Imaging pancreatic cancer with a peptide-nanoparticle conjugate targeted to normal pancreas

Most attempts to develop imaging agents that can better distinguish tumors from healthy tissue focus on finding molecules that are more abundant on malignant cells than on normal cells and using those as cellular targets.

Turning this strategy on its head, researchers at the MIT-Harvard Center of Cancer Nanotechnology Excellence (CCNE) have created a targeting agent that binds to a molecule found only on healthy pancreatic tissue. They then used this peptide to create a multifunctional nanoparticle-based imaging agent capable of pinpointing pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer death in the United States.

Reporting its work in the journal Bioconjugate Chemistry, a research team led by Lee Josephson, Ph.D., of Harvard Medical School and a member of the MIT-Harvard CCNE, and Ralph Weissleder, M.D., co-principal investigator of the MIT-Harvard CCNE, described its novel tack to creating its new imaging agent. As its target, the team chose a cell surface protein known as the bombesin receptor, which binds to naturally occurring peptide bombesin. Initial work by this group had already confirmed reports in the literature suggesting that this receptor, abundant on the surface of healthy pancreatic cells, may be missing on PDAC cells.

The investigators created the new imaging agent by first linking a fluorescent molecule to the bombesin peptide and then attaching this molecular construct to dextran-coated iron oxide nanoparticles. As an experimental control, they also prepared a version containing a peptide that does not bind to bombesin receptors.

As an initial test, the researchers added the two peptide-nanoparticle conjugates to thin tissue slices taken from both healthy and malignant mouse and human pancreas samples. The presence of the fluorescent label on the conjugates enabled the investigators to see that the bombesin-tagged nanoparticles bound to healthy mouse and human pancreas, while the control did not. Neither the experiment nor the control peptide-nanoparticle conjugate bound to malignant pancreatic tissue.

Then came the key experiment to determine if the bombesin-tagged nanoparticle would enable the researchers to distinguish between healthy and malignant tissue in a living animal. Using a mouse model of human PDAC, the answer was a resounding yes. Without the contrast agent, tumors were barely visible in magnetic resonance images. With the contrast agent, the tumors were visible as bright spots in an otherwise dull image. In addition, when viewed under a fluorescence microscope, the margin between tumor and healthy tissue was readily apparent.

This work, which was funded in part by the National Cancer Institute, is detailed in a paper titled, “Imaging pancreatic cancer with a peptide-nanoparticle conjugate targeted to normal pancreas.” This paper was published online in advance of print publication. An abstract is available at the journal’s website. View abstract.