which means it is viable as a contrast agent for MR imaging. Furthermore, MN-EPPT particles are coated with a Cy5.5 dye, which allows them to be used for optical near-infrared imaging (NIRF). This dual functionality lets the probe take advantage of the unique benefits of each type of imaging. MRI provides high spatial and temporal resolution, and NIRF is known for its sensitivity. In addition, the presence of Cy5.5 dye allows for correlative fluorescence microscopy of excised tissues. The current project will evaluate MN-EPPT’s utility as a device for assessing tumor response to a standard chemotherapeutic, Gemcitabine, in a preclinical model of orthotopic pancreatic adenocarcinoma. This study will also validate the work done in previous projects that demonstrated MN-EPPT’s ability to accumulate selectively at the site of the tumor. Both MR and NIRF imaging will be used to examine the probe's feasibility as a tool for tracking changes in tumor size. In addition, we will investigate whether Gemcitabine causes downregulation of uMUC1 antigen during treatment, which may affect MN-EPPT’s ability to accumulate in tumor cells. This will be done by investigating uMUC1 mRNA expression and correlating it with MN-EPPT accumulation in tumors.
A) NIRF images showing the accumulation of the MN-EPPT probe in colon tumors. The tumor on the left lacks the uMUC-1 antigen (uMUC-1 -), while the tumor on the right does have the uMUC-1 antigen (uMUC-1 +). Signal from the probe is much higher in the uMUC-1 + tumor, as demonstrated by the center and right images showing raw fluorescence and a color coded map, respectively. B) NIRF images of excised tumor C) Fluorescence microscopy of the probe in excised tissue. Images demonstrate that the nanoprobe retained its structural integrity. Source: