Bioresponsive MR probes for imaging pancreatic cancer

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Pancreatic cancer holds the poorest prognosis of any cancer with an incident rate nearly equal to its mortality rate. While significant advances in treatment have been made for many other cancers, the outcomes for pancreatic cancer have only marginally improved. Current diagnostic methods are only able to detect the disease at late stages, at which point the primary tumor is often too advanced for curative surgery and has metastasized. By enabling detection of early stages of pancreatic cancer, the outcome of patients could be drastically improved. By specifically detecting changes in local biochemistry and cell biology through environmental and molecular tumor markers, it is possible to detect a nascent tumor before it has developed enough to cause anatomical or functional disturbances. Key environmental markers of proliferating tumors include a high reduction potential, induced by tumor hypoxia, and collagen-rich desmoplasia. Pancreatic cancer molecular markers of aggressive disease types include high levels of αvβ6 integrin receptor and elevated matrix metalloproteinase-9 (MMP-9) activity. These molecular markers can be detected by bioresponsive magnetic resonance (MR) contrast agents that are targeted to tumor markers. Clinically-approved Gd(III) MR contrast agent (CAs) provide a versatile platform for developing molecular imaging probes for pancreatic cancer through the detection of environmental and molecular markers. The Meade lab has continued to develop responsive Gd(III) CAs with a variety of activation mechanisms that alter the probe's signal in response to specific conditions. Electronic spin relaxation time (T1e) modulated molecular imaging probes provide a promising bioactivatable platform for Gd(III)-based CA with a low r1,off and bright r1,on. Because T1e is the only parameter to affect all coordination spheres of the CA, its modulation can establish a lower background signal than modulation of T1 parameters. Redox-sensitive T1e- modulated probes will use a collagen-targeting cyclic peptide to accumulate in the desmoplastic microenvironment and will be tuned for a tumor specific redox potential. MR shift probes provide a bioactivatable method of distinguishing tumor tissue from healthy tissue based on ratiometric imaging, in which the signal of the probe shifts in response to environmental conditions. Using cyclic RGD to target integrin receptors overexpressed in pancreatic cancer and a short peptide cleaved by MMP-9, this probe will accumulate in pancreatic tumors and provide ratiometric data on MMP-9 activity. The performance of the new probes will be evaluated in vivo using healthy mice and an orthotopic model of pancreatic cancer. This proposal meets the mission statement and funding plans of the NCI. The project involves the development of new imaging probes for molecular detection of pancreatic cancer. Environmental and molecular markers of pancreatic cancer provide a target for early detection. Because of the poor prognosis associated with pancreatic cancer, advances in disease detection could drastically improve patient outcome.